Search

Biometric authentication is increasingly being used for large scale human authentication and identification, creating the risk of leaking the biometric secrets of millions of users in the case of database compromise. Powerful "fuzzy" cryptographic techniques for biometric template protection, such as secure sketches, could help in principle, but go unused in practice. This is because they would require new biometric matching algorithms with potentially much diminished accuracy. We introduce a new primitive called a multisketch that generalizes secure sketches. Multisketches can work with existing biometric matching algorithms to generate strong cryptographic keys from biometric data reliably. A multisketch works on a biometric database containing multiple biometrics --- e.g., multiple fingerprints --- of a moderately large population of users (say, thousands). It conceals the correspondence between users and their biometric templates, preventing an attacker from learning the biometric data of a user in the advent of a breach, but enabling derivation of user-specific secret keys upon successful user authentication. We design a multisketch over tenprints --- fingerprints of ten fingers --- called TenSketch. We report on a prototype implementation of TenSketch, showing its feasibility in practice. We explore several possible attacks against TenSketch database and show, via simulations with real tenprint datasets, that an attacker must perform a large amount of computation to learn any meaningful information from a stolen TenSketch database.

Background: Patient-specific design (PSD) total knee arthroplasty implants are marketed to restore neutral mechanical-axis alignment (MAA) and provide better anatomic fit compared with standard off-the-shelf (OTS) total knee arthroplasty designs. The purpose was to compare the Knee Society scores, radiographic outcomes, and complications of PSD and OTS implants. Methods: Retrospective study analyzing PSD and OTS by a single surgeon. Implant design change in PSD occurred during the period of data collection leading to PSD-1 and PSD-2 subgroups. Radiographic data including MAA, femorotibial angle, coronal-tibial angle, tibial slope and patella-sulcus angle, and complications were analyzed. Minimum follow-up was 2 years or until revision, and patients completed Knee Society scores preoperatively and postoperatively at 3, 6, 12, 24 weeks, and final follow-up. Results: There were 136 patients (154 knees), average age (62.76 +/− 8.4 years), and follow-up (3.1 +/− 1.5 years). The groups included PSD-1 (77 knees), PSD-2 (36 knees), and OTS (41 knees). The PSD-2 group had better Knee Society function scores compared with PSD-1 and OTS at all timepoints except final follow-up. PSD-2 had significantly shorter hospital stay (P = 0.000012) and less hemoglobin drop (P = 0.032) compared with PSD-1 and OTS. No differences were observed in MAA (P = 0.349) or final range of motion (P = 0.629) between the 3 groups. PSD-2 had more normal femorotibial angle, coronal-tibial angle, and tibial slope compared with PSD-1 and OTS. Failures requiring revision were 23% (18/77) PSD-1, 0% PSD-2, and 3% (1/35) OTS. Most common modes of failure were tibial subsidence (56%) and polyethylene locking mechanism failure (22%) in PSD-1. Conclusion: Catastrophic failure was seen in the PSD-1 group with tibial subsidence and polyethylene locking mechanism failure. PSD-2 had better early Knee Society function scores, shorter hospital stay, lower hemoglobin drop, radiographic alignment, and no failures compared with PSD-1 and OTS.

Technological advances have led to the development of automated methods for personnel assessment that are purported to augment or outperform human judgment. However, empirical research providing validity evidence for such techniques in the selection context remains scarce. In addressing this void, this study focuses on language-based personality assessments using an off-the-shelf, commercially available product (i.e., IBM Watson Personality Insights) in the context of video-based interviews. The scores derived from the language-based assessment were compared to self and observer ratings of personality to examine convergent and discriminant relationships. The language-based assessment scores showed low convergence with self-ratings for openness, and with self- and observer ratings for agreeableness. No validity evidence was found for extraversion and conscientiousness. For neuroticism, the patterns of correlations were in the opposite of what was theoretically expected, which raised a significant concern. We suggest more validation work is needed to further improve emerging assessment techniques and to understand when and how such approaches can appropriately be applied in personnel assessment and selection.

Photoplethysmography is a well-established minimally invasive method for estimating heart rate and blood oxygen saturation in clinical settings. Photoplethysmography, with limitations, can also be extended to estimate respiration rate. Recently many off the shelf photoplethysmography sensors have been released in a form factor suitable for wearable devices. In this study we evaluate two photoplethysmography front ends (inclusive of suitable signal conditioning module and digitizer) from Maxim Integrated™. The tri-wavelength MAX30101 sensor and bi-wavelength MAX30102 sensor were evaluated on the forehead, in a truly non-obtrusive wearable friendly position. Heart rate, respiration rate and blood oxygen saturation were extracted from both sensors and compared with a FDA/TGA/CE approved photoplethysmography device placed on the finger. All data were captured simultaneously and at rest. The MAX30101 sensor was more accurate in measuring heart rate, blood oxygen saturation and respiration rate compared to the MAX30102. Additionally, we found that the red wavelength was best for measuring heart rate and the green wavelength was best for respiration rate.

Light and light-based technologies play important roles in modern life, especially for lighting purposes. A simple pico-solar lighting system will be very helpful to improve the quality of life of communities which do not have access to electricity grid. This paper reports the work in designing a simple solar lantern system using off-the-shelf components suitable for STEM outreaches at high schools in form of workshop, while at the same time the outcomes of the workshop be used for humanitarian activities for simple lighting in communities which lack of access to electricity grid. The work includes workshops in several high schools in the surrounding of Jakarta, which includes lecture, hand-on session on construction, troubleshooting, and outdoor measurements of the solar lantern. The resulted solar lanterns were then donated to people in remote areas in the interior of Papua. With slight modification, the system was also turned into cheap street lighting poles for a garbage collector community in Bintara, Bekasi.

To determine if trochlear morphology in healthy knees depends on sex and ethnicity, and to compare it to off-the-shelf TKA prostheses. Three retrospective series of CT angiograms from France (female, 124; male, 135), China (female, 122; male, 137) and South Africa (female, 21; male, 62) were used to digitize osseous landmarks at the level of the femoral epicondyles. Sulcus angle, trochlear rotation, lateral trochlear inclination, trochlear asymmetry ratio, and trochlear depth index were quantified for each knee and for 10 total knee arthroplasty (TKA) models. Univariable regression analyses were performed to determine associations of the five trochlear parameters with sex and ethnicity. Interquartile ranges (IQR) of native trochlear parameters were compared to the trochlear parameters of 10 off-the-shelf TKA prostheses. Compared to French knees, Chinese knees had greater sulcus angle (β = 6.3°, p

Superior capsular reconstruction can effectively relieve pain and improve function in the rotator cuff–deficient shoulder, but the optimal graft has not been determined. Multiple authors have demonstrated the effectiveness of the procedure, but bias and heterogeneity between studies do not allow valid comparative analysis of graft type. Until we can adequately compare outcomes, complications, or survival, graft availability and cost may be the greatest determinants of graft selection.

Objective Treatment of complex aortic pathologies with customised fenestrated/branched stent grafts (F/BEVAR) is associated with a longer waiting time to the procedure. This study aimed to investigate the prevalence of aneurysm rupture and mortality during the waiting time for a fenestrated/branched stent graft in a single centre. Methods All patients with a pararenal (PAA), thoraco-abdominal (TAAA), or aortic arch aneurysm planned to be treated with a customised F/BEVAR between January 2010 and December 2018 were included. Patients planned for F/BEVAR who in the end did not undergo the procedure were analysed. Results 906 patients were planned to undergo F/BEVAR during the study period. Of those, 862 (95.1%) underwent the procedure as planned (FEVAR for PAA; n = 494, F/BEVAR for TAAA; n = 348, F/BEVAR for arch aneurysm; n = 20). In 44 (4.9%) patients, the procedure was cancelled. Thirty-seven (4.1%) patients died before the procedure, four (0.4%) patients turned down the procedure, two (0.2%) were cancelled because of worsened general condition, and one (0.1%) ruptured but underwent emergency open repair in another institution. Causes of death during the waiting time were: aneurysm rupture, n = 15 (1.7%); cardiac, n = 7 (0.8%); stroke, n = 3 (0.3%); gastrointestinal, n = 3 (0.3%); death after complete arch debranching, n = 2 (0.2%); infection, n = 2 (0.2%); death after transcatheter aortic valve implantation, n = 1 (0.1%); death after urological surgery, n = 1 (0.1%); unknown, n = 3 (0.3%). Aneurysm diameter was larger in patients who died of aneurysm rupture compared with patients who died as a result of other causes (79.2 ± 13 mm vs. 66.7 ± 12 mm, respectively, p = .005). Conclusion Aneurysm rupture during the waiting time for F/BEVAR can occur but is rare. Patients with a larger aneurysm diameter may be at higher risk of rupture. Measures to reduce the risk of rupture during the waiting time might include the use of off the shelf devices for larger aneurysms, quicker measurement and graft plan order processes, and quicker graft construction and delivery.

Contaminants can leach into drinking water in transport from water-treatment facilities or treated water storage to consumer taps. In this work, we design a low-cost mobile system that can use off-the-shelf web-cameras as an ultraviolet (UV) spectrometer. We posit to analyze and categorize impurities present in water by using fundamental image processing and computer vision techniques. In this poster paper, we qualitatively and quantitatively analyze the ultraviolet absorption and scattering through images captured of an UV light source (at 385nm wavelength) transmitted through de-ionized water containing varying contaminants and at different concentrations. We particularly explore the tests for lead, arsenic, table salt, charcoal, and coconut oil, and run a pilot-study on ground-truth analysis of tap water from five counties around Atlanta, Georgia, USA.

Purpose: To demonstrate different techniques and device modifications that can expand the anatomic suitability of the off-the-shelf multibranched t-Branch for treatment of thoracoabdominal aortic aneurysm. Technique: The t-Branch device is not customized for specific patient anatomy, and the most frequent limitations to its use are an inadequate sealing zone and renal artery anatomy. Experience with this device has prompted the development of several techniques that can be employed to maximize the suitability of this stent-graft. Advice is offered on modification of the device to minimize the risk of paraplegia or better match patient anatomy. Maneuvers are explained to ease delivery through tortuous anatomy or existing stent-grafts, catheterize visceral target vessels, select a bridging stent, reduce ischemia time in the limbs, and alter the configuration of the branches. Conclusion: Employing adjunctive maneuvers can increase the anatomic suitability of the t-Branch; in our experience, these techniques have increased the applicability to more than 80% of all elective and urgent thoracoabdominal aortic aneurysm cases.

Purpose: To evaluate the orientation of the standardized off-the-shelf multibranched t-Branch after implantation in urgent thoracoabdominal aortic aneurysm (TAAA) repairs, to characterize the impact of branch malorientation on procedural success, and to identify any predictive factors associated with malorientation. Methods: A retrospective analysis was conducted of 42 consecutive patients (mean age 73.3±7 years; 25 men) with urgent TAAA presentation treated with the t-Branch from January 2014 to June 2017. The primary objective was to quantify the preoperative clock position of the target vessels and determine any rotational deviation between the pre- and postoperative measurements and between the postoperative measurements and the standard branch configuration. Secondary outcomes were to identify factors influencing malorientation (>2 clock face hours) that could affect outcome. Results were compared for early (learning curve; n=18) vs late (n=24) experience and for adherence to (n=23) vs nonobservance of (n=19) the instructions for use (IFU). Results: Technical success was 93% (39/42). No significant difference in rotational deviation was identified between patients treated within the IFU vs outside the IFU. Seven (17%) patients had at least one target vessel maloriented after the procedure, which was not associated with total procedure time, fluoroscopy time, contrast volume, radiation dose, or adherence to the IFU. Female gender was associated with increased rotational deviation in postprocedure measurement for the celiac trunk (p=0.044) and superior mesenteric artery (SMA; p=0.006). Female gender was also associated with increased rotational deviation between the branch origin after deployment and the standard configuration of the t-Branch for every target vessel [celiac trunk (p=0.005), SMA (p=0.001), right renal artery (p=0.037), and left renal artery (p=0.003)]. Conclusion: The implantation of the t-Branch device in urgent cases achieved accurate apposition without rotational deviation between the target vessels and the position of the endograft branches. Gender may have an impact on orientation of the device. The t-Branch appears to have a “forgiving” nature for higher malorientation with no effect on procedure time, target vessel revascularization, or early branch patency.

Fixed pericardial tissue is commonly used for commercially available xenograft valve implants, and has proven durability, but lacks the capability to remodel and grow. Decellularized porcine pericardial tissue has the promise to outperform fixed tissue and remodel, but the decellularization process has been shown to damage the collagen structure and reduce mechanical integrity of the tissue. Therefore, a comparison of uniaxial tensile properties was performed on decellularized, decellularized‐sterilized, fixed, and native porcine pericardial tissue versus native valve leaflet cusps. The results of non‐parametric analysis showed statistically significant differences (p .05). Scanning electron microscopy confirmed that valvular endothelial and interstitial cells colonized the decellularized pericardial surface when seeded and grown for 30 days in static culture. Collagen assays and transmission electron microscopy analysis showed limited reductions in collagen with processing; yet glycosaminoglycan assays showed great reductions in the processed pericardium relative to native cusps. Decellularized pericardium had comparatively low mechanical properties among the groups studied; yet the stiffness was comparatively similar to the native cusps and demonstrated a lack of cytotoxicity. Suture retention, accelerated wear, and hydrodynamic testing of prototype decellularized and decell‐sterilized valves showed positive functionality. Sterilized tissue could mimic valvular mechanical environment in vitro, therefore making it a viable potential candidate for off‐the‐shelf tissue‐engineered valvular applications.

In total knee arthroplasty (TKA), surgeons often face the decision of maximizing tibial component fit and achieving correct rotational alignment at the same time. Customized implants (CIMs) address this difficulty by aiming to replicate the anatomical joint structure, utilizing data from patient-specific knee geometry during the manufacturing. We intraoperatively compared component fit in four tibial zones of a CIM to that of three different off-the-shelf (OTS) TKA designs in 44 knees. Additionally, we assessed the rotational alignment of the tibia using computed tomography (CT)-based computer aided design model analysis. Overall the CIM device showed significantly better component fit than the OTS TKAs. While 18% of OTS designs presented an implant overhang of 3 mm or more, none of the CIM components did (p

Measurement of rates of oxygen consumption ( Mo2) in small aquatic embryos or larvae (2in small numbers of individuals when sequentially exposed to different environmental conditions (e.g., changes in seawater pH) through a gravity-driven media replacement perfusion system. We first show that the FTC can be used in “static” mode while incubating small numbers of embryos/larvae contained within the planar oxygen sensor (POS) chamber with Nitex filters. We then demonstrate the use of the MIFR by exposing larval echinoderms ( Fellaster zelandiae, Evechinus chloroticus, and Centrostephanus rodgersii) to seawater equilibrated with elevated CO2and measured Mo2during acute and chronic exposure to hypercapnia. This MIFR method will allow investigators to address questions regarding the respiratory physiology of small aquatic animals, such as the thresholds for metabolic depression in embryonic and larval forms.NEW & NOTEWORTHY A manual intermittent flow respirometer (MIFR), allowing media exchange in a flow-through cell containing small aquatic organisms, permits repeated measurement of Mo2of individuals not only in a single medium (e.g., technical replication), but also in different media (here, high CO2-equilibrated seawater), enabling measurement of acute physiological responses to changed conditions. This versatile technique has wide-ranging implications for the study of the Mo2response of aquatic organisms in the face of climate change.

While metal halide perovskite solar cells (PVSCs) have drawn intense attention due to their high solar-to-power conversion efficiency (PCE), their practical application is hampered by their poor long-term stability against moisture. Although strategies have been reported to solve this issue, these methods are introduced during core-device fabrication processes which will increase the risk of introducing unexpected impurities during the fabrication. Herein, we introduce the first kind of simple post-device ligand (PDL) treatment to significantly improve the PCE of completely fabricated PVSCs from 18.7% to 20.13%. Meanwhile, the stability of the treated devices without any encapsulation remarkably improves, with 70% PCE maintained under ambient conditions after a 500-hour maximum-power-point tracking test, while the control unencapsulated device will completely break down within 100 hours. Equally important is that this post-device treatment shows a special ‘stitching effect’, namely repairing the as-fabricated ‘poor devices’ by healing the defects of the perovskite active region, and can improve the PCE by over 900%. We also experimentally and theoretically study the fundamental mechanism of the improvement. Consequently, our approach greatly improves the production yield of high-quality PVSCs and their module performances as well as the reduction of lead-waste. Additionally, the treatment is an off-the-shelf post-device approach that can be integrated into any existing perovskite-device fabrication, offering a general strategy to improve the stability and performance of perovskite optoelectronic devices.

An "off-the-shelf" cell therapy derived from induced pluripotent stem cells (iPSCs) has entered clinical trials in the United States. Other companies are following suit, harnessing iPSCs' self-renewal ability to manufacture cell therapies that don't require customization for each patient. But some experts aren't sure such therapies are a good idea.

Inexpensive plug-and-play temperature controllers have recently become available. These allow a chest freezer to be programmed easily to hold a desired set point across a range of biologically relevant temperatures. Installation can be completed in a few minutes using consumer-grade chest freezers. We used these temperature controllers to create five temperature-controlled chambers at 12, 14, 16, 18, and 20 °C. We demonstrated the use of these controlled-temperature chambers with two biologic assays: floral budbreak of peach [Prunus persica (L.) Batsch] stem cuttings and germination of sunflower (Helianthus annuus L.) seeds. We used the budbreak and germination rates at multiple temperatures to estimate base temperatures and thermal time requirements for development.

Treatments for B-cell malignancies have improved over the past several decades with clinical application of the CD20-specific antibody rituximab and chimeric antigen receptor (CAR) T cells targeting CD19. Despite the success of these therapies, loss of CD20 after rituximab treatment has been reported in leukemia and lymphoma patients. Additionally, up to 50% of all patients receiving anti-CD19 CAR T-cell therapy relapse within the first year with many of those patients exhibiting CD19 loss. Thus, new therapeutic approaches are needed to address tumor antigen escape. Accordingly, we generated triple gene-modified iPSC-derived NK (iNK) cells, termed "iDuo" NK cells, tailored to facilitate multi-antigen targeting. The iPSC line was clonally engineered to express high-affinity, non-cleavable CD16a (hnCD16), an anti-CD19 CAR optimized for NK cell signaling, and a membrane-bound IL-15/IL-15R fusion (IL-15RF) molecule to enhance NK cell persistence (Fig. 1A). To model antigen escape, we generated CD19 knockout AHR77 lymphoma cells alongside wild type AHR77 cells (both CD20 +) as targets in cytotoxicity assays. Activated peripheral blood NK (PBNK) cells, non-transduced iNK cells, and iDuo NK cells were tested as effectors. Unlike PBNK cells or non-transduced iNK cells, iDuo NK cells efficiently eliminated wild type AHR77 cells with or without the addition of rituximab at all tested E:T ratios. Similarly, iDuo NK cells in combination with rituximab were uniquely able to efficiently eliminate CD19 KO AHR77 cells due to enhanced antibody-dependent cellular cytotoxicity (ADCC) driven by hnCD16 (Fig. 1B-E). Cytotoxicity mediated by iDuo NK cells was also evaluated using primary chronic lymphocytic leukemia (CLL) cells. Compared to expanded PBNK cells and non-transduced iNK cells, only iDuo NK cells (in the absence of rituximab) were able to kill primary CLL cells (Fig. 1F). Expression of IL-15RF by iDuo NK cells uniquely supports in vitro expansion without the need for cytokine supplementation. To determine whether IL-15RF supports in vivo persistence of iDuo NK cells, CD19 CAR iNK cells (lacking IL-15RF) and iDuo NK cells were injected into NSG mice without the addition of cytokines or CD19 antigen availability. iDuo NK cell numbers peaked within a week after injection and persisted at measurable levels for ~5 weeks, in marked contrast to CD19 CAR iNK cell numbers that were undetectable throughout (Fig. 1G). To evaluate the in vivo function of iDuo NK cells, NALM6 leukemia cells were engrafted into NSG mice. Groups of mice received tumor alone or were treated with 3 doses of thawed iDuo NK cells. iDuo NK cells alone were highly effective in this model as evidenced by complete survival of mice in the treatment group (Fig. 1H). To assess iDuo NK cells in a more aggressive model, Raji lymphoma cells were engrafted, and groups of mice received rituximab alone, iDuo NK cells alone, or iDuo NK cells plus rituximab. Mice given the combination of iDuo NK cells and rituximab provided extended survival compared to all other arms in the aggressive disseminated Raji lymphoma xenograft model (Fig. 1I). One disadvantage of anti-CD19 CAR T cells is their inability to discriminate between healthy and malignant B cells. Because NK cells express inhibitory receptors that enable "self" versus "non-self" discrimination, we reasoned that iDuo NK cells could have higher cytotoxicity against tumor cells relative to healthy B cells. To address this, we labeled Raji cells, CD19 + B cells from healthy donor peripheral blood mononuclear cells (PBMCs) and CD19 - PBMCs. Labeled populations of cells were co-cultured with iDuo NK cells, and specific killing was analyzed. As expected, iDuo NK cells did not target CD19 - PBMCs. Intriguingly, iDuo NK cells had much higher cytotoxic activity against Raji cells compared to primary CD19 + B cells, suggesting a preferential targeting of malignant B cells compared to healthy B cells. Together, these results demonstrate the potent multi-antigen targeting capability and in vivo antitumor function of iDuo NK cells. Further, these data suggest that iDuo NK cells may have an additional advantage over anti-CD19 CAR T cells by discriminating between healthy and malignant B cells. The first iDuo NK cell, FT596, is currently being tested in a Phase I clinical trial (NCT04245722) for the treatment of B-cell lymphoma. Figure 1 Figure 1. Disclosures Cichocki: Gamida Cell: Research Funding; Fate Therapeutics, Inc: Patents & Royalties, Research Funding. Bjordahl: Fate Therapeutics: Current Employment. Gaidarova: Fate Therapeutics, Inc: Current Employment. Abujarour: Fate Therapeutics, Inc.: Current Employment. Rogers: Fate Therapeutics, Inc: Current Employment. Huffman: Fate Therapeutics, Inc: Current Employment. Lee: Fate Therapeutics, Inc: Current Employment. Szabo: Fate Therapeutics, Inc: Current Employment. Wong: BMS: Current equity holder in publicly-traded company; Fate Therapeutics, Inc: Current Employment. Cooley: Fate Therapeutics, Inc: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment. Miller: Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees.

FT819 is a first-of-kind, allogeneic, off-the-shelf CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line precisely engineered to insert a novel 1XX anti-CD19 chimeric antigen receptor (CAR) under the regulation of the T-cell receptor alpha constant (TRAC) locus for optimized control of anti-tumor activity and to completely delete T-cell receptor (TCR) expression to eliminate the potential of graft-versus-host disease (GvHD). Unlike conventional allogeneic CAR T-cell therapies which require repeatedly sourcing of T cells from various donors as the starting material, the use of a clonal master engineered iPSC line serves as a renewable starting cell source and ensures routine mass production of a uniformly engineered, homogenous CAR T-cell product for broad patient access. T cell-derived iPSCs were generated using a proprietary non-integrating cellular reprogramming system and genetically modified to integrate a novel anti-CD19 1XX CAR into both alleles of the TRAC gene. After single cell subcloning, each engineered iPSC clone was screened for multiple critical quality attributes including pluripotency, identity, genomic stability, cassette integration, on/off-target integration, T-cell differentiation propensity, and CAR T-cell function. Accordingly, the ideal single cell-derived engineered iPSC clone was selected as the clonal master iPSC line for FT819 and was converted into a master cell bank (MCB). The iPSC MCB serves as a renewable source for the routine GMP manufacture of FT819 drug product. The FT819 production process consists of three stages: 1) generation of CD34-expressing hematopoietic progenitor cells from iPSCs (>90% CD34+ cells post enrichment); 2) lineage-specification to T cells followed by T-cell expansion (>5e5 fold expansion); and 3) fill/finish and cryopreservation of the drug product. As an example, in an initial small-scale manufacturing campaign, a total of 2.5 × 10 10 FT819 CAR T-cells were generated and filled and finished starting from one vial of the MCB. The FT819 drug product was tested on safety, identity, purity, and potency. The final product was comprised of CD45+CD7+ lymphocytes (>99%), with homogeneous CAR expression (>99% CAR+) and lacking expression of TCRαβ (not detected) on the cell surface. Importantly, there were no residual iPSCs detected in the FT819 drug product. The FT819 drug product exhibited potent and consistent effector function against NALM6 leukemia cells. The FT819 drug product is currently being used in a landmark Phase I study (NCT04629729), the first-ever iPSC-derived T-cell therapy to undergo clinical investigation, for the treatment of patients with relapsed/refractory B-cell lymphoma, chronic lymphocytic leukemia and precursor B-cell acute lymphoblastic leukemia. In summary, FT819 is a first-of-kind, off-the-shelf, CAR T-cell therapy uniquely derived from a clonal multiplexed-engineered master iPSC line. The novel manufacturing paradigm enables mass production of a uniformly engineered, homogenous cell therapy product that is available on-demand for broad patient access. A multi-center Phase 1 study of FT819 is currently ongoing for the treatment of B-cell malignancies. Key Words: cancer immunotherapy, cell therapy, CAR-T, CD19, allogeneic, induced pluripotent stem cell, iPSC, clonal master iPSC line, engineered, off-the-shelf, cGMP, production, manufacturing, FT819 Disclosures Yuan: Fate Therapeutics, Inc.: Current Employment. Clarke: Fate Therapeutics, Inc.: Current Employment. Lai: Fate Therapeutics, Inc.: Current Employment. Chang: Fate Therapeutics, Inc.: Current Employment. Yang: Fate Therapeutics, Inc.: Current Employment. Hsia: Fate Therapeutics, Inc.: Current Employment. Abujarour: Fate Therapeutics, Inc.: Current Employment. Lee: Fate Therapeutics, Inc.: Current Employment. van der Stegen: Fate Therapeutics, Inc.: Current Employment. Shaked: Fate Therapeutics, Inc.: Current Employment. Jalloh: Fate Therapeutics, Inc.: Current Employment. Moreno: Fate Therapeutics, Inc.: Current Employment. ORourke: Fate Therapeutics, Inc.: Current Employment. Sung: Fate Therapeutics, Inc.: Current Employment. Gutierrez: Fate Therapeutics, Inc.: Current Employment. Rezner: Fate Therapeutics, Inc.: Current Employment. Eberhart: Fate Therapeutics, Inc.: Current Employment. Magdaleno: Fate Therapeutics, Inc.: Current Employment. Farnan: Fate Therapeutics, Inc.: Current Employment. Plavsic: Fate Therapeutics, Inc.: Current Employment. Bressi: Fate Therapeutics, Inc.: Current Employment. Rivière: Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); FloDesign Sonics: Other: Provision of Services; Juno Therapeutics: Patents & Royalties. Valamehr: Fate Therapeutics, Inc.: Current Employment.

Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of hematologic malignancies, however, logistical complexities associated with patient-specific CAR T-cell therapies often limit broad accessibility to patients. Many of these challenges can be overcome with an allogeneic cellular product that is available off-the-shelf, and overcoming immune cell-mediated rejection of allogeneic cell therapy is an area of significant research. Conditioning chemotherapies, which are commonly administered with CAR T-cell therapy, suppress a patient's immune system and may create a suitable window of activity for allogeneic cell therapies to elicit clinical response. However, protracted lympho-conditioning has been associated with poor immune reconstitution and increased susceptibility to opportunistic infections. Deletion of human leukocyte antigen (HLA) surface expression is known to abrogate T-cell alloreactivity, but deletion of class I HLA must be combined with other immune-modulating strategies to avoid NK cell-mediated recognition. To this end, allogeneic models combining class I HLA deletion with NK cell inhibitory molecules, such as HLA-E and CD47, have been shown to abrogate NK cell reactivity in mouse models. However, since HLA-E is the canonical activator of NKG2C, a dominant activating receptor found on human NK cells, and since the ligand for CD47, SIRPα, is known to be expressed on macrophages and dendritic cells and not on human NK cells, the observed effects of these immune-modulating strategies may not translate into the patient-treatment setting. In assessment of their protective effects in a defined human system, we found that HLA-E or CD47 overexpression on class I HLA null human cells offer only partial protection in evading various human NK cell compartments. We found that class I HLA-null K562 cells engineered to over-express CD47 were ineffective in inhibiting NK cells (0 to 7% inhibition). Separately, K562 cells engineered to over-express HLA-E, while effective in inhibiting NKG2A+ NK cells (90.2% +/- 3.7% inhibition), were unable to completely inhibit CD56 dim NK cells (33.2% +/- 29.6% inhibition) and not only failed, but instead activated, NKG2C+ NK cells (167% +/- 69% activation). Our data highlight the limitations of engineered CD47 and HLA-E modalities in suppressing broad populations of NK cells in clinically relevant settings. We therefore evaluated expression of the alloimmune defense receptor (ADR) that uniquely targets alloreactive immune cells (Mo et al. Nat Biotechnol 2021). We have shown that the expression of ADR has the potential to evade host immune cells without the need for further genetic editing such as class I HLA deletion. To determine its applicability for off-the-shelf cell therapy, ADR expression was engineered into induced pluripotent stem cells (iPSCs) and iPSC-derived CAR-NK (CAR-iNK) cells were generated. CAR-iNK cells carrying the ADR modality (ADR+ CAR-iNK cells) showed normal patterns of differentiation (>99% CD56+ with co-expression of NK cell receptors such as NKG2D, NKp30 and NKp46), suggesting that ADR expression did not disrupt hematopoiesis or the expansion of iNK cells. Additionally, ADR+ and ADR-negative CAR-iNK cells produced similar cytotoxicity against tumor cells. We next tested the ability of ADR to provide resistance to alloimmune rejection by coculturing ADR+ CAR-iNK cells with allogeneic pBMCs in a mixed lymphocyte reaction (MLR) assay. Notably, ADR+ CAR-iNK cells maintained durable persistence throughout the entire duration of the MLR assay and suppressed the expansion of alloreactive T- and NK-cells in comparison to the control arm (Figure 1). Collectively, initial preclinical studies suggest that ADR-modified CAR-iNK cells resist host immune cell rejection, while eliciting a durable anti-tumor response. Our preliminary data show evidence toward a promising off-the-shelf solution for elimination of broad pools of alloreactive T- and NK- effector cells in the clinical setting without the need for lympho-depleting conditioning or genetic editing strategies. Figure 1 Figure 1. Disclosures Williams: Fate Therapeutics: Current Employment. Abujarour: Fate Therapeutics, Inc.: Current Employment. Lee: Fate Therapeutics, Inc.: Current Employment. Malmberg: Merck: Research Funding; Vycellix: Consultancy; Fate Therapeutics: Consultancy, Research Funding. Mamonkin: Beam Therapeutics: Other: Licensing payments; Fate Therapeutics: Other: Licensing payments; Allogene Therapeutics: Consultancy, Other: Licensing payments; Xenetic Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bjordahl: Fate Therapeutics: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment.

Background: Tabelecleucel (Tab-cel) is an investigational, off-the-shelf, allogenic Epstein-Barr virus (EBV)-specific T-cell immunotherapy. Tab-cel has shown clinical activity in patients with EBV + post-transplant lymphoproliferative disease (PTLD). Previously we have shown that the process for generating tab-cel from healthy donors results in a net amplification of EBV-target responsive T-cell clonality, and that upon activation, tab-cel demonstrates polyfunctionality associated with the secretion of effector and chemoattractive cytokines. Objective: We aim to comprehensively profile tab-cel through immunophenotype, TCR repertoire by analyzing overall repertoire overlap across lots, and TCR sequence homology (GLIPH 2.0 algorithm), cytokine polyfunctionality (PF), and differential gene expression patterns (GEP) between resting and TCR-MHC-driven EBV antigen stimulation states to replicate intrinsic effector responses associated with EBV + disease engagement. Methods: Immunophenotyping was performed using targeted FACS activation profiling (CD25/CD69), and 40-plex CyTOF. PF response and cytokine profiles were evaluated using the IsoLight single-cell PF strength assay. TCR repertoires were assessed using TCRβ immunoSEQ, and the GLIPH 2.0 algorithm was utilized to cluster TCRs that are predicted to bind the same MHC-restricted peptide antigen. GEP were evaluated using a custom Nanostring panel consisting of 333 T-cell lineage gene targets. Results: Baseline control activation levels of 7.9±1.3% increased specifically to 54.3±3.7% post-activation with EBV + targets (Figure 1A). Baseline PF was 0.54±0.14%, and upon EBV-specific activation, product cells demonstrated an average PF of 12.1±1.5%, demonstrating a 22.7-fold average increase (Figure 1B).The cytokine profile for activated tab-cel lots is primarily comprised of effector and chemoattractive cytokines including IFNγ and MIP1β. Baseline TCR repertoires of the initial donor peripheral T-cells are highly diverse; however, the tab-cel manufacturing process effectively amplified and enriched for EBV-specific TCRs that correspond back to a starting frequency of 2.6±0.58% of the initial donor TCR repertoire (Figure 1C). Notably, cross comparison of tab-cel-enriched TCRs against publicly available databases (VDJdb, McPas-TCR) identified previously curated EBV-specific TCRβ sequences as a component of the expanded repertoire. Additionally, using the GLIPH 2.0 clustering algorithm we were able to identify previously unannotated TCR sequences that clustered with known EBV-specific TCRβ sequences. The tab-cel post-activation GEP revealed associations with T-cell activation and polyfunctionality. The CD4/CD8 composition of a subset of tab-cel lots was analyzed: the average CD4:CD8 ratio of 0.25, with an average of CD8+ T-cells comprising 73% of the product. An extended immunophenotyping by CyTOF is currently being completed and will be reported at the time of presentation. Conclusions: In this expanded analysis we again demonstrate that the process for generating tab-cel from healthy donors enriches for known EBV-specific clones and results in a net amplification of EBV-target responsive T-cell clonality. Additionally, utilization of the GLIPH 2.0 clustering algorithm has led to the identification of novel putative EBV-specific TCR sequences that are enriched through the tab-cel manufacturing process. Upon activation, tab-cel exhibits a robust multifactorial activation signaling and demonstrates PF associated with secretion of effector and chemoattractive cytokines. Gene expression profiling of activated tab-cel lots highlights a conserved activation gene signature that is associated with post-activation PF. Lastly, these above analyses are being leveraged to perform correlation studies of immunophenotyped to post-activation PF, TCR repertoire characteristics, and GEP. These data support that the process for generating tab-cel from healthy donor PBMCs leads to the enrichment for EBV-specific T-cell clones that are capable of becoming activated upon stimulation with consistent final product characteristics. Figure 1 Figure 1. Disclosures Benoun: Atara Biotherapeutics: Current Employment. Ruiz: Atara Biotherapeutics: Current Employment. Widmann: Atara Biotherapeutics: Current Employment. Jehng: Atara Biotherapeutics: Current Employment. Spindler: Atara Biotherapeutics: Current Employment. Abraham: Atara Biotherapeutics: Current Employment. Minne: Atara Biotherapeutics: Consultancy. Tracy: Atara Biotherapeutics: Current Employment. Munson: Atara Biotherapeutics: Current Employment. Thota: Atara Biotherapeutics: Current Employment. Wang: Atara Biotherapeutics: Current Employment. Chuan: Atara Biotherapeutics: Current Employment. Yedwabnick: Atara Biotherapeutics: Current Employment. Dubovsky: Atara Biotherapeutics: Current Employment.

The manufacture of individual patient-derived CAR T-cells is expensive, frequently unsuccessful, too time consuming to benefit acutely ill patients and difficult to scale for large numbers of patients. "Off-the-shelf" T cell products that are banked from healthy donors would improve accessibility, allow rapid treatment, and reduce costs. The major obstacles to the success of allogeneic T cells are graft-versus-host disease (GVHD) and graft rejection, mediated by host and recipient alloreactive T cells, respectively. To address GVHD, we are using allogeneic Epstein-Barr Virus-specific T cells (EBVSTs), which have not produced GVHD in more than 300 recipients. To prevent graft rejection we have expressed a chimeric antigen receptor for CD30 (CD30.CAR) in EBVSTs. CD30 will be upregulated by host alloreactive T cells when they encounter infused CD30.CAR EBVSTs. As a consequence, they will become targets for the CD30.CAR EBVSTs. Previous clinical studies (NCT02917083, NCT01555892, and NCT00062868) have shown that CD30.CAR T cells can destroy CD30+ lymphoma cells through their chimeric receptor, while EBVSTs can kill EBV+ lymphoma cells through their native TCR. Thus, once engrafted, banked CD30.CAR EBVSTs may kill both CD30+ and EBV+ lymphomas through their CAR and TCR respectively without causing GVHD. To assess the safety and activity of banked CD30.CAR EBVSTs, we treated patients with multiply relapsed (median of 4 prior lines of therapy; range 3-5) or refractory CD30-positive lymphomas in a Phase 1 dose escalation study using 4 × 10 7, 1 × 10 8 or 4 × 10 8 CD30.CAR EBVSTs infused after lymphodepletion with cyclophosphamide and fludarabine. Although CD30.CAR killing is not HLA restricted, selection of the CD30.CAR EBVST product for each recipient was based on the best HLA class I and class II match; this should allow endogenous EBV (when present) to boost the in vivo activity of CD30.CAR EBVSTs via their native TCRs, and augment reactivity in patients whose CD30+ malignancies are also EBV+. We have currently treated eight patients, including two at the highest dose level. The infusions have been well tolerated with no dose-limiting toxicities and in particular no cytokine release syndrome (CRS) or GVHD of any grade. We have evaluated seven of the patients. At 6-week evaluation, per Lugano criteria, two patients have had a complete response (one shown in Figure 1) and three have had a partial response (overall response rate of 71%). CD30.CAR EBVSTs were detectable for 1 week in peripheral blood, but there was no evidence of expansion. We are analyzing tumor samples for CD30.CAR EBVSTs, and will continue to assess the safety, efficacy and durability of these responses. Thus banked CD30.CAR EBVSTs can safely be given to allogeneic recipients and may cause significant tumor responses including complete remissions. These cells may be a suitable platform for other "off-the-shelf" CAR-T cell therapies. Figure 1 Figure 1. Disclosures Quach: Tessa Therapeutics: Research Funding. Ramos: Athenex: Research Funding; Novartis: Consultancy; Genentech: Consultancy; Tessa Therapeutics: Patents & Royalties, Research Funding. Grilley: Allovir: Current equity holder in publicly-traded company, Other: Leadership; QB Regulatory Consulting: Other: Ownership, project management support, Research Funding; Marker: Consultancy, Other: Regulatory and project management support. Brenner: Athenex: Membership on an entity's Board of Directors or advisory committees; Turnstone Biologics: Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Membership on an entity's Board of Directors or advisory committees; Coya Therapeutics: Membership on an entity's Board of Directors or advisory committees; CellGenix GmbH: Membership on an entity's Board of Directors or advisory committees; Walking Fish Therapeutics: Membership on an entity's Board of Directors or advisory committees; Poseida Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onkimmune: Membership on an entity's Board of Directors or advisory committees; Memgen: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Abintus: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Allovir: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company. Heslop: Kiadis: Membership on an entity's Board of Directors or advisory committees; Allovir: Current equity holder in publicly-traded company; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Kuur Therapeutics: Research Funding; Marker Therapeutics: Current equity holder in publicly-traded company; GSK: Membership on an entity's Board of Directors or advisory committees; Fresh Wind Biotherapies: Membership on an entity's Board of Directors or advisory committees. Rouce: Tessa Therapeutics: Research Funding; Pfizer: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lapteva: Tessa Therapeutics: Consultancy. Rooney: Tessa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Marker Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Allovir: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Background: The use of a clonal master engineered induced pluripotent stem cell (iPSC) line as a renewable source for the mass production of immune effector cells offers distinct advantages over existing patient (pt)- and donor-derived cell-based cancer immunotherapy approaches, including off-the-shelf availability for broad pt access and multi-dose administration. FT596 is an iPSC-derived, off-the-shelf, CD19-directed chimeric antigen receptor (CAR) natural killer (NK) cell therapy capable of multi-antigen targeting in combination with monoclonal antibody (mAb) therapies. FT596 has three anti-tumor modalities: (1) a proprietary CD19-targeting CAR; (2) a novel high-affinity, non-cleavable CD16 Fc receptor that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity in combination with a therapeutic mAb; and (3) IL-15/IL-15 receptor fusion promoting cytokine-autonomous persistence. Preclinical in vivo models of leukemia and lymphoma demonstrate potent CAR-mediated efficacy of FT596 against CD19+ tumor cells and activity against both CD19+ and CD19- tumor cells when combined with the anti-CD20 agent rituximab (Goodridge et al. 2019). Methods: FT596 is being investigated in a multicenter, Phase I clinical trial in pts with relapsed/refractory (R/R) B-cell lymphomas (BCLs) and chronic lymphocytic leukemia (ClinicalTrials.gov: NCT04245722). Conditioning chemotherapy (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 on Days -5 to -3) is administered followed by a single dose of FT596 as monotherapy (Regimen A) or combined with rituximab (R) 375 mg/m 2 (Regimen B1) or obinutuzumab 1000 mg/m 2 (Regimen B2) on Day -4. FT596 single-dose levels between 30 and 900 million cells are being tested. Pts experiencing clinical benefit may receive a second cycle of conditioning followed by a single dose of FT596 with FDA approval (Cycle 2). Primary objectives are to determine the recommended Phase II dose of FT596 and safety and tolerability. Additional key objectives include preliminary anti-tumor activity per the Lugano Classification, pharmacokinetics, and anti-product immunogenicity. Results: As of a data cutoff date of 25 June 2021, 20 pts with R/R BCL (12 with aggressive histology, 8 indolent) were treated in dose escalation with FT596, including 10 in Regimen A and 10 in Regimen B1 (3 with 30 million cells, 4 with 90 million cells, and 3 with 300 million cells in each regimen). Pts had received a median of 4 prior therapies, with 7 having received CAR T-cell therapy and 5 with autologous stem cell transplant. Ten of 20 pts were refractory to last prior therapy. No dose-limiting toxicities were reported with either regimen. No graft-versus-host disease (GvHD) or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Two cases of cytokine release syndrome (CRS) were reported (one Gr 1 and one Gr 2). The most common treatment-emergent adverse events of any grade were neutrophil count decreased (85%), nausea (75%), anemia (50%), WBC count decreased (45%), fatigue and platelet count decreased (40% each), and peripheral edema (35%). No B- or T-cell mediated anti-product responses were observed. Of 17 efficacy-evaluable pts, 5 of 8 in Regimen A and 4 of 9 in Regimen B achieved an objective response after the first FT596 treatment cycle. At single-dose levels of ≥90 million cells, 8 of 11 efficacy-evaluable pts achieved an objective response, including 7 complete responses (CR). Of 4 pts with prior CAR T-cell therapy treated at ≥90 million cells, 2 achieved CR. The FDA approved all requests for FT596 retreatment. Seven of 9 responders received Cycle 2; 1 pt with CR elected not to receive Cycle 2, and 1 pt with partial response (PR) experienced disease progression prior to initiation of Cycle 2. Five pts (4 with CR, 1 with PR after Cycle 1) completed Cycle 2, and 2 pts initiated Cycle 2 after data cutoff. CR was maintained after Cycle 2 in all 4 pts with CR, while the 1 pt with PR experienced a deepening PR after Cycle 2. No CRS, ICANS, or GvHD were reported with Cycle 2. Conclusions: FT596 monotherapy or in combination with R was well tolerated and demonstrated activity in pts with R/R BCL, including in pts previously treated with CAR T-cell therapy. Administration of a second FT596 treatment cycle was well tolerated with evidence of continuing clinical benefit. Dose escalation of FT596 is ongoing. Updated clinical and translational data will be presented at the conference. Disclosures Bachanova: Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Patel: Kite Pharma: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Park: Kite Pharma: Consultancy; BMS: Consultancy; Artiva: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Amgen: Consultancy; Affyimmune: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Novartis: Consultancy. Flinn: Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Shah: Fate Therapeutics, Inc.: Current Employment. Wong: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Bickers: Fate Therapeutics, Inc.: Current Employment. Szabo: Fate Therapeutics, Inc: Current Employment. Wong: BMS: Current equity holder in publicly-traded company; Fate Therapeutics, Inc: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment. Atwal: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Chu: Gilead: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Elstrom: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy.

Allogeneic off-the-shelf cell therapies offer distinct advantages over conventional autologous cell therapies in terms of scaled manufacturing, on-demand availability and optimization of cellular starting material. A unique consideration in the use of allogeneic cell therapies is the potential for immune cell-mediated recognition of the allogeneic cell product by the patient's immune system. CAR T-cell therapies are commonly combined with conditioning chemotherapies that suppress a patient's immune system, creating a suitable window of activity to elicit clinical response. However, protracted lympho-conditioning also affects immune reconstitution and can negatively impact the rate of infection. Alternative approaches to prevent allorejection may therefore help to enhance the efficacy of the therapy while preserving the immune system of the patient. Elimination of cell-surface human leukocyte antigen (HLA) molecule expression by genetic knockout (KO) has long been known to abrogate T-cell reactivity. However, loss of class I HLA elicits NK cell-mediated recognition and clearance, and therefore must be combined with other immune-modulating strategies to limit host NK cell reactivity. Allogeneic models combining class I HLA deletion with NK cell inhibitory molecules, such as HLA-E and CD47, have been shown to abrogate NK cell reactivity in mouse models. However, HLA-E is the canonical activator of NKG2C, a dominant activating receptor found on human NK cells. Likewise, the expression of signal regulatory protein alpha (SIRPα), the major interactor for CD47, is mostly restricted to macrophages and dendritic cells and not human NK cells, and the observed effects of this immune-modulating strategy in the mouse system may only offer partial or incomplete immune evasion in the human system. In this study, we provide details of a bona fide off-the-shelf strategy where iPSC-derived NK (iNK) cell therapy is multiplexed engineered with a novel combination of immune-evasion modalities; beta 2 microgobulin (B2M) KO to prevent CD8 T-cell mediated rejection; class II transactivator (CIITA) KO to prevent CD4 T-cell mediated rejection; and CD38 KO to enable combination with anti-CD38 mAbs, which can be administered to deplete host alloreactive lymphocytes, including both NK and T cells. In vitro mixed lymphocyte reaction (MLR) data demonstrated that upon co-culture with allogeneic PBMCs, B2M KO iNK cells stimulated less T-cell activation than their B2M sufficient counterparts as evidenced by reduced CD38, 41BB, and CD25 levels on T cells. Additionally, B2M KO iNK cells impaired T-cell expansion over the duration of co-culture, resulting in a 50% decrease in expansion at the peak of the control response. However, B2M KO iNK cells were depleted over time, suggesting activation of an NK cell "missing self" response by the peripheral blood NK (pbNK) cells. In contrast, when the assay was performed in the presence of anti-CD38 mAb, depletion of B2M KO iNK cells was blocked, and instead B2M KO iNK cell numbers increased by 3.5-fold, comparable to the iNK cell numbers found in the control arm (cultured without allogeneic PBMCs). Interestingly, pbNK cell numbers decreased, while T-cell activation and expansion remained lower than in B2M-sufficient MLR cultures. Furthermore, when B2M KO iNK cells were cocultured with tumor cells and anti-CD38 mAb in vitro, ADCC was comparable to the B2M sufficient cells, indicating uncompromised effector function. Finally, in vivo studies suggested that co-administration of anti-CD38 mAbs can significantly enhance the persistence of B2M KO iNK cells in the presence of allogeneic pbNK cells as seen in the spleen and bone marrow (Figure 1). Together these data demonstrate that the combination of triple-gene knockout of CD38, B2M and CIITA with a CD38-targeting mAb is an effective strategy to avoid host immune rejection, and highlights the potential advantages of multiplexed engineered iPSCs to facilitate large-scale manufacture of complex engineered, off-the-shelf cellular therapies. Figure 1 Figure 1. Disclosures Williams: Fate Therapeutics: Current Employment. Malmberg: Merck: Research Funding; Vycellix: Consultancy; Fate Therapeutics: Consultancy, Research Funding. Lee: Fate Therapeutics, Inc.: Current Employment. Bjordahl: Fate Therapeutics: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment.

Background: Chimeric antigen receptor T cell (CAR-T) therapy is an adoptive T cell immunotherapy that employs the genetically modified T cell to attack the cancer cell. It is widely studied across various hematological and solid organ malignancies. Several autologous CD19 CAR-T cell therapy constructs are now approved for various B cell lymphomas, including aggressive B cell lymphomas, indolent follicular lymphoma and mantle cell lymphoma, and acute lymphoblastic leukemia (ALL). Autologous CD19 CAR-T cell therapy has unprecedented success in relapsed and refractory disease. Long time to manufacture (2-5 weeks) and manufacture failure are challenges associated with risk of interim death and deterioration of CAR-T candidates with rapidly progressive disease. T cell fitness of the autologous product in heavily pretreated patients is also potentially compromised. To overcome these shortcomings, universal "off the shelf" allogeneic CAR-T cell therapy constructs are being developed and studied. Donor sources include healthy donors and cord or induced pluripotent stem cells (iPSCs). These CAR-T constructs have additional gene modifications to mitigate the risk of rejection and graft versus host disease (GVHD). We performed a systematic review and meta-analysis to assess the safety and efficacy of allogeneic CD19 CAR-T cell therapy. Methods: Four databases (Web of Science/MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) were searched for this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using MeSH terms and keywords for "Receptors, Chimeric antigen" OR "Artificial-T-cell receptor" OR "immunotherapy, adoptive" OR "CD-19". Our search produced 3506 articles and after removing duplicates, 2243 records were screened. After excluding reviews and irrelevant articles, we included 8 prospective trials of allogeneic CD-19 CAR-T cell therapy enrolling two or more than two patients from Jan 2013 to Nov 2020. We also searched ASH 2020 abstracts to include any additional trials. The methodological quality of the included studies was evaluated using NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 68 patients from 8 studies were evaluated. Median age was 22.5 (4.8-64) years. (Table 1) The median follow-up time was 10 (2-18) months with median number of prior therapies of 3.2 (2-11) as reported by 5 studies. Underlying diagnosis was acute lymphocytic lymphoma (n=49, 72%), chronic lymphocytic leukemia (n=6, 9%), and non-Hodgkin lymphoma (n=13, 19%). The pooled overall response rate (ORR) was 77% (95% CI 0.63-0.89, I 2 =22%, n=68) with a complete response (CR) of 75% (95% CI 0.57-0.90, I 2 =48%, n=65). The pooled incidence of cytokine release syndrome grade I/II and grade III/IV was 53% (95% CI 0.16-0.89, I 2 =89%, n=65) and 10% (95% CI 0.01-0.25, I 2 =50%, n=65) respectively. Neurotoxicity grade I/II was 12% (95%CI 0.01-0.30, I 2 =47%, p=0.09, n=47) and GVHD grade I/II was 8% (95%CI 0.01-0.19, I 2 =0%, p=0.57 n=53). None of the clinical trials reported the duration of response. Conclusion: "Off the shelf" universal CAR-T therapy is early in development. Our available data suggest that allogeneic CD19 CAR-T constructs offer high ORR and CR rates with acceptable safety profiles. GVHD was mainly low grade (grade I-II). Given these findings, allogeneic CAR-T cell therapy is an attractive option to improve timely access compared to available autologous therapy. Extensive preclinical research to develop novel constructs and several phase I/II clinical trials are ongoing to shape the future of "off the shelf" CAR-T cell therapy. Figure 1 Figure 1. Disclosures Hoffmann: Pharmcyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

Natural killer (NK) cells are innate lymphocytes that target malignant cells via non-clonotypic receptors to induce natural cytotoxicity and that recognize tumor-bound antibodies to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Human NK cells exclusively mediate ADCC through the IgG Fc receptor, CD16A, and studies have demonstrated that increasing the binding affinity between CD16A and therapeutic monoclonal antibodies (mAbs), mediated by the high-affinity 158V polymorphism, can augment clinical efficacy. Given the exquisite specificity and diverse antigen detection of anti-tumor mAbs, we sought to arm iPSC-derived NK (iNK) cells expressing a high-affinity recombinant FcγR with various mAbs as unique tumor-targeting strategy for various malignancies. As a member of the FcγR family, CD64 (FcγRI) possesses the highest affinity and can uniquely facilitate antibody preabsorption but it is normally expressed by myeloid cells. To leverage CD64 in NK cells, we developed a novel FcγR recombinant fusion comprising the extracellular region of CD64 with the transmembrane and intracellular regions of other NK cell activating receptors, including CD16A (CD64/16A) (figure 1A). The recombinant CD64/16A engineered into a clonal master induced pluripotent stem cell (iPSC) line for mass production of off-the-shelf iPSC-derived CD64/16A NK (iNK-CD64/16A) cells, can be armed with mAbs, including various combinations thereof to enable multi-antigen targeting and to address tumor heterogeneity (figures 1B and 2). To determine optimal binding and FcR saturation of iNK-CD64/16 cells, rituximab (anti-CD20 therapeutic mAb) was added in a two-hour preabsorbtion assay (figure 3A). Using an in vitro Delfia® ADCC assay, we show that iNK-CD64/16A cells mediated ADCC against Raji cells, a Burkitt Lymphoma cell line, when the iNKs were preabsorbed and armed with rituximab (figure 3B). Considering the high-affinity state of CD64, we examined the effects of free IgG on ADCC by iNK-CD64/16A cells. Using an IncuCyte® Live Cell Analysis, ADCC was evaluated in the presence of purified human IgG. Despite the high levels of excess IgG, iNK-CD64/16A cells mediated efficient ADCC when rituximab was either added to the assay (figure 4A) or preabsorbed to the cells (figure 4B), demonstrating that saturating levels of free IgG did not prevent ADCC in either setting. To determine the ability of preabsorbed and armed iNK-CD64/16 cells to retain rituximab and perform serial killing, we performed a sequential killing assay using an IncuCyte® Live Cell Analysis where preabsorbed iNK-CD64/16A cells were thawed and co-cultured with or without Raji cells for 48 hours, followed by a second round of co-culture. As shown in figure 5, iNK-CD64/16A cells armed with rituximab retain ADCC capacity and perform serial killing for an extended time. To establish that iNK-CD64/16A cells can be armed with assorted therapeutic mAbs to target other tumor-associated antigens, we next determined the ability of iNK-CD64/16A cells preabsorbed and armed with anti-HER2 mAb, trastuzumab, to target the adenocarcinoma ovarian cancer cell line SKOV-3. Indeed iNK-CD64/16A cells armed with preabsorbed trastuzumab were able to effectively kill SKOV-3 cells via in vitro ADCC by IncuCyte® Live Cell Analysis (figure 6). We next investigated in vivo ADCC using NSG mice implanted with 3x10 5 SKOV-3 cells expressing firefly luciferase intraperitoneally (IP). 10 million iNK-CD64/16A with or without preabsorbed trastuzumab were injected IP (figure 7A), and a significant reduction in tumor volume in animals treated with iNK-CD64/16A cells armed with trastuzumab compared to unarmed iNK-CD64/16A cells (figure 7B). Collectively, our data show that iNK-CD64/16A cells can be armed with various therapeutic mAbs through a unique preabsorption strategy to mediate a potent and durable ADCC activity. The versatility of mAb-armed iNK-CD64/16A cells is being further investigated in various preclinical models to further elucidate the potential of this approach to overcome antigen escape and address tumor heterogeneity. Figure 1 Figure 1. Disclosures Lee: Fate Therapeutics, Inc: Current Employment. Chu: Fate Therapeutics: Current Employment. Rogers: Fate Therapeutics: Current Employment. Bjordahl: Fate Therapeutics: Current Employment. Hosking: Fate Therapeutics: Current Employment. Shirinbak: Fate Therapeutics, Inc.: Current Employment. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees. Valamehr: Fate Therapeutics, Inc.: Current Employment. Walcheck: Fate Therapeutics: Research Funding.

Background: Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are at high risk of reactivation or de novo infection with double-stranded (ds) DNA viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), adenovirus (AdV), BK virus (BKV), and JC virus (JCV). After allo-HCT, up to 90% patients develop detectable viremia by PCR. EMR data collected between 2018 and April 1, 2021, from over 1400 high-risk allo-HCT patients at 21 US centers suggest that 40-50% develop clinically significant viral infection or disease associated with ≥1 of these dsDNA viruses within 200 days of transplant. Multiple studies demonstrate increased morbidity and mortality associated with viremia, with or without end-organ disease. Prophylactic and preemptive therapies have substantial side effects and can lead to the development of resistance, especially in CMV. HCT donor-derived virus-specific T-cells have shown promise in preventing single virus infections in prior clinical trials but were infeasible for wide-scale use. There is an urgent unmet medical need for preventive strategies targeting multiple viruses in patients undergoing high-risk allo-HCT. Methods: We are conducting a clinical trial (NCT04693637) to evaluate the safety and efficacy of posoleucel (ALVR105, Viralym-M) for preventing clinically significant viral infections due to CMV, EBV, HHV-6, AdV, BKV, and JCV in high-risk allo-HCT recipients. Posoleucel is an ex-vivo expanded, partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product generated from healthy, third-party donors targeting CMV, EBV, HHV-6, AdV, BKV, and JCV. In the open-label portion of the study, patients receive up to seven infusions of 4×10 7 cells of posoleucel administered once every 14 days. High-risk patients are those who received a graft from a sibling or unrelated donor with ≥1 HLA mismatch; from a haploidentical donor; from umbilical cord blood or with T-cell-depletion; as well as patients with lymphocytes 0.5 mg/kg/day prednisone equivalent) at enrollment are ineligible. Patients are tested weekly for viremia using quantitative PCR assays and are monitored every other week for adverse events. The primary endpoint is the number of clinically significant viral infections or episodes of end-organ disease due to CMV, EBV, HHV6, AdV, BKV, or JCV by week 14. Results: Data are available for 12 of 25 planned participants thus far (Table 1). No patient developed a clinically significant infection within 14 weeks, the primary study endpoint. Over the entire study duration, defined as the primary 14-week treatment period plus the additional 12-week follow-up, 11 (92%) patients have remained free of any clinically significant viral infections, the key secondary endpoint. One patient, a 49-year-old female haploidentical transplant recipient, developed clinically significant AdV viremia after receiving over a month of high-dose methylprednisolone exceeding 0.5 mg/kg/day for recurrent aGVHD. This patient was administered IV cidofovir in week 15 of the study. During the primary study efficacy period one participant received 2 doses of valganciclovir following transient CMV viremia deemed not to be clinically significant by the principal investigator. Posoleucel has been well tolerated to date, with no drug-related serious adverse events, new-onset acute GVHD, or cytokine release syndrome. Safety and efficacy data from the entire open-label cohort will be presented. Conclusions: Preliminary results in this open-label cohort show that in high-risk allo-HCT patients receiving off-the-shelf posoleucel, clinically significant viral infections or disease from the 6 targeted dsDNA viruses were uncommon. No clinically significant infections were observed among participants treated in accordance with the protocol. These results, combined with the favorable safety and tolerability profile of posoleucel, support its continued evaluation in high-risk allo-HCT recipients for the prevention of CMV, EBV, HHV6, AdV, BK virus, or JC virus infection and disease. Figure 1 Figure 1. Disclosures Dadwal: Shire/Takeda: Research Funding; Astellas: Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AlloVir: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Shuster: Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company; Rafael: Research Funding; Celgene: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; Beigene: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Actinium: Research Funding; GSK: Research Funding; Pharmcyclics: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AlloVir: Research Funding; Janssen: Consultancy, Speakers Bureau; Astellas: Consultancy, Research Funding, Speakers Bureau; MorphSys: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau. Myers: Novartis: Consultancy, Speakers Bureau; AlloVir: Research Funding; Eliana: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boundy: AlloVir: Current Employment, Current equity holder in publicly-traded company. Warren: AlloVir: Consultancy. Stoner: AlloVir: Current Employment, Current equity holder in publicly-traded company. Hill: Octapharma: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; Allogene therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Karius: Research Funding.

Introduction: CD19-directed autologous CAR-T products induce high response rates in adults with R/R B-ALL, yet many patients relapse within the first year. Additionally, cell manufacturing timelines, and poor t-cell fitness may imperil efficacy, especially among those with proliferative disease. This makes access to a donor-derived, readily available CAR-T product of great interest in this patient population, particularly when consolidation with allogeneic stem cell transplant (allo-SCT) is possible. We report preliminary safety, efficacy, and correlative data for the R/R B-ALL patients dosed with at least 3 x 10 6 CAR-T cells/kg of PBCAR0191, an allogeneic 'off-the-shelf' CD19-directed CAR-T. Methods: Subjects were 18 years or older with CD19+ R/R B-ALL after at least 2 prior lines of therapy. Patients were required to have adequate organ function and no active GvHD, CNS disease, active infections, or other active medical issues. Prior allo-SCT and/or autologous CAR-T therapy were allowed. Subjects received either standard (sLD; 30mg/m2/day and 500mg/m2/day x 3 days fludarabine and cyclophosphamide, respectively) or enhanced (eLD; 30mg/m2/day x 4 days flu and 1000mg/m2/day x 3 days cy) lymphodepletion preceding PBCAR0191 infusion. Correlative laboratory samples were taken for CAR-T expansion, persistence, molecular response to treatment and safety assessments. Results: As of August 2, 2021, 15 subjects with R/R CD19+ B-ALL have been dosed with dose Dose level 3/4a (3 X 10 6 CAR-T cells/kg or equivalent, n=11) or a Dose level 4b (flat dose of 5 X 10 8 CAR-T cells, n=4). Demographics, baseline disease, and prior treatment data are presented in the table. Most of the Adverse events (AE) reported to date were mild, with no cases of GvHD, no Grade ≥3 CRS and 1 case of Grade 3 ICANS which resolved within 48 hours. 67% of subjects treated (10/15) experienced PBCAR0191 related AEs, with 60% (9/15) of subjects experiencing serious AEs (one related to PBCAR0191, ICANS Grade 3). The complete response (CR) or CRi (incomplete marrow recovery) rate at Day ≥28 is 33% (2/6) in DL3/4a and sLD, 80% (4/5) in DL3/4a with eLD and 75% (3/4) in DL4b with sLD. Importantly, 4/15 (27%) responding subjects underwent allo-SCT, with one additional subject not able to receive transplant due to eligibility yet maintaining an MRD- CR for >250 days, and one refusing to proceed with transplant. Product accessibility was evident compared to autologous CAR-T products, with median time from screening completion to PBCAR0191 infusion of 7 days (median of 1 day until start of LD) and all eligible subjects receiving PBCAR0191 infusion. Conclusion: PBCAR0191 has demonstrated a manageable safety profile and high complete response rate at day 28 or later, providing an adequate window for potential bridge to allo-SCT. Figure 1 Figure 1. Disclosures Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Pfizer: Research Funding; Janssen: Honoraria; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kantarjian: KAHR Medical Ltd: Honoraria; Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Heery: Precision BioSciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Arcellx: Current Employment, Current holder of stock options in a privately-held company. List: Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; CTI Biosciences: Consultancy; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Johnson: Precision BioSciences, Inc: Current Employment, Current equity holder in publicly-traded company. Lou: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company. Vainorius: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; United Therapeautics: Current equity holder in publicly-traded company. Olszewski: Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genmab: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Shah: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other. OffLabel Disclosure: PBCAR0191 is not FDA approved

Introduction. Despite the success of autologous chimeric antigen receptor (CAR)-T cells, barriers to a more widespread use of this potentially curative therapy include manufacturing failures and the high cost of individualized production. There is a strong desire for an immediately available cell therapy option; however, development of "off-the-shelf" T cells is challenging. Alloreactive T cells from unrelated donors can cause graft versus host disease (GvHD) for which researchers have successfully used nucleases to reduce expression of the endogenous T cell receptor (TCR) in the allogeneic product. The recognition of allogeneic cells by the host is a complex issue that has not been fully solved to date. Some approaches utilize prolonged immune suppression to avoid immune rejection and increase persistence. Although showing responses in the clinic, this approach carries the risk of infections and the durability of the adoptive T cells is uncertain. Other strategies include deletion of the B2M gene to remove HLA class I molecules and avoid recognition by host CD8 T cells. However, loss of HLA class I sends a "missing-self" signal to natural killer (NK) cells, which readily eliminate B2Mnull T cells. To overcome this, researchers are exploring insertion of the non-polymorphic HLA-E gene, which can provide partial but not full protection from NK cell-mediated lysis. Because activated T cells upregulate HLA class II, rejection by alloreactive CD4 T cells should also be addressed. Methods. Here, we developed an immunologically stealth "off-the-shelf" T cell strategy by leveraging our CRISPR/Cas9 platform and proprietary sequential editing process. To solve the issue of rejection by alloreactive CD4 and CD8 T cells, we knocked out (KO) select HLA class I and class II expression with a sequential editing process. Additionally, we utilize potent TCR-α and -β constant chain (TRAC, TRBC) gRNAs that achieve >99% KO of the endogenous TCR, addressing the risk of GvHD. An AAV-mediated insertion of a CAR or TCR into the TRAC locus is used in parallel with the TRAC KO step to redirect the T cells to tumor targets of interest. Alloreactivity by CD4 and CD8 T cells, NK killing, GvHD induction and T cell function was assessed in vitro and/or in vivo. Results. By knocking out select HLA class I and class II proteins, we were able to avoid host CD4- and CD8-T cell-mediated recognition. Edited T cells were protected from host NK cells, both in vitro and in an in vivo model engrafted with functional human NK cells. TRAC edited donor T cells did not induce GvHD in an immune compromised mouse model over the 90-day evaluation period. Using our proprietary T cell engineering process, we successfully generated allogeneic T cells with sequential KOs and insertion of a tumor-specific TCR or CAR with high yield. Importantly, these allogeneic T cells had comparable functional activity to their autologous T cell counterparts in in vitro assays (tumor cell killing and cytokine release) as well as in vivo tumor models. With a relatively small bank of donors, we can provide an "off-the-shelf" CAR or TCR-T cell solution for a large proportion of the population. Conclusions. We have successfully developed a differentiated "off-the-shelf" approach, which is expected to be safe and cost-effective. It is designed to provide long-term persistence without the need for an immune suppressive regimen. This promising strategy is being applied to our T cell immuno-oncology and autoimmune research candidates. Disclosures Zhang: Intellia Therapeutics: Current Employment. Goel: Intellia Therapeutics: Current Employment. Prodeus: Intellia Therapeutics: Current Employment. Jetley: Intellia Therapeutics: Current Employment. Tan: Intellia Therapeutics: Current Employment. Averill: Intellia Therapeutics: Current Employment. Ranade: Intellia Therapeutics: Current Employment. Balwani: Intellia Therapeutics: Current Employment. Dutta: Intellia Therapeutics: Current Employment. Sharma: Intellia Therapeutics: Current Employment. Venkatesan: Intellia Therapeutics: Current Employment. Liu: Intellia Therapeutics: Current Employment. Roy: Intellia Therapeutics: Current Employment. O′Connell: Intellia Therapeutics: Current Employment. Arredouani: Intellia Therapeutics: Current Employment. Keenan: Intellia Therapeutics: Current Employment. Lescarbeau: Intellia Therapeutics: Current Employment. Schultes: Intellia Therapeutics: Current Employment.

Background: Allogeneic natural killer (NK) cell therapies have documented anti-tumor activity in patients with relapsed/refractory (R/R) hematologic malignancies, including B-cell lymphoma (BCL), and may offer an improved safety profile characterized by the absence of cytokine release syndrome (CRS) and neurologic toxicity compared with T-cell therapies (Liu et al. 2020). However, limited availability of suitable donors, relatively short in vivo persistence, and manufacturing constraints limiting the ability to consistently deliver multiple doses remain barriers to maximizing the clinical benefit of NK cell therapy. FT516 is a first-of-kind, off-the-shelf, NK cell therapy manufactured from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of NK cells for multi-dose treatment and immediate patient access. FT516 expresses a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, which has been demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity in combination with an anti-CD20 monoclonal antibody (Zhu et al. 2020). Methods: Primary objectives of the study are to determine the recommended Phase II dose of FT516 in combination with rituximab (R) or obinutuzumab (G) in R/R BCL and to evaluate safety and tolerability in patients (pts) with R/R BCL. Key secondary objectives include evaluation of FT516 anti-tumor activity by Lugano Classification and pharmacokinetics when combined with R or G in R/R BCL. The ongoing dose-escalation stage assesses FT516 for up to 2 cycles, each consisting of 3 days of conditioning chemotherapy (cyclophosphamide [CY] 500 mg/m 2 and fludarabine [FLU] 30 mg/m 2), a single-dose of R (375 mg/m 2), and 3 weekly doses of FT516 (30-900 million cells per dose) each with IL-2 support (6 MIU). FT516 may be administered in the outpatient setting with no mandatory hospitalization. Following dose escalation, further investigation of safety and efficacy will be conducted as follows: FT516 + R or G following FLU/CY in pts with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma (FL) who have not received prior CAR T-cell therapy; FT516 + R following FLU/CY in pts with R/R BCL who have previously received CAR T-cell therapy; and FT516 + R following bendamustine. Results: As of 07 July 2021, 13 pts (2 at 30 million cells per dose, 4 at 90 million cells per dose, and 7 at 300 million cells per dose) were enrolled and had at least 3 months of follow-up or discontinued. Pts had DLBCL, including transformed indolent (7 pts), high-grade BCL (HGBCL, 3 pts), low-grade FL (2 pts), or marginal zone lymphoma (1 pt), and received a median of 3 prior lines of therapy and a median of 2 prior lines containing CD20-targeted therapy. Ten of 13 pts received both planned treatment cycles (6 doses of FT516); 3 pts discontinued after a single cycle due to disease progression. No dose-limiting toxicities, FT516-related serious adverse events, or FT516-related Grade ≥3 adverse events (AEs) were observed. No CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. Grade ≥3 AEs occurring in ≥2 pts were neutrophil count decreased (6 pts), neutropenia (5 pts), febrile neutropenia (3 pts), and thrombocytopenia (2 pts). Eight of the 11 pts (72%) treated with ≥90 million FT516 cells achieved an objective response. Seven pts achieved complete response (CR), including 2 pts whose disease progressed following treatment with autologous CD19 CAR T-cell therapy. Two pts treated at the lowest dose of 30 million FT516 cells experienced progressive disease. Of the 8 responders, 5 continue in remission at between 4.6 and 9.5 months. One pt with primary refractory triple-hit HGBCL that had progressed after 7 prior regimens, including CAR T-cell therapy, continues in CR with minimal residual disease negativity by local ctDNA analysis 4.9 months from initiation of FT516 treatment. Conclusions: Administration of up to 6 doses of FT516 cells in combination with R appears safe and tolerable up to 300 million cells per dose, without CRS, ICANS, or GvHD. Deep responses were observed in heavily pretreated pts, with several with ongoing CR at data cutoff. Updated clinical and translational results of ongoing dose escalation will be presented at the conference. Disclosures Patel: Pharmacyclics: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Janssen: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; Lilly: Consultancy. Bachanova: Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goodman: EUSA Pharma: Consultancy, Honoraria; Seattle Genetics: Consultancy, Speakers Bureau. Pagel: Pharmacyclics/AbbVie: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; Incyte/MorphoSys: Consultancy. Griffis: Fate Therapeutics, Inc.: Current Employment. Anderson: Fate Therapeutics, Inc.: Consultancy. Atwal: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Bickers: Fate Therapeutics, Inc.: Current Employment. Szabo: Fate Therapeutics, Inc: Current Employment. Wong: BMS: Current equity holder in publicly-traded company; Fate Therapeutics, Inc: Current Employment. Chu: Gilead: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Elstrom: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company. Strati: Roche-Genentech: Consultancy; Astrazeneca-Acerta: Research Funding.

BackgroundagenT-797 is an allogeneic, native invariant natural killer T (iNKT) cell therapy product currently in phase I clinical trials for cancer (heme and solid). iNKT cells are a distinct population of T cells that can recognize tumors via direct recognition of CD1d (an MHC-I like molecule presenting glycolipids) through the TCR or recognition of NK cell receptor ligands via various NK receptors. We developed agenT-797 from isolated and ex-vivo expanded peripheral blood iNKT cells. Here we describe in vivo xenograft models to demonstrate the overall tissue distribution, tumor infiltration and efficacy of agenT-797 in liquid as well as solid tumors.MethodsWe utilized NOG-hIL15 (human IL-15) transgenic mice to ensure persistence/maintenance of ex-vivo expanded human iNKT cells throughout the studies. For studying efficacy in liquid tumors, we used NALM6, an acute lymphoblastic leukemia (ALL) cell line and for solid tumors selected A375, a melanoma cell line. Both cell lines were engineered to overexpress CD1d. Upon injection of iNKT cells, tumor growth and iNKT cell tissue/tumor infiltration as well as phenotype were studied.ResultsInjection of iNKT cells in NALM6- engrafted NOG-hIL15 mice resulted in an overall reduction in leukemic burden as measured by luminescence-based imaging. Flow cytometric analysis revealed infiltration of iNKT cells at the site of leukemic expansion, namely blood, spleen, bone marrow and liver. Cells were activated when reaching the site of the tumor. In addition, iNKT cells produced IFNγ and TNFα and low levels of IL-13/IL-4, consistent with a Th1 response. When iNKT cells were injected into A375 engrafted mice we observed infiltration of iNKT cells into the tumor, where they become activated and proliferate overtime. We observed an overall reduction in tumor size when iNKT cells were injected compared to control group, demonstrating the impact of iNKT cells on tumor growth.ConclusionsWe established xenograft mouse models to address various biological questions around human iNKT cells as a cell therapy product. We have demonstrated homing and infiltration of iNKT cells at the site of tumor and relative proliferation and expansion. These models provide a suitable platform for in-vivo preclinical studies on agenT -797 in cancer.Ethics ApprovalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

BackgroundVaccines have little chance of destroying heterogeneous tumor cells since they rarely induce polyclonal T-cell responses against the tumor. The main challenge is the accurate identification of tumor targets recognizable by T cells. Presently, 6–8% of neoepitopes selected based on the patients‘ tumor biopsies are confirmed as real T cell targets.1 2. To overcome this limitation, we developed a computational platform called Personal Antigen Selection Calculator (PASCal) that identifies frequently presented immunogenic peptide sequences built on HLA-genetics and tumor profile of thousands of real individuals.3 Here we show the performance of PASCal for the identification of both shared and personalized tumor targets in metastatic colorectal cancer (mCRC) and breast cancer subjects.MethodsExpression frequency of the tumor-specific antigens (TSAs) ranked in PASCal’s database (based on 7,548 CRC specimen) was compared to the RNA-sequencing data of CRC tumors obtained from TCGA. Using PASCal, 12 shared PEPIs (epitopes restricted to at least 3 HLA class I alleles of a subject from an in silico cohort) derived from 7 TSAs were selected as frequent targets (calculated probability: average 2.5 [95%CI 2.4–2.8] TSAs/patient). Spontaneous immune responses against each of the twelve 9mer peptides were determined by ELISpot using PBMCs of 10 mCRC subjects who participated in the OBERTO-101 study.4 PEPIs selected for a breast cancer subject based on her HLA genotype were also tested.ResultsEach of the 106 tumors analyzed expressed at least 13, average 15 of the 20 top-ranked TSAs in PASCal’s database confirming their prevalence in CRC. 7/10 subjects had spontaneous CD8+ T-cell responses against at least one peptide selected with PASCal. Each peptide (12/12) was recognized by at least one patient. Patients‘ T-cells reacted with average 3.6/12 (30%) peptides confirming the expression of average 2.8 [95%CI 1.0–4.6] TSAs (n=10). After HLA-matching, among the subjects for whom we could select at least 4 PEPIs (average 5) from the list of 12 peptides (n=6), average 2.5 (50%) peptides were positive. Of the 12 PEPIs selected with PASCal for a breast cancer subject, we detected spontaneous T-cell responses against 9 PEPIs, indicating that at least 75% of the selected peptides were present in the subject’s tumor and were recognized by T-cells.ConclusionsPASCal platform accommodates both tumor- and patient heterogeneity and identifies non-mutated tumor targets that may trigger polyclonal cytotoxic T-cell responses. It is a rapid tool for the design of both off-the-shelf and personalized cancer vaccines negating the need for tumor biopsy.ReferencesWells DK, van Buuren MM, Dang KK, et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 2020:183(3):818–34.e13.Bulik-Sullivan B, Busby J, Palmer CD, et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat Biotech 2018:37:55–63.Somogyi E, Csiszovszki Z, Lorincz O, et al. 1181PDPersonal antigen selection calculator (PASCal) for the design of personal cancer vaccines. Annal Oncol 2019:30(Supplement_5):v480-v81.Hubbard J, Cremolini C, Graham R, et al. P329 PolyPEPI1018 off-the shelf vaccine as add-on to maintenance therapy achieved durable treatment responses in patients with microsatellite-stable metastatic colorectal cancer patients (MSS mCRC). J ImmunoTher Cancer 2019:7(1):282.

Objective We compared the theoretical anatomic feasibility of endovascular treatment of thoracoabdominal aortic aneurysms (TAAAs) with three off-the-shelf multibranched stent-grafts: t-Branch (Zenith t-Branch; Cook Medical, Bloomington, Ind), Gore Excluder thoracoabdominal branch endoprosthesis (TAMBE; W. L. Gore & Associates, Flagstaff, Ariz), and E-nside (E-nside multibranch stent graft system; Jotec GmbH, Hechingen, Germany). Methods Computed tomography scans of patients with degenerative TAAAs treated from 2007 to 2019 were reviewed, and the anatomic feasibility of the multibranched stent-grafts was assessed according to the manufacturer's instructions for use. The anatomic factors determining the overall feasibility were divided into access feasibility, aortic feasibility, and visceral vessel feasibility. Results Degenerative TAAAs in 268 patients were analyzed. The overall feasibility did not differ significantly (TAMBE, 33%; t-Branch, 39%; E-nside, 43%; P = .271). Access, aortic, and visceral vessel feasibility alone excluded 18% to 22%, 35% to 49% and 21% to 26% of the patients respectively. The only significant difference between the devices was in aortic feasibility (P = .005), which was more frequently limited by the proximal aortic neck diameter in the TAMBE cohort and the inner visceral aortic diameter in the t-Branch cohort. The overall treatment feasibility using any of the three devices would have been 58%. Conclusions The new investigational off-the-shelf multibranched stent-grafts did not significantly improve the theoretical applicability in an extensive cohort of patients with TAAAs. Improvements are warranted to increase their overall feasibility.

Purpose: To assess the short-term outcomes of the multibranched off-the-shelf t-Branch stent-graft for urgent thoracoabdominal aortic aneurysm (TAAA) repair and to evaluate the impact on outcomes of the learning curve and adherence to the instruction for use (IFU). Methods: Between 2014 and 2017, 42 patients (mean age 73.3±7 years; 26 men) underwent urgent TAAA treatment using the t-Branch stent-graft [18 in the early (2014–2015) period and 24 in the late (2016–2017) period]. Nearly half the patients were symptomatic (n=18) and 12 had contained rupture. Aneurysm diameter >80 mm was present in 12 (mean diameter 77.7±13.2 mm). Nineteen patients did not meet the IFU for the t-Branch due to target vessel anatomy. The primary endpoints were spinal cord ischemia (SCI), renal function impairment, and 30-day mortality. Target vessel patency and endoleak incidence were assessed at 30 days. Multivariate analyses examined associations between perioperative variables and outcomes; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Results: The technical success rate was 93% (39/42). Successful catheterization was achieved in 150/155 target vessels (97%). The postoperative SCI rate was 21% (5 paraplegia/4 transient paraparesis) and was correlated with age (OR 1.26, 95% CI 1.01 to 1.56, p=0.04). The renal function impairment rate was 23% (10/42; 2 temporary, 2 permanent dialysis) and was correlated with early experience (OR 7.74, 95% CI 1.3 to 43.9, p=0.019). The 30-day mortality was 14% (no intraoperative deaths); no factor was associated with mortality. During the first month, the incidences of type I, II, and III endoleaks were 0%, 43%, and 0%, respectively; branch patency was 99% (150/151). Procedure time decreased in the later experience (479±333 vs 407±25 minutes, p=0.09), though it was increased in cases outside the IFU (497±135 vs 389±118 minutes, p=0.009), along with fluoroscopy time (121±48 vs 92±33 minutes, p=0.036). Conclusion: Endovascular repair of urgent TAAA using the t-Branch is a feasible treatment option with acceptable 30-day mortality and morbidity in terms of SCI and renal function impairment. Adherence to the IFU prolonged procedure time but had no effect on outcomes. Increased experience of such cases over time may improve outcomes.

The question of whether allogeneic chimeric antigen receptor (CAR) T cells could replace autologous CAR T cell therapy has garnered considerable interest, but limited data have been available for comparisons to date. Now, Benjamin et al. have reported their experience with allogeneic anti-CD19 CAR T cells in 21 paediatric and adult patients with acute lymphoblastic leukaemia.

Viologens and the stable, water-soluble nitroxide radical known as TEMPOL have been studied extensively with respect to applications in energy storage. Here we report formulations wherein high concentrations of both are achieved in a single solution and the reversible electrochemistry of each is retained. We demonstrate one of several potential applications by constructing a high optical density electrochromic device.

Mesenchymal stem cells (MSC) have been extensively investigated as cell carriers or cell therapies for treating a wide range of malignant and inflammatory diseases. In addition, recent studies show that MSCs' tropism to malignant and inflamed tissues as well as their immunomodulatory capacity, both are largely governed by direct cell-cell interactions facilitated by membrane-bound proteins. Never the less the translation of MSCs into broadly-applicable clinical applications may face obstacles due to MSCs' susceptibility to host-induced changes, limiting their ability to deliver a long-lasting effect. Based on this knowledge we developed a scalable technology for the production of nano-vesicles from the cell membrane of MSCs. These nano-vesicles, termed Nano-Ghosts (NGs), and our data demonstrate that these NGs can be used as a cancer targeted delivery platform, effectively loaded and used to selectively deliver diverse therapeutics including biological drugs, small molecules, and nucleic acids. In several preclinical cancer models (pancreatic, NSCLAC) we have shown selective NG targeting resulting in reduction in tumor growth and prolonged survival. In this study, we extend previous data and demonstrate the ability of NGs to penetrate the BBB in a two mice models for GBM demonstrating high and specific accumulation of NGs in the tumor while no off-target inn normal brain tissue nor filtrating organs. The lethal effect of drug carrying NGs was expanded by using cytotoxic ligand derived from CTLs (TRAIL) genetically engineered on the surface of the MSC-NGs, creating a new class of NGs termed immunotherapeutic NGs (iNGs). The membrane bound TRAIL enable the iNGs to inhibit significantly mice bearing melanoma tumors, without the need of a loaded drug. Our results, clearly demonstrate the translational potential of NGs, both as targeted carriers and as novel immunomodulatory biologics, for oncological and immunological applications. Citation Format: Marcelle Machluf, Marcelle Machluf, Shani Hamias, Lior Levii, Osnat Bohana Kashtan. NanoGhost: Harnessing the power of stem cell in an off-the-shelf novel targeted nano-delivery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1320.

Chimeric antigen receptor (CAR) directed therapies have been used successfully to treat a variety of hematological malignancies. With the advent of multi-modal engineering, adoptive cell therapy offers the opportunity to tackle increasingly complex disease settings such as multiple myeloma (MM), where targeting of single tumor associated antigen by CAR or monoclonal antibodies (mAb) is confounded by antigen loss and clonal heterogeneity. Further, expanding treatment options beyond primary T and NK cell based therapies has multiple advantages, including the use of induced pluripotent stem cells (iPSC) to derive effector cells using precision genetic engineering that can be uniformly manufactured at scale from a clonally-derived master cell bank (MCB).FT576 is a multiplex-edited, iPSC-derived CAR-NK (CAR-iNK) cell therapy designed for treatment of Multiple Myeloma. FT576 is engineered 1) to express a recombinant IL-15/IL-15 receptor signaling complex (IL-15RF) for enhanced persistence; 2) to express an enhanced high-affinity, non-cleavable CD16 (hnCD16) ; 3) to disrupt expression of CD38, allowing for enhanced ADCC without NK cell fratricide; and 4) to express a BCMA-targeted CAR with NK-cell optimized signaling.CAR-directed specificity of the FT576 cells for BCMA was demonstrated using a short-term cytotoxicity assay (90.8% cytotoxicity against BCMA+ vs 22.1% BCMA- cells, p Citation Format: Jode P. Goodridge, Ryan Bjordahl, Sajid Mahmood, John Reiser, Svetlana Gaidarova, Robert Blum, Frank Cichocki, Hui-yi Chu, Greg Bonello, Tom Lee, Brian Groff, Miguel Meza, Thomas Daley, Yu-waye Chu, Bruce Walcheck, Karl-Johan Malmberg, Jeffrey S. Miller, Armin Rehm, Bahram Valamehr. FT576 path to first-of-kind clinical trial: translation of a versatile multi-antigen specific off-the-shelf NK cell for treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1550.