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Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.

Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity.Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response.Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

SUPPLEMENTARY TABLES Supplementary Table 1. Treatment-emergent grade 3/4 adverse events in the safety population (n=116) Supplementary Table 2. MEDI3617 pharmacokinetic parameters Supplementary Table 3. Treatment outcome: objective response and progression-free survival, by cohort

Figure S1. Top: mRNA differential expression of individual proliferation genes (AURKA, CCNB1, MKI67, and MYBL2) and cancer invasion genes (CTSL2 and MMP11) and the bladder cancer marker, UPK3A, in biopsy samples (from patients with bladder cancer at pretreatment and after treatment at 5 mg/kg and 15 mg/kg. Bottom: Composite differential expression score from pretreatment and post-treatment tissues of proliferation, invasion, and bladder cancer markers in cohorts 5 mg/kg and 15 mg/kg.

Clinically effective CAR-T cell therapy for solid tumors, such as clear cell renal cell carcinoma (ccRCC), will require substantial T cell engineering to increase their specificity and potency. We have developed an Integrated Circuit T cell (ICT) that encodes multiple synthetic “modules” in order to overcome diverse barriers to efficacy in ccRCC; ICT cells are generated via CRISPR-mediated, targeted knock-in of a single large transgene into the novel GS94 safe-harbor locus. Both primary and metastatic sites of ccRCC are highly vascularized, with the majority of tumor cells expressing elevated levels of carbonic anhydrase IX (CA9), suggesting CA9 may be an excellent CAR target. However, CA9 is also expressed in healthy bile ducts and stomach tissue which has led to on-target, off-tumor toxicities in patients treated with constitutive CA9 CAR T cells. To improve the therapeutic index of CA9 CAR T cells, we developed an “AND” logic gated ICT cell that requires the presence of two antigens to trigger tumor cell killing, thereby enhancing tumor specificity. Induction of the CA9 CAR is gated on the expression of PSMA found on the tumor neovasculature of ccRCC. Importantly, PSMA and CA9 are not co-expressed in normal tissues. When the anti-PSMA priming receptor (PrimeRTM) binds PSMA, PrimeRTM engagement triggers proteolytic release of a chimeric, fully human transcription factor that induces expression of a CA9 CAR. We confirmed the feasibility of vascular priming using a transwell assay where ICTs were primed by a PSMA expressing endothelial cell line and then migrated across the transwell membrane to kill CA9 expressing RCC cells. In addition, a dual flank xenograft model was used to show logic gated circuits selectively kill tumors that express both CA9 and PSMA, and not tumors that express CA9 alone. Transforming growth factor beta (TGFb) is an immunosuppressive cytokine known to be highly expressed in ccRCC. To further increase the potency and persistence of the ICT cells an shRNA cassette was developed targeting both FAS and TGFBR2, a receptor required for TGFB signaling in T cells. Addition of FAS/TGFBR2 shRNA enhanced antitumor activity of PSMAxCA9 logic gate expressing T cells during in vitro chronic stimulation assays conducted in the presence of exogenous TGFb. Furthermore, FAS/TGFBR shRNA containing ICTs demonstrated enhanced antitumor activity in multiple xenograft RCC models. Collectively, these results demonstrate that PSMAxCA9 ICT cells can (i) selectively target antigens that cannot be safely targeted by conventional CARs and (ii) overcome multiple suppressive mechanisms in the tumor microenvironment. Citation Format: Angela C. Boroughs, Irene Scarfo, Nickolas Attanasio, Thomas Gardner, Jenessa B. Smith, Jennifer McDevitt, Laura Lim, Nishant Mehta, Suchismita Mohanty, James Zhang, Eric Cui, Vibhavari Sail, Amanda Fearon, Samuel Williams, Stephen Santoro, W. Nicholas Haining, Levi Gray-Rupp. A neovasculature-inducible CA9 CAR resistant to FASL and TGFb mediated suppression for the treatment of ccRCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4088.

Ecology, economy, equity. Exemplars, educators, enablers. Librarianship centres around the values ofcommunity-building, access to information, and advocating for the public good, and so librarians arepoised to be leaders when it comes to environmentally-friendly and sustainable practices and policies.Our commitment to intellectual freedom demands that we ensure facts about climate change reach thepublic, while social responsibility asks that we consider the harm that can be done by the spread ofdisinformation like climate change denial—the kind of harm that has led to the devastating, irreversiblecircumstances we’re in today. To ensure there will continue to be a community for libraries to serve,librarians must allow sustainability to underpin all their choices, especially with regard to educating thepublic, devaluing disinformation, and advocating for concrete collective action.

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

This participatory case study, which consisted of a co-designed virtual program through the Camrose Public Library, investigates how teen readers engage with the social justice themes in YA fiction, how and if they find these themes useful for understanding and engaging in activism on their own, and the influence of public library programming on these actions. I approached my research from a teen-centred perspective, inviting the youth who participated to make adjustments to each stage of the process. My research design, data collection, and data analysis were informed by critical ethnography as theory and reader-response theory. This case study found that, on their own, neither social activism narratives nor library programs motivate teens to conduct social justice actions; instead, they contribute to a network of learning opportunities and information that leads to teens becoming motivated to make a difference in their communities. Thus, public libraries can provide teen programming that uses social activism narratives and collaborative discussions to teach teens more about social justice issues, show them how to get involved in social justice movements, and instill in them the confidence to do so.

Since the practice of web archiving, or the act of preserving websites as historical, legal, and informational records, become more commonplace in the 2000s, web archives have become valuable sources for historical research. Unfortunately, many archived websites are of low quality and are missing crucial elements. In this paper, we examine the issue of quality and focus on visual correspondence, the similarity in appearance between the original website and its archived counterpart. We examine how the visual correspondence of an archived website can be measured using image similarity measures. Our results indicate that the Structural Similarity Index metric (SSIM) was able to successfully measure visual correspondence. If applied to the Quality Assurance process of an institution, this similarity metric could help web archivists quickly detect quality problems in their web archives, and fix them in order to create high-quality web archives. Depuis que la pratique de l'archivage Web, ou l'acte de préserver les sites Web en tant que documents historiques, juridiques et informatifs, est devenue plus courante dans les années 2000, les archives Web sont devenues des sources précieuses pour la recherche historique. Malheureusement, de nombreux sites Web archivés sont de mauvaise qualité et manquent d'éléments cruciaux. Dans cet article, nous examinons la question de la qualité et nous nous concentrons sur la correspondance visuelle, la similitude d'apparence entre le site Web d'origine et son homologue archivé. Nous examinons comment la correspondance visuelle d'un site Web archivé peut être mesurée à l'aide de mesures de similitude d'image. Nos résultats indiquent que la Structural Similarity Index metric (SSIM) a pu mesurer avec succès la correspondance visuelle. S'il est appliqué au processus d'assurance qualité d'une institution, cette indicateur de similitude pourrait aider les archivistes Web à détecter rapidement les problèmes de qualité dans leurs archives Web et à les résoudre afin de créer des archives Web de haute qualité.

In solid tumors, CAR T cell efficacy is limited by off-tumor toxicity, poor persistence, and suppression by the tumor microenvironment (TME). To address these challenges we have engineered AB-1015, an integrated circuit T cell (ICT cell) intended for the treatment of ovarian cancer. The AB-1015 transgene cassette encodes an “AND” logic gate designed to limit off-tumor toxicity through dual tumor antigen recognition and a dual shRNA-miR to resist TME suppression and improve ICT cell function and persistence. The AB-1015 DNA cassette is inserted into the T cell genome at a defined novel genomic site via CRISPR-based gene editing. The AB-1015 logic gate consists of a priming receptor that induces expression of an anti-mesothelin (MSLN) CAR upon engagement of a ALPG/P (alkaline phosphatase germ-line/placental). The dual-antigen specificity of the logic gate was assessed in mice engrafted with MSLN+ and ALPG/P+MSLN+ K562 tumors established on contralateral flanks. AB-1015 ICT cells eliminated ALPG/P+MSLN+ tumors, while sparing tumors that lacked ALPG/P. To assess the ability of AB-1015 to mediate killing of MSLN+ tumor cells in the context of heterogeneous cultures, we utilized an admixed co-culture system where ALPG/P+ target cells were spiked into cultures that were otherwise MSLN+. AB-1015 was able to eliminate admixed co-cultures where as few as 5-15% of the target cells expressed ALPG/P.The AB-1015 also contains a dual shRNA-miR that targets FAS and PTPN2, two critical mediators of T cells survival and function. FASL, the cognate ligand for FAS receptor, is expressed on the surface of activated T cells and is significantly overexpressed in the ovarian cancer TME. In vitro, AB-1015 demonstrated resistance to FAS-mediated apoptosis. Knockdown of PTPN2, a phosphatase involved in T cell proliferation and functional persistence, resulted in enhanced AB-1015 ICT cell expansion during repetitive stimulation over a period of 14 days, as well as a 30-fold reduction in tumor outgrowth compared with logic gated T cells alone. In summary, AB-1015 ICT cells are specific for ALPG/P+MSLN+, demonstrate superior potency, expansion, and persistence compared with logic gated T cells alone, and are resistant to ovarian TME suppression. These results support further evaluation of AB-1015 as a novel therapy for indications including ovarian, fallopian tube, or primary peritoneal cancer. Citation Format: Stephen Santoro, Aaron Cooper, Natalie Bezman, Jun Feng, Kanika Chawla, Jennifer McDevitt, Tarjei Mikkelsen, Susie Jun, W. Nicholas Haining. AB-1015, a novel integrated circuit T cells containing an ALPG/MSLN logic gate and FAS/PTPN2 shRNA-miR, demonstrates specific and potent activity against ALPG/MSLN tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 585.

2529 Background: Allogeneic CAR T cell therapy addresses logistical/manufacturing challenges inherent in autologous (auto) CAR T therapy. ALLO-501A, which uses Cellectis technologies, is an allogeneic anti-CD19 CAR T cell product whose a) disrupted TCRα gene may reduce GvHD risk, and b) edited CD52 gene may permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells. Methods: The ongoing ALPHA2 study is a single-arm, open-label, 2 phase study of ALLO-501A in non-HLA matched patients (pts) with R/R LBCL and ≥2 prior lines of therapy. Prior auto CD19 CAR T therapy is allowed if tumors remain CD19+. Following lymphodepletion (LD) with ALLO-647 (60 mg or 90 mg), fludarabine 30 mg/m2/d x 3d (Flu), and cyclophosphamide 300 mg/m2/d x 3d (Cy), escalating doses of ALLO-501A (40 [DL1] or 120 [DL2] x 106 viable CAR T cells) were administered. Retreatment was allowed for PD or SD with suboptimal CAR T expansion. Pts who had ≥SD at D28 could receive a second dose in a consolidation cohort. Phase 1 assessed safety/tolerability and cell kinetics of escalating doses of ALLO-501A following LD. Results: By 1/15/21, 11/11 enrolled pts received ALLO-647 (60 mg: n=6; 90 mg: n=5). Mean duration from enrollment to start of therapy was 6 days. After LD, 1 and 9 pt(s) were treated with ALLO-501A at DL1 and DL2, respectively; 1 pt developed CNS lymphoma and was not treated. Of 10 pts treated, 1 pt received retreatment and 4 pts were enrolled in the consolidation cohort. Pts had a median age of 60 years; 8 were ≥ stage III at diagnosis, 5 had IPI scores ≥3, and 3 had baseline LDH > 2x ULN. Median number of prior therapies was 3 (range 2 – 7); 3 pts had received auto CD19 CAR T cell therapy. 4/8 evaluable pts had rapidly PD at study entry. Median FU was 1.7 months. No dose modifications were required and no pt experienced DLTs. The most common AEs were anemia, leukopenia, neutropenia and thrombocytopenia (73%); and lymphopenia (64%). No GvHD or ICANS were reported. CRS was seen in 2 (18%) pts, both Grade < 3. Infusion-related reactions, all grade

Introduction MEDI-565, a bispecific, single-chain antibody targeting human carcinoembryonic antigen on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex, showed antitumor activity in carcinoembryonic antigen-expressing tumors in murine models. Patients and Methods This phase I, multicenter, open-label dose escalation study enrolled adults with gastrointestinal adenocarcinomas. MEDI-565 was given intravenously over 3 hours on days 1 through 5 in 28-day cycles, with 4 single-patient (0.75-20 μg) and 5 standard 3 + 3 escalation (60 μg-3 mg; 1.5-7.5 mg with dexamethasone) cohorts. Primary objective was determining maximum tolerated dose; secondary objectives were evaluating pharmacokinetics, antidrug antibodies, and antitumor activity. Results Thirty-nine patients were enrolled (mean age, 59 years; 56% male; 72% colorectal cancer). Four patients experienced dose-limiting toxicities (2 at 3 mg; 2 at 7.5 mg + dexamethasone): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Five patients reported grade 3 treatment-related adverse events: diarrhea, CRS, increased alanine aminotransferase, hypertension (all, n = 1), and hypoxia (n = 2); 6 experienced treatment-related serious adverse events: diarrhea, vomiting, pyrexia, CRS (all, n = 1), and hypoxia (n = 2). MEDI-565 pharmacokinetics was linear and dose-proportional, with fast clearance and short half-life. Nineteen patients (48.7%) had antidrug antibodies; 5 (12.8%) had high titers, 2 with decreased MEDI-565 concentrations. No objective responses occurred; 11 (28%) had stable disease as best response. Conclusions The maximum tolerated dose of MEDI-565 in this patient population was 5 mg administered over 3 hours on days 1 through 5 every 28 days, with dexamethasone. Pharmacokinetics were linear. No objective responses were observed.

8002 Background: Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges and variable product quality of autologous CAR T therapy. ALLO-501 is a genetically modified anti-CD19 CAR T cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion. Methods: This is an open-label, Phase 1 trial (NCT03939026) in adults with R/R LBCL/FL who have received ≥ 2 prior lines of therapy; prior anti-CD19 cell therapy is allowed. Patients (pts) receive fludarabine (flu) 90 mg/m2, cyclophosphamide (cy) 900 mg/m2, and ALLO-647 39 or 90 mg followed by ALLO-501 at 1 of 3 dose levels (DL) in a 3+3 design: 40, 120, and 360 × 106 CAR+ T cells. Results: As of 20 January 2020, 12 pts were enrolled: 9 received ALLO-501 at 3 DLs (4, 4 & 1 pts in DL1, DL2 and DL3 respectively), 1 pt discontinued due to kidney injury prior to lymphodepletion and 2 are starting treatment. Of the 9 treated pts aged 42 to 70 years: 5 had LBCL, 2 were female, 3 had primary refractory disease, and 3 had prior autologous stem cell transplants. The median number of prior lines of therapies was 3 (range 2 to 4). All treated pts received 39 mg of ALLO-647. No DLTs or GvHD have been observed to date. Most common Grade (Gr) ≥ 3 adverse events were neutropenia (55.6%), leukopenia (33.3%) and anemia (22.2%). Two pts (22.2%) developed cytokine release syndrome (1 Gr1 and 1 Gr2) that resolved within 72 hrs without steroids or tocilizumab. One pt developed Gr1 neurotoxicity that resolved without treatment. Infections included upper respiratory tract infection (Gr2), CMV (Gr3) and EBV viremia (Gr1), all reported in a single pt and resolved. One pt had a Gr2 infusion reaction to ALLO-647 which resolved with antihistamines. The overall response rate is 78% (95% exact CI: 40%, 97%): 3 complete and 4 partial responses. With a median follow up of 2.7 mos, 4 pts have ongoing responses and 3 pts progressed at 2, 4 and 6 mos. ALLO-501 cell expansion by qPCR was observed in 4 of 6 pts in varying degrees. Conclusions: These early data suggest that ALLO-501 and ALLO-647 have a manageable safety profile. ALLO-647 may be an effective and selective lymphodepleting agent with CD52 gene editing, and ALLO-501 shows evidence of clinical activity in pts with advanced NHL. Enrollment is ongoing, and updated safety, efficacy, PK/PD data will be presented including pts treated with increasing doses of ALLO-647. Clinical trial information: NCT03939026 .

Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy. Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed. Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively. Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.

Tumors evolve to modulate metabolism to promote their own survival and to suppress tumor-specific immunity. Hypoxic conditions in the tumor microenvironment (TME) induce fatty acid oxidation (FAO), and diverse malignancies are reliant on this metabolic pathway. Additionally, suppressive immune cell populations including M2 macrophages, myeloid-derived suppressor cells and regulatory T cells preferentially utilize FAO. Peroxisome proliferator-activated receptor alpha (PPARα) is the principal transcription factor that regulates the expression of FAO genes, and this metabolic checkpoint is critical for tumor proliferation. TPST1120 is a first-in-class selective competitive antagonist of the human PPARα. To test the hypothesis that blocking FAO with TPST-1120 confers anti-tumor efficacy, we assessed TPST-1120 in multiple syngeneic and xenograft mouse models. Blockade of PPARα with TPST-1120 mediated potent anti-tumor immune responses and significant tumor regression in syngeneic models of breast, lung, colon, pancreatic and melanoma in addition to xenograft models of CLL, AML, pancreatic and melanoma cancers as a monotherapy or in combination with chemotherapy. In pancreatic and breast cancer models, TPST-1120 augmented regression of tumor growth in combination with chemotherapy. In combination with anti-PD1, TPST-1120 treatment resulted in significant reduction of tumor growth in ovarian orthotopic (ID8) and colon (MC38) models; cured mice were completely protected against autologous tumor challenge, strongly suggesting immunological T cell memory against the primary tumor. Studies in genetic knock-out mice indicated that macrophages and antigen cross-presenting dendritic cells are required for TPST-1120 activity, mediated through thrombospondin-1(TSP-1) and stimulator of interferon genes (STING). Consistent with prior reports, inhibition of PPARα with TPST-1120 skewed macrophages in vivo toward an M1 effector phenotype. These results provide the rationale for evaluating TPST-1120 in patients with advanced malignancies. A Phase 1/1b open-label, dose-escalation and dose-expansion study of TPST-1120 as a single agent or in combination with systemic anti-cancer therapies is planned in early 2019. Citation Format: Chan C. Whiting, Nick Stock, Davorka Messmer, Traci Olafson, Derek Metzger, Amanda Enstrom, Jennifer McDevitt, David Spaner, Peppi Prasit, Dipak Panigrahy, Ginna Laport. Blockade of the PPARα metabolic checkpoint with TPST-1120 suppresses tumor growth and stimulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3606.

Background: The anti-PD-L1 antibody durvalumab (D) has shown manageable safety and encouraging clinical activity in patients with advanced NSCLC. Combination of D with anti-CTLA-4 antibody tremelimumab (T) may amplify T-cell responses against tumors through non-redundant immune checkpoint blockade and provide synergistic antitumor activity. We previously reported that D+T showed antitumor activity and manageable tolerability in the dose-escalation part of a phase 1b study (NCT02000947) of patients with advanced NSCLC. Here we present safety, clinical activity, and long-term follow-up for one of 3 expansion cohorts. Methods: Immunotherapy-naive patients with non-squamous NSCLC who progressed after 1 prior platinum-based therapy, ECOG PS 0-1, received D IV 20 mg/kg every 4 weeks (Q4W) for up to 12 months and T IV 1 mg/kg Q4W with the first 4 cycles of D. Tumor PD-L1 expression (fresh biopsy or archival sample within 3 mo) was assessed with the Ventana PD-L1 (SP263) assay, PD-L1 cutoff: ≥25% of tumor cells with membrane staining. Results: As of 20 Oct 2017, 213 patients (71% ECOG PS 1) received therapy and were followed for a median of 13.3 (0.5-21.0) mo. Treatment-related adverse events (AEs) were reported in 76% of patients; the most common were fatigue (19%), pruritus (17%), diarrhea (15%), decreased appetite (14%), and rash (14%). 14 patients (7%) had a treatment-related AE leading to discontinuation, with colitis (1%), diarrhea (1%), and pneumonitis (1%) reported in more than 1 patient. Grade 3/4 treatment-related AEs occurred in 23% of patients; the most common were increased lipase (5%), colitis (3%), and increased amylase (3%). There was 1 treatment-related death (multifactorial hypoxia). The 12-month OS rate was 53.8% (95% CI, 46.4-60.6). The Table shows antitumor activity and survival by PD-L1 status. Conclusions: Second-line D+T had a manageable safety profile in patients with non-squamous NSCLC. Clinical activity was seen in both PD-L1 ≥25% and Response and survivalPD-L1 ≥25% n=57PD-L1 Citation Format: Jamie Chaft, Byoung Chul Cho, Myung-Ju Ahn, Sylvestre Le Moulec, Eun Kyung Cho, Vassiliki Papadimitrakopoulou, Edward Garon, Sylvia Lee, Santiago Ponce Aix, Patrick C. Ma, Gregory Otterson, Rajesh Narwal, Guozhi Gao, Jennifer McDevitt, Judson Englert, Scott Antonia. Safety and activity of second-line durvalumab + tremelimumab in non-squamous advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT113.

4031Background: The combination of durvalumab (D; anti–PD-L1) and tremelimumab (T; anti–CTLA-4) has the potential to amplify T-cell responses against tumors through immune checkpoint blockade, resu...

TPS3100 Background: Recent advances in treatment of solid tumors include single or combined use of monoclonal antibodies (mAbs) against the immune checkpoints CTLA-4 or PD-1/PD-L1 that can reactivate antitumor cytotoxic tumor-infiltrating lymphocytes (TILs) and significantly improve OS (Menon S, et al. Cancers (Basel). 2016;8:E106.) (Antonia S, et al. Lancet Oncol. 2016; 17:299-308). Activation of TILs via the costimulatory OX40 (CD134) molecule, may offer an alternative and non-redundant pathway for increasing antitumor immunity. OX40 costimulation promotes effector T cell expansion and longevity, overcomes regulatory T cell suppression and provides survival benefit in animal models of tumor challenge (Linch SN, et al. Front Oncol. 2015;5:34). MEDI0562 is an investigational, humanized IgG1κ anti-OX40 mAb that triggers OX40 signaling. Coadministration of an OX40 agonist and either a CTLA-4 or PD-1/PD-L1 pathway inhibitor may promote synergistic effects against certain solid tumors and may be tolerable administered in combination. Methods: A Phase 1, multicenter, open-label study (NCT02705482) is underway to evaluate safety (primary endpoint), pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity (secondary endpoints) of MEDI0562 in combination with either anti-PD-L1 mAb durvalumab or anti-CTLA-4 mAb tremelimumab in adult subjects with previously treated advanced solid tumors. Subjects with primary CNS tumors and hematologic malignancies are excluded. The study includes a dose escalation and expansion phase, with 2 treatment arms in each: MEDI0562/durvalumab combination (Arm A) and MEDI0562/tremelimumab combination (Arm B). Safety assessments include AEs, serious AEs, dose-limiting toxicities, abnormal laboratory parameters, vital signs, and electrocardiogram results. Antitumor efficacy will be assessed as OR, disease control, duration of response, PFS, and OS using RECIST Version 1.1. Subjects will remain on treatment until unacceptable toxicity, progressive disease or other reasons for discontinuation. Clinical trial information: NCT02705482.

Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.

TPS6083 Background: Co-stimulatory signals delivered via binding to OX40 on T cells increase T-cell survival, proliferation, and effector function, and result in the generation of long-lived memory...

TPS3091 Background: Anti-CTLA-4 and anti-PD-1/PD-L1 have shown antitumor activity in 10–30% of patients (pts) with select tumors. Combinations of co-stimulatory agonists, such as OX40, and antagoni...

3012 Background: MEDI3617 (M) is an investigational monoclonal antibody that inhibits angiogenesis by preventing the interaction of angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: Th...

TPS2621 Background: MEDI3617 is an investigational monoclonal antibody that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an ongoing phase 1 dose-escalation and dose-expansion study in patients with advanced solid tumors, Karnofsky performance status ≥70, and adequate organ function. Patients were treated with escalating IV doses of MEDI3617 on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are to evaluate the safety profile and determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and clinical activity of MEDI3617. Results: Preliminary data are presented for 21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT occurred: grade 4 neutropenia lasting more than 7 days. The most frequently reported drug-related adverse events (% of patients) were fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and headache (14%), all of which were ≤ grade 2. All monotherapy dose levels have completely enrolled patients without exceeding the maximum tolerated dose. The exposure of MEDI3617 after the first dose showed a more than dose-proportional increase. Suppression of free Ang2 was dose-dependent. Maximum accumulation of total Ang2 was observed at the lowest administered dose. No anti-MEDI3617 neutralizing antibodies were detected. Of the 21 patients, 4 continue on treatment (maximum of 6+ months in a patient with carcinoid tumor of the jejunum) as of the data cut-off date. Of the 17 patients for whom response data are available, 5 had stabilization of disease of 12 weeks or greater. Conclusions: Preliminary safety and activity signals warrant continued evaluation of MEDI3617. This study was funded by MedImmune, LLC.

Abstract 3246 Although most children and adolescents with ALL are cured, treatment-associated side effects are significant and outcome after relapse is poor. New therapies are needed to overcome drug resistance and reduce toxicities of chemotherapy. CD22 is a B-lymphoid differentiation antigen expressed on most B-lineage ALL blasts. We recently conducted a Phase I trial of the anti-CD22 immunotoxin RFB4(dsFv)-PE38 (CAT-3888 or BL22) in children with ALL or non-Hodgkin lymphoma (NHL). The safety profile was acceptable and transient clinical activity was seen; however, no objective responses were observed (Clin Cancer Res 2010;16:1894). We are conducting a Phase I trial of a modified agent with higher CD22 binding affinity (moxetumomab pasudotox, also known as CAT-8015 or HA22). Methods: Patients 6 months to 24 years of age with relapsed or refractory CD22+ B-lineage ALL or NHL are eligible for enrollment. Moxetumomab pasudotox is being administered at doses of 5, 10, 20, or 30 μg/kg every other day for 6 doses, every 21 days for up to 6 cycles. All patients receive pre-medication with acetaminophen, ranitidine, and diphenhydramine and prophylaxis for central-nervous-system leukemia with intrathecal hydrocortisone, cytarabine, and methotrexate. An initial completed cohort (A) consisted of one patient each treated at the first 3 dose levels (5, 10, 20 μg/kg) followed by standard 3+3 dose escalation commencing at 30 μg/kg. In attempt to reduce the incidence of vascular leak syndrome (VLS), a second ongoing cohort (B) is also receiving dexamethasone 2.5 mg/m2 every 12 hours around doses of moxetumomab pasudotox during cycle 1 with standard 3+3 dose escalation commencing at 20 μg/kg. Results: At the time of reporting, 14 patients 5 to 22 years of age (median, 11) with ALL (13 precursor-B, 1 mature B-cell) have been treated in the clinical trial. Patients had received a median of 4 prior regimens (range, 2–8), 12 were chemotherapy refractory, and 7 had received prior stem cell transplantation. Thirteen had leukemia-associated baseline cytopenias and thus were not evaluable for hematologic toxicities. The most common adverse events observed to date have been hyperbilirubinemia, transaminase elevations, hypoalbuminemia, elevated creatinine, febrile neutropenia, hypertension, microscopic proteinuria, hemoglobinuria, hypoxia, and pleural effusion. Two of 7 patients in Cohort A treated at 30 μg/kg experienced Grade 3 and Grade 4 VLS. None of 7 patients treated in Cohort B developed VLS. All toxicities attributed to moxetumomab pasudotox were reversible. Twelve patients were evaluable for response: 3 (25%) achieved complete remission by morphology and flow cytometry after 1, 1, and 2 cycles, respectively; 5 (42%) had hematologic activity (blood count improvement, blast reduction); and 3 (25%) had stable disease. One patient treated at the lowest dose level had progressive disease. Two patients developed high-titer neutralizing antibodies. Conclusions: Moxetumomab pasudotox has shown clinical activity against chemotherapy-refractory pediatric ALL, with complete remissions achieved in 3 of 12 patients. The demonstration of clinical activity and the safety profile exhibited by this agent to date support further study in ALL. ClinicalTrials.gov Identifier: NCT00659425 This study was sponsored by MedImmune, LLC. Disclosures: Off Label Use: Moxetumomab pasudotox is an investigational agent. Bhojwani:MedImmune: Research Funding. Silverman:Enzon: Consultancy, Honoraria; EUSA: Consultancy, Honoraria. Jeha:Genzyme: Honoraria, Research Funding. Pui:EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria. McDevitt:MedImmune, LLC: Employment. FitzGerald:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Kreitman:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Lechleider:MedImmune, LLC: Employment. Pastan:NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties.

6523 Background: CAT-8015 (HA22) contains the Fv domains of the anti-CD22 Mab RFB4 and truncated pseudomonas exotoxin, inducing cell death after binding, internalization, and ADP-ribosylation of elongation factor 2. CAT-8015 is a high-affinity mutant of BL22 (CAT-3888), with increased cytotoxicity toward chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) cells ex vivo. Methods: To determine the clinical activity of CAT-8015, separate phase I trials were initiated in CLL, HCL, and non-Hodgkin lymphoma, and the HCL trial completed accrual. Eligible patients had several prior therapies including purine analogs and needed treatment for cytopenias or symptoms. CAT-8015 was administered over 30 min iv days 1, 3 and 5 (QODx3) at 28-day intervals for up to 10 cycles. Results: 28 HCL patients received CAT-8015: 3 each at 5, 10, 20, and 30 ug/kg QODx3, 4 at 40 and 12 at 50 ug/kg QODx3. Patients had 2-7 (median 3) prior therapies. Patients received 1-9 (median 4) cycles of CAT-8015 each. Dose-limiting ...

Abstract 839 Although most children with ALL are cured, treatment is associated with multiple toxicities and outcome after relapse is poor. New therapies are needed to overcome drug resistance and reduce non-specific toxicities of chemotherapy. CD22 is a B-lineage differentiation antigen expressed on most B-lineage ALL blasts. The anti-CD22 immunotoxin RFB4(dsFv)-PE38 CAT-3888 (BL22) was recently shown to have clinical activity with an acceptable safety profile in children with ALL (Blood 2007;110:262a). We undertook a Phase I trial of a modified agent with higher CD22 binding affinity (CAT-8015 or HA22). Methods: Patients 6 months to 24 years of age with relapsed or refractory CD22 + B-lineage ALL or non-Hodgkin lymphoma were eligible for enrollment into this Phase I trial. CAT-8015 was administered at doses of 5, 10, 20, or 30 mcg/kg every-other-day for 6 doses every 21 days for up to 6 cycles. One patient was enrolled at each of the first 3 dose levels (5, 10, 20 mcg/kg) with standard 3+3 dose escalation commencing at 30 mcg/kg. All patients received acetaminophen, ranitidine and diphenhydramine to mitigate infusion-related symptoms, and prophylaxis for central-nervous-system leukemia with intrathecal hydrocortisone, cytarabine and methotrexate. Patients at high risk for tumor lysis syndrome received standard prophylaxis. Results: Seven patients with ALL (6 precursor-B, 1 mature B-cell) 5 to 17 years of age (median, 10) were treated on the clinical trial. All patients had been heavily pre-treated and had baseline cytopenias due to active malignancy and thus were not evaluable for hematologic toxicities. The most common adverse events observed to date have been hyperbilirubinemia, transaminase elevations, hypoalbuminemia, elevated creatinine, febrile neutropenia, abdominal pain, pyrexia, hypertension, microscopic proteinuria, hemoglobinuria, hypoxia and pleural effusion. Two of 4 patients treated at 30 mcg/kg experienced Grade 3 or greater toxicity consistent with capillary leak: 1 with Grade 3 pleural effusion and hypoxia and 1 with Grade 4 vascular leak syndrome. All toxicities attributed to CAT-8015 were reversible. Clinical activity was demonstrated in 4 of 7 subjects. One patient treated at 10 mcg/kg had a complete remission by morphology and flow cytometry. Three patients met the protocol definition for hematologic activity (blood count improvement). One of these patients developed high-titer neutralizing antibodies. Two patients met the protocol definition for stable disease. The patient treated at the lowest dose level had progressive disease. Conclusions: CAT-8015 appears to be active against chemotherapy-refractory ALL. Strategies to predict and/or prevent vascular leak syndrome are currently being developed. Disclosures: No relevant conflicts of interest to declare.