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Background: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma., Methods: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 10 6 CAR T cells, 150 × 10 6 CAR T cells, 300 × 10 6 CAR T cells, and 450 × 10 6 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals., Findings: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 10 6 CAR + cells, and the recommended phase 2 dose was not reached., Interpretations: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials., Funding: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health., Competing Interests: Declaration of interest AJC receives research funding from Juno Therapeutics—a Bristol Myers Squibb company, Nektar, Janssen, Abbvie, Harpoon, Sanofi, Adaptive Biotechologies, and Celgene; is a consultant for Adaptive Biotechnologies, Bristol Myers Squibb, and Abbvie; and receives payment for presentations from Curio Science, DAVA Oncology, and MJH Life Sciences. XS receives research funding from Juno Therapeutics—a Bristol Myers Squibb company. MJP is a consultant for SpringWorks Therapeutics, owns stock or has stock options in Lyell Immunopharma, and is currently employed by CellPoint. CJT receives research funding from Bristol Myers Squibb; has right to receive payments from royalties for inventions licensed to third parties, including Bristol Myers Squibb; is a consultant for Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal Bio, Century Therapeutics, Allogene, Legend Bio, Nektar, Syncopation Life Sciences, Sobi, Expert Connect, Decheng Capital, Asher Bio, Genentech, and Amgen; has received payment for presentations from St Judes, Malaysian Society for Hematology, Japan Society for Transplantation and Cell Therapy, and Bristol Myers Squibb; and has stock or stock options in Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal bio, and Eureka Therapeutics. BGT receives research funding from Bristol Myers Squibb; royalties from Mustang Bio; has patents with Mustang Bio; participates on a data safety monitoring board with Mustang Bio and Proteios Technology; and has stock or stock options with Proteios Technology. ENL has research funding from GSK, Celgene, Amgen, Genentech, Beigene, and Seattle Genetics and has received payment for presentations from Curio Science, Janssen, and Pharmacyclics. SAT has stock or stock options in Bristol Myers Squibb and is a current employee of Juno Therapeutics—a Bristol Myers Squibb company. BW has research funding from Amgen, Novartis, Kite, Beam, Wugen, and Biosight and receives payment for lectures from Amgen. MS receives research funding from Mustang Bio, Bristol Myers Squibb, Pharmacyclics, Genentech, Abbvie, TG Therapeutics, BeiGene, AstraZeneca, Genmab, Morphosys, Incyte, and Vincerx; is a consultant for AbbVie, Genentech, AstraZeneca, Pharmacyclices, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma; and receives payment for presentations from AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma. JG receives research funding from Sobi, Juno Therapeutics— a Bristol Myers Squibb company, Celgene—a Bristol Myers Squibb company, and Angiocrine Bioscience; is a consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, and MorphoSys;, and is on an advisory board for Century Therapeutics. DGM receives research funding from Kite Pharma, Juno Therapeutics—a Bristol Myers Squibb company, Celgene, Legend Biotech, and Bristol Myers Squibb; is a consultant for A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, Bristol Myers Squibb, ImmmPACT Bio, and Gilead Sciences; has rights to royalties for patents licensed to Juno Therapeutics—a Bristol Myers Squibb company; serves as an advisory board member for Bristol Myers Squibb, Caribou Biosciences, Celgene, Genentech, Incyte, Janssen, Juno Therapeutics—a Bristol Myers Squibb company, Mustang Bio, Morphosys, Kite, Lilly, Novartis, and Umoja; and has stocks or stock options in A2 Biotherapeutics and Navan Technologies. SRR has research funding from the National Institutes of Health, Leukemia and Lymphoma Society, Juno Therapeutics—a Bristol Myers Squibb company, Lyelle Immunopharma, and Outpace Biosciences; has rights to royalties from Juno Therapeutics—a Bristol Myers Squibb company, Lyell Immunopharma, Deverra Therapeutics; is a consultant from Lyell Immunopharma and Adaptive Biotechnologies; has patents from Juno Therapeutics—a Bristol Myers Squibb company and Lyell Immunopharma; serves on a board of directors for Ozette Technologies; and has stocks or stock options from Lyell Immunopharma and Adaptive Biotechnologies. DJG held the sponsor-investigator investigational new drug application from the US Food and Drug Administration for this study; has obtained grants or contracts through Fred Hutchinson Cancer Center with Juno Therapeutics—a Bristol Myers Squibb company, Seattle Genetics, Janssen Biotech, SpringWorks Therapeutics, Cellectar Biosciences, The Allen Institute for Immunology, The Leukemia and Lymphoma Society, and the National Institutes of Health; is in consulting agreements with Ensoma; has served on an advisory board for GSK, Janssen Biotech, Legend Biotech, and Celgene; and has two US provisional patent applications (62/582,270 and 62/582,308) through Fred Hutchinson Cancer Center and Juno Therapeutics—a Bristol Myers Squibb company. BDS, DGC, TG, JV, VQW, AGC, and FM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.

Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH)., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/ relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment. We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission. We evaluated the effect of consolidative HCT on LFS in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (ClinicalTrials.gov identifier NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled in PLAT-02 phase 1 and early phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed, or died before day 63 post-CAR T cell therapy. An improved LFS (P = .01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend toward significance (P = .09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of prior HCT (P = .45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P = .01). These data support the use of consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT and those with short functional CAR T cell persistence., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

CD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities of cytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 years after treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, global physical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored ≤40 in global mental health, indicating at least 1 standard deviation worse than the general population mean. Younger age was associated with worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR T cell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients (37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statistically significantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there was a trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08). Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physical health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T cell therapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likely benefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition., Experimental Design: A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo ., Results: The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR + targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen., Conclusions: DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape., (©2019 American Association for Cancer Research.)