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•PKCα is novel and positive regulator of Fpn by modulating the trafficking and localization of Fpn.•Inhibition of PKCα reduces body iron content in physiology, diabetes, and hereditary hemochromatosis.

•Damage-associated molecular patterns from conditioning-related tissue injury have been shown to aggravate acute graft-versus-host disease.•Results support a role for enhancing CD24–Siglec-10 interactions in regulating graft-versus-host disease after HSCT.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab’s efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2–containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation “armored” chimeric antigen receptor (CAR) engineering of cord blood–derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15–secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.

Madduri: Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Berdeja:Teva: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; Celgene: Consultancy, Research Funding; EMD Sorono: Research Funding; Kite Pharma: Consultancy; Prothena: Consultancy; Cellularity: Research Funding; Karyopharm: Consultancy; Servier: Consultancy; Legend: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Kesios: Research Funding; Novartis: Research Funding. Usmani:Celgene: Other; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Patents/Intellectual property licensed, Research Funding. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Htut:City of Hope Medical Center: Current Employment. Munshi:OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; C4: Current equity holder in private company. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; GenMab: Consultancy, Honoraria. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Zhuang:Janssen: Current Employment. Infante:Janssen: Current Employment. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Rizvi:Legend Biotech USA Inc.: Current Employment. Fan:Legend Biotech USA Inc.: Current Employment. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; GSK: Consultancy; Sanofi: Research Funding.

•Dexamethasone dose reductions <40 to 60 mg weekly are common in multiple myeloma, even for patients enrolled on clinical trials.•In our large analysis of 2 clinical trials, dexamethasone dose reductions did not impact PFS or OS.

•Better clinical responses to teclistamab correlate with a more functional initial immune T-cell repertoire in the periphery and tumor site.•More durable responses to teclistamab associate with lower Tregs and lower expression of inhibitory receptors on T cells at baseline.

Introduction:Sickle cell anemia (SCA) is a hereditary genetic disorder characterized by the production of abnormal hemoglobin (HbS), which leads to altered physiological properties. Hydroxyurea (HU) is an established oral drug that has demonstrated the ability to ameliorate the severity of the disease mainly by increasing the production of fetal hemoglobin (HbF), thereby reducing sickle cell crises. Studies in the Indian population have shown positive clinical outcomes with a low dose (10 mg/kg/day) of hydroxyurea. Low dose is recommended by most of the physicians in India due to fear of adverse events and noncompliance of patients for regular monitoring of blood parameters. However, the effectiveness of low-dose HU compared to the standard dose (20 mg/kg/day) in reducing sickle cell anemia crises remains uncertain due to the diverse clinical severity of SCD in the Indian population. To address this question, the study aimed to conduct a national level randomized control trial involving SCA patients from various ethnic backgrounds to definitively establish the benefits of low-dose HU for Indian patients compared to the standard dose.

BackgroundSickle cell disease (SCD) is an inherited disorder of red blood cells affecting millions of people worldwide. SCD is characterized by recurrent episodes of severe pain attacks, also called vaso-occlusive crisis (VOC), and are the most common reason for hospitalization. Approximately 90% of the hospital admissions are for pain treatment and the hospital readmission rate is alarmingly high, as 30-50% are re-admitted within 30 days. We previously were successful in developing machine learning models to predict pain using inpatient vital signs data as well as Apple Watch data in patients with SCD hospitalized for VOC. We now aimed to predict reutilization of care within 30 days in patients with SCD treated for a VOC.

Despite the high response rates of chimeric antigen receptor (CAR) - T cells targeting the B-cell maturation antigen (BCMA) for multiple myeloma (MM), patients eventually still relapse. At this time there is no clear subsequent therapy. Furthermore, CAR T-cell therapy is associated with significant toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

Introduction: Patients with multiple myeloma (MM) are at ongoing risk of financial toxicity (FinTox) from medication costs and lost productivity (Richter CLML 2020, Fiala CLML 2023). Given MM's incurable nature with ongoing monitoring and supportive care, time toxicity (TimeTox) from frequent healthcare interactions may persist into the maintenance phase as well. The prevalence, predictors, and impact of FinTox and TimeTox on QOL have not been fully characterized in this population.

Background: Dex is a key component of induction regimens for NDMM despite common toxicities including insomnia and anxiety. The E4A03 randomized trial (Rajkumar, Lancet Oncol 2010) demonstrated that dex dosed at 40 mg weekly outperformed higher-intensity dex and established this regimen as the standard of care for NDMM. In standard practice as well as clinical trials, however, dex doses are often reduced to 20 mg weekly or lower (if not stopped entirely) among older patients or among patients experiencing toxicities. As a first step toward establishing the equipoise of planned dex dose reductions in NDMM, we investigated outcomes with patients from two previous SWOG trials to understand the impact of dex dose reductions on post-induction outcomes.

Pts with refractory Hodgkin (HL) and other CD30+ lymphomas have few effective therapies available and targeted NK cell immunotherapy is an active area of research. Transfer of non-targeted NK cells has shown limited clinical benefit as target recognition of cancer cells by NK cells constitutes a barrier. The innate cell engager AFM13 is a first-in-class CD30/CD16A bispecific antibody construct that induces selective killing of CD30+ tumor cells by engaging and activating NK cells. As a single agent, AFM13 has limited clinical activity against HL, likely due to the reduced effector function of autologous NK cells in these pts, which provides the rationale for combining AFM13 with allogeneic NK cells. Our prior preclinical work identified a promising combination of CB-derived NK cells that were first IL-12/IL-15/IL-18-preactivated followed by ex vivoexpansion (P+E) with engineered K562 feeder cells expressing membrane-bound IL-21, 4-1BBL and CD48 and exogenous IL-2, and subsequently complexed with AFM13 just before infusion; these cytokine-induced memory-like NK cells presented chimeric antigen receptor (CAR)-NK-like features and increased in vitroand in vivoantitumor activity compared to either non-AFM13-precomplexed P+E NK cells or to AFM13 alone (Kerbauy et al, Clin Cancer Res 2021). Building on this work we wished to study this CB NK-cell therapy in pts with refractory CD30+ lymphomas.

Pain is a debilitating consequence of sickle cell disease (SCD). We examined the potential of novel topical transdermal curcumin (TDC) gel with transdermal systemic delivery to target pain and SCD pathobiology. Curcumin is an antioxidant and anti-inflammatory polyphenol with therapeutic potential but has poor oral bioavailability. TDC gel (Vasceptor TM, Vascarta Inc.), containing 0.1 M of curcuminoids (derived from Curcugen, Dolcas-Biotech, LLC), or vehicle were applied (0.1 mL) topically by gentle rubbing to the abdomen on alternating days for 3 weeks followed by analysis of blood, organ pathology and skin secretome. Using high-performance liquid chromatography, we found that curcumin levels peaked in the plasma (7.87 µg/mL) and blood cells (6.78 µg/mL) 60 min following administration in C57BL/6 mice, thus, showing efficient bioavailability.

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA.

Relapsed/refractory T-cell malignancies have a particularly poor prognosis and novel therapies are direly needed. CD5 is a great candidate for adoptive cellular therapy to target T-cell malignancies since it is ubiquitously expressed on T cells with restricted expression on other hematopoietic cells. NK cells are an attractive platform for CAR engineering to target CD5 since, unlike T cells, they do not express CD5 on their surface, which eliminates the risk of fratricide. Another advantage of NK cells for CAR engineering is their safety profile; in contrast to T cells, they do not cause cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) and they are not associated with graft-versus-host disease (GVHD) in the allogeneic setting, opening the potential for a completely off-the-shelf cellular product to be used at point of care. Therefore, we sought to develop CD5 targeting CAR-NK cells for the treatment of T-cell malignancies.

Introduction

Introduction:CARTITUDE-4 (NCT04181827) is a randomized, phase 3 trial comparing ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in patients (pts) with lenalidomide (len)-refractory multiple myeloma (MM). The trial recently showed that pts in the cilta-cel arm experienced significantly improved progression-free survival (PFS) vs SOC (HR, 0.26; P<0.0001) and a significantly higher rate of complete response (CR) or better and overall response rate (ORR) in the intent-to-treat (ITT) set (San-Miguel et al, New Engl J Med2023). We report efficacy and safety in pts who received cilta-cel as study treatment (‘as-treated’ set) in the experimental (cilta-cel) arm of the study.

BACKGROUND

The ability to re-direct the intrinsic power of the immune system against cancer has resulted in unprecedented outcomes in certain patients with otherwise incurable diseases. Natural killer (NK) cells, similar to T cells, are powerful immune effectors that possess intrinsic anti-tumor properties and are capable of generating a strong cytotoxic response upon engaging tumor cells. However, unlike T cells, NK cells do not identify specific antigens and do so in a way that is HLA-independent, posing minimal risk of GvHD. Thus, NK cells have are being explored as a possible allogeneic source for over-the-counter cellular immunotherapy. CD70, the ligand for the CD27 receptor, is an attractive “pan-cancer antigen”, since in addition to being expressed in hematologic malignancies such as acute myeloid leukemia (AML) and lymphoma, it is also expressed on many solid tumors, including bladder, lung, triple negative breast cancer, renal cell carcinoma, pancreatic cancer, and melanoma. Moreover, CD70 is only transiently found on activated T and B lymphocytes and on dendritic cells. To target CD70-expressing cancers, we designed and tested a number of different chimeric antigen receptors (CAR). Briefly, we used the natural interaction between CD70 and CD27 to make a CAR construct that incorporated the extracellular domain of human CD27, which is the natural receptor for CD70. We generated various second-generation CAR constructs that differed in their transmembrane domains (CD27 vs. CD28) and costimulatory domains. We included co-stimulatory domains that are NK-centric (DAP10 and DAP12), T-cell-centric (CD28), or bi-centric (4-1BB). The CD3ζ chain was used as a signaling endodomain, and all the CAR constructs also included IL-15 to enhance in vivo proliferation and persistence. Cord blood (CB)-derived NK cells were efficiently retrovirally transduced with the different CAR constructs and subjected to an in vitro functional screen against various cancer cells to evaluate the best constructs for in vivo validation (Figure 1). The top constructs from our in vitro screen were further evaluated in multiple in vivo models, including a Raji lymphoma model and a THP-1 AML model. The best CAR construct in terms of superior tumor control and prolongation of survival was selected for GMP manufacturing. Based on these preclinical findings, a Phase I/II clinical study is now being conducted at our center to assess the safety and effectiveness of CD70 CAR NK cells against CD70-expressing hematologic malignancies (NCT05092451).

Background:Natural killer (NK) cells are part of the innate immune system, and their killing capacity depends on the inputs from activating and inhibitory receptors. CD226 is an activating receptor that plays a role in the immune surveillance of acute myeloid leukemia (AML). AML cells have developed mechanisms to escape NK cell cytotoxicity including downregulating activating receptors such as CD226 on the surface of NK cells. Chimeric antigen receptors (CARs) are synthetic receptors integrated into NK cells to direct their anti-leukemia activity, and CD38 is a potential target for NK CAR-based cellular therapy against AML. Understanding the dynamics between the endogenous activating and inhibitory NK cell receptors (such as CD226) and the introduced CAR can determine the development of more effective NK CAR-based therapy for AML. We hypothesize that CD38-directed CAR NK cells may overcome CD226 downregulation as a mechanism of immune escape in AML.

Introduction:Rareevents of T-cell lymphoma (TCL) derived from CAR-T cells (2 cases) have been reported in patients receiving nonviral piggyBac transposon-based CAR-T therapy (Micklethwaite et al, Blood, 2021). Ciltacabtagene autoleucel (cilta-cel) is an anti-BCMA CAR-T therapy produced via conventional lentiviral transduction. In the randomized, phase 3 CARTITUDE-4 study (NCT04181827), cilta-cel significantly improved PFS (HR=0.26) vs standard of care in lenalidomide-refractory patients with multiple myeloma and 1-3 prior lines of therapy. We present the clinicogenomic characterization of a CARTITUDE-4 patient who developed a CAR+ TCL post cilta-cel.

Prolonged antibiotic administration has been associated with peripheral cytopenias in up to 10-15% of patients. Of these, neutropenia is particularly notable because of the associated risk of severe bacterial infections. Yet, the mechanisms underlying antibiotic-associated neutropenia remain poorly understood. Recent studies in murine models demonstrate that antibiotics suppress hematopoiesis by depletion of the intestinal microbiota, with concomitant suppression of basal Type I interferon (IFN) and STAT1 signaling. Oral administration of the microbial metabolites that induce Type I IFN restores normal hematopoiesis in antibiotic-treated mice. These findings support a paradigm in which products of the intestinal microbiota enter the bloodstream and travel to the bone marrow where they promote production of growth cytokines that support normal hematopoiesis.

Background: Digital life coaching (DLC) pairs patients with a certified health coach to identify and achieve wellness-related goals through phone calls and text messages. DLC has been shown to improve physical quality of life in a recent randomized trial of patients with multiple myeloma (MM) undergoing upfront transplantation (Banerjee, BMT 2023). However, transplantation is an acute life disruption that may not necessarily reflect long-term wellness; this is particularly true for patients living with relapsed/refractory (R/R )MM, for which symptom burden and uncertainty may be chronically higher. As such, a new study (clinicaltrials.gov ID: NCT05956457) is under way to explore the feasibility and outcomes of DLC with integrated symptom monitoring (via a wearable activity tracker) to inform a more complete understanding of the patient experience with R/R MM. Endpoints from this study will include symptom burden, health self-efficacy, and financial, physiologic, and psychosocial well-being, and if and how DLC may be used to support this population.

BACKGROUND

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) belong to the same spectrum of myeloid malignancies and have extremely poor outcomes in the relapsed/refractory setting. Despite advances in the understanding of the pathogenesis and molecular mechanisms of these disorders, and incremental improvements in treatment regimens, patients with MDS and AML often relapse and fail to achieve cure. These and other factors underscore the urgent need for new therapeutic alternatives that will improve the clinical outcomes of these patients. Immunotherapy using checkpoint molecule inhibitors and adoptive cell therapy using autologous immune effector cells have been mostly unsuccessful in patients with MDS and AML. This could be due to the immunosuppressive tumor microenvironment in the bone marrow niche or to intrinsic dysfunction in the immune effector cells of these patients.

T-cell lymphomas (TCL) are a heterogenous group of non-Hodgkin lymphoma characterized by resistance to conventional therapies posing an urgent need for safe and effective therapies. CAR-NK cells have emerged as a promising “off-the-shelf” cancer immunotherapy and are especially attractive for the treatment of T-cell malignancies. This is especially the case given the challenge of targeting T cell malignancies with CAR T cells due to shared antigens across the therapeutic, normal and malignant T cells posing the risk of CAR T cell fratricide, T-cell aplasia, and contamination of the CAR T products with malignant T cells. We have developed an FDA-approved system for ex vivoNK cell expansion, which reliably generates clinically relevant doses of GMP-grade NK cells from a cord blood (CB) unit. We have used this platform to engineer NK cells to express a CAR targeting CD19 using GMP-grade retroviral vectors and demonstrated the safety and efficacy of this platform in the clinic. We now propose to expand this approach to target TCL. CD70, a surface ligand of CD27, is overexpressed in a variety of cancers, including TCL. Signaling mediated by CD70-CD27 is thought to induce proliferation of TCL cells via activation of the NF-κB pathway. Thus, CD70 is an attractive target for CAR NK-cell therapy against TCL. We analyzed the publicly available primary TCL dataset (GSE19069) including anaplastic large cell lymphoma (30 samples), angioimmunoblastic TCL (37 samples), peripheral TCL (PTCL; 50 samples), and adult T cell leukemia/lymphoma (13 samples) for CD70 expression. The majority of the samples expressed CD70 transcript with a variable level of expression ( Figure 1). Using flow cytometry, we screened a panel of TCL cell lines with diverse histologic, cytogenetic and molecular properties for the expression of CD70. We demonstrated positive CD70 expression on most of the TCL cell lines profiled encompassing anaplastic large cell lymphoma (ALK+: KAR299; ALK-: MAC2A; fusion gene NPM-ALK+: SU-DHL1 and SUP-M2), hepatosplenic gamma-delta TCL (DERL-7), Sezary syndrome (SS; H9 and HuT78), and PTCL NOS (OCI-LY12). The CD70 intensity was highest on MAC2A, HuT78, KAR299 and SUP-M2, intermediate to low on DERL-7 and H9, and negative on SU-DHL1 and OCI-LY12. We designed a novel retroviral vector targeting CD70 that: 1) encodes the CD70-targeting CAR gene based on the CD27 extracellular domain; 2) ectopically produces interleukin (IL)-15 to support NK cell proliferation; and 3) expresses the suicide gene inducible caspase 9 ( iC9) that can be pharmacologically activated to eliminate transduced cells in the event of toxicity. The construct will be referred to as CAR.70/IL-15. Non-transduced (NT) NK cells and NK cells transduced with a construct that leads to IL-15 production without a CAR (IL-15 NK cells) were used as controls. We demonstrated that CAR.70/IL-15 NK cells had a significantly enhanced cytotoxicity compared to NT- and IL-15 NK cells against the CD70+ cell lines while there was no difference in cytotoxicity between the NK cell conditions in the negative cell lines pointing to a CD70-targeted fashion of anti-TCL NK cell cytotoxicity. Moreover, CAR.70/IL-15 NK cells exhibited greater cytotoxicity against CD70+ cell lines in long-term cytotoxicity assays ( Figure 2). In a tumor rechallenge assay against KAR299 where fresh tumor cells were added every 3-4 days, CAR.70/IL-15 NK cells showed superior potency in continuous tumor control. In addition, CAR.70/IL-15 NK cells exhibited higher levels of degranulation (CD107a) and cytokine production (TNFα and INF-γ) when cocultured with CD70+ TCL cell lines, compared to NT and IL-15 NK cells. Furthermore, these CAR NK cells targeting CD70 outperformed CAR NK cells engineered to target CD19, which is an irrelevant target for TCL, further confirming the specific CD70-targeted activity of CAR.70/IL-15 NK cells. CyTOF immunophenotyping revealed that CAR.70/IL-15 NK cells are characterized by the increased expression of markers of cytotoxicity such as granzyme-b, perforin, TRAIL; and activating coreceptors/proliferation markers such as DNAM, CD25 and Ki67. Taken together, our findings validate CD70 as a promising target for TCL treatment using CAR NK cells. Our approach provides a solid foundation for the clinical translation of CD70-targeting CAR NK-cell therapy for patients with TCL.

Background: Bortezomib (Velcade), a mainstay of treatment regimens for newly diagnosed multiple myeloma (MM), is often dosed twice-weekly in trials (i.e., Days 1, 4, 8, 11 in 21-day cycles). However, several analyses have shown that once-weekly bortezomib performs comparably and is associated with less peripheral neuropathy (Sidana PLoS One 2017, Mateos L&L 2020, Cook AJH 2021). Many centers thus use once-weekly bortezomib in MM induction regimens regardless of transplant eligibility, e.g. modified VRd or Dara-VRd in 28-day cycles with once-weekly subcutaneous (SC) bortezomib 1.3 mg/m 2(McCaughan BJH 2022). Physician attitudes and perceptions regarding how bortezomib should be dosed, an important step toward establishing a global standard of care in MM, have not been investigated.

Introduction: CART-ddBCMA, an autologous anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy with a unique, synthetic binding domain, is being studied in a first-in-human clinical trial in patients (pts.) with relapsed &/or refractory multiple myeloma (RRMM). One-year or more follow-up clinical data from all patients are presented in this report.

Introduction: Most induction regimens for multiple myeloma (MM) contain bortezomib. In most clinical trials, bortezomib has been prescribed either intravenously or subcutaneously twice per week in 21-day or 28-day cycles. However, several retrospective single-center studies have shown that once-weekly bortezomib has comparable efficacy and less peripheral neuropathy compared to twice-weekly bortezomib ( Sidana et al, PLoS One 2017; Cook et al, AJH 2021). These findings have also been confirmed by a secondary analysis of data from three prospective Phase 3 randomized studies ( Mateos et al, Haematologica 2014). As such, many clinicians have adopted once-weekly bortezomib regimens in routine care in the past decade. However, the real-world (RW) prevalence and efficacy of once-weekly vs twice-weekly bortezomib regimens in a larger population have not yet been characterized.

Introduction:

Introduction:Approved BCMA-directed cellular therapies (BDCT) for multiple myeloma (MM) include chimeric antigen receptor T cell therapies (CART): idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), and T cell engagers (TCE) such as teclistamab (tec). Despite promising efficacy and safety profiles, limited access is a challenge since the first BDCT approval in 2021. We conducted this TACTUM-23 survey to gain insights into the practices and perspectives of oncologists from BDCT-referring and treating centers and identify potential areas of improvement.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, presenting with a highly variable clinical course, outcome and response to therapy. This variability has been linked to a complex tumor microenvironment and genetic/epigenetic modifications that lead to immunosuppression. Indeed, the clinical hallmark of this disease is the susceptibility to infections and secondary malignancies. While T cell dysfunction in CLL has been well described, conflicting information exists on NK cell changes in CLL and their role in CLL immunosurveillance. Here, we analyzed samples from 75 untreated (or completed treatment >2 years ago) CLL patients and 30 healthy controls. We discovered a substantial variation in NK cell function compared with healthy controls, which we further classified into hyperfunctional, normofunctional and dysfunctional based on their ability to degranulate, and produce IFN- γ in response to K562 targets ( Figure 1). NK cells from ‘dysfunctional’ CLL samples also displayed impaired cytotoxicity against K562 targets, weaker synapse formation and Syk/Zap70 signaling in response to antibody-dependent cellular cytotoxicity (ADCC) compared to those from ‘functional’ samples. The NK functional status was strongly associated with multiple prognostic markers, including cytogenetics, IgVH mutation status, ZAP-70 expression and disease stage, with patients with dysfunctional NK cells having significantly higher rates of secondary malignancies and viral infections ( Table 1). Using multispectral flow cytometry we discovered high phenotypic heterogeneity with unique NK cell clusters present in the dysfunctional samples. Those clusters express a pattern of activation-induced exhaustion, with upregulation of multiple checkpoint molecules such as PD-1, TIGIT, LAG-3, KLRG-1, TIM-3 but not evidence of terminal differentiation (CD57 negative). Those clusters also showed concomitant expression of activating molecules such as NKG2D and DNAM-1, suggesting reversibility of their dysfunctional status. We subsequently found significantly higher (p<0.0001) constitutive phosphorylation of SHP-1 protein, a phosphatase downstream of multiple inhibitory NK cell receptors, in NK cells from dysfunctional samples. Treatment with a SHP-1 inhibitor NSC-87877 (EMD Millipore) or use of siRNA targeting SHP-1 (ThermoFisher scientific), resulted in reversal of NK dysfunction with full restoration of their functional capacity. Taken together, our data suggest that NK cells functional status plays an important role in CLL disease progression and secondary complications. The novel mechanism of NK cell immune dysfunction in CLL described here has the potential to improve outcomes with novel immunotherapies such as chimeric antigen receptors, checkpoint inhibitors and bi-specific antibody therapy that have shown disappointing results in CLL to date when compared with other B cell malignancies.

Introduction:Teclistamab is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) with personalized, weight-based dosing for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM).In the MajesTEC-1 study (NCT03145181 and NCT04557098), the incidence of all grade (mostly grade 1 or 2) cytokine release syndrome (CRS) was 72.1% (Moreau et al. 2022). The cytokine interleukin-6 (IL-6) is found to be increased in the serum of patients with CRS (Shimabukuro-Vornhagen et al. 2018). Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody. As a competitive antagonist, tocilizumab inhibits the IL-6 pathway by competing with IL-6 for binding to IL-6 receptor (IL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6, thereby blocking IL-6 signaling. By blocking IL-6R, tocilizumab also reduces IL-6R-mediated IL-6 clearance, which leads to an increase in serum IL-6 levels (Uchiyama et al. 2008). It has been published previously that a single dose of prophylactic tocilizumab reduced the overall incidence of CRS to 26% after teclistamab administration, which represents a 64% reduction compared to the CRS incidence observed in MajesTEC-1 (van de Donk et al. 2023). A mechanism-based PK/PD model was used to evaluate the impact of tocilizumab prophylactic treatment on the soluble IL-6R (sIL-6R), IL-6 and the duration of the blockade of IL-6 signaling pathway in the patients following teclistamab treatment.

Background: Treatment options are limited for patients with relapsed multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) after CAR-T failure. While checkpoint inhibition may theoretically improve T-cell effector activity following CAR-T, a prospective trial of pembrolizumab (a monoclonal antibody targeting PD-1 on T-cells) following CD19 CAR-T in NHL showed an ORR of only 25% (Chong Blood 2022). In a recent multicenter NHL cohort (Major Blood Advances 2023), responses were similarly low with both pembrolizumab and nivolumab (nivo). However, nivo has not been studied prospectively in this setting, and the efficacy of checkpoint inhibition after CAR-T failure in MM has not been characterized.

Background: Understanding the treatment experience of patients (pts) with relapsed/refractory multiple myeloma (RRMM) is important to providing timely, appropriate supportive care. A multi-center trial (NCT05053607) is examining patient experience with isatuximab for treatment of RRMM, triangulating quantitative data from patient-reported outcomes (PRO) and wearable devices, along with qualitative data collected via individual interviews. Here we present outcomes from the qualitative data analysis, the aim of which was to describe experience with diagnosis and treatment, as well as the digital life coaching (DLC) intervention.

Background:Multiple myeloma (MM) treatments have grown more complex in the past 5 years, with several approved treatment options targeting B-cell maturation antigen (BCMA) and emerging data around soluble BCMA and sequencing BCMA-directed therapies. Understanding these new diagnostic and treatment paradigms is important to inform rational clinical decision making in MM. Video platforms such as YouTube and VuMedi can provide a convenient and costless method to deliver content, but their ability to reach and teach US physicians has not been studied extensively for MM. We investigated usage and pre/post survey data from viewers of a continuing medical education (CME) video activity about BCMA in MM, which was available on several online platforms.

Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Hari:GSK: Consultancy; Amgen: Consultancy; Incyte Corporation: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy. Htut:City of Hope Medical Center: Current Employment. Berdeja:CURIS: Research Funding; Constellation: Research Funding; Janssen: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Poseida: Research Funding; Kesios: Research Funding; EMD Sorono: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Acetylon: Research Funding; Prothena: Consultancy; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Cellularity: Research Funding; Lilly: Research Funding; Bluebird: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Bioclinica: Consultancy; Karyopharm: Consultancy. Madduri:Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; AbbVie: Consultancy, Honoraria. Usmani:Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Merck: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Crawford:RTI Health Solutions: Current Employment. Morrison:RTI Health Solutions: Current Employment. Doward:RTI Health Solutions: Current Employment. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.