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Abstract: We report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients than in both cytopenic and noncytopenic cohorts of CAR-19-treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.)., (Copyright © 2024 Massachusetts Medical Society.)

Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care. This review includes clinical and toxicity management guidelines pertaining to the TIL cell therapy regimen prepared by the TIL Working Group, composed of internationally recognized hematologists and oncologists with expertize in TIL cell therapy, and relates to patient care and operational aspects. Expert consensus recommendations for patient management, including patient eligibility, screening tests, and clinical and toxicity management with TIL cell therapy, including tumor tissue procurement surgery, non-myeloablative lymphodepletion, TIL infusion, and IL-2 administration, are discussed in the context of potential standard of care TIL use. These recommendations provide practical guidelines for optimal clinical management during administration of the TIL cell therapy regimen, and recognition of subsequent management of toxicities. These guidelines are focused on multidisciplinary teams of physicians, nurses, and stakeholders involved in the care of these patients., Competing Interests: Competing interests: ABW reports receiving assistance with medical writing only from Iovance Biotherapeutics; consulting fees from Bristol Myers Squibb, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Novartis, and Pfizer; and travel support from Iovance Biotherapeutics. OH reports receiving honoraria and has consulting or advisory role with Aduro, Akeso, Alkermes, Amgen, BeiGene, BioAtla, Bristol-Myers Squibb, Roche Genentech, GlaxoSmithKline, Immunocore, Idera, Incyte, InstilBio, Iovance Biotherapeutics, Janssen, Merck, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seagen, Tempus, and Zelluna; research funding from Arcus, Aduro, Akeso, Amgen, BioAtla, Bristol-Myers Squibb, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance Biotherapeutics, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Rubius, Sanofi-Regeneron, and Seagen; and is on the speaker’s bureau for Bristol-Myers Squibb, Novartis, Pfizer, and Sanofi Regeneron. KK reports ad hoc consulting for Incyte, Iovance, CRISPR Therapeutics, Cargo Therapeutics, Genentech/Roche, Rigel, Allogene, Sanofi, Janssen; and serves on the Clinical Advisory Board for OptumHealth; and is a Scientific advisory board member, equity: Aegle Therapeutics, Avacta TherapeuticsRNA reports consulting for Novartis and Erasca; grants/contracts from Roche, Obsidian, and Onkure; and participation in data safety monitoring board/advisory board for Erasca and Novartis. MOB reports receiving funding for clinical trial from Merck, Takara Bio; funding for quality improvement project from Novartis; is on advisory board for Bristol Myers Squibb, Merck, Novartis, Adaptimmune, Immunocore, GlaxoSmithKline, Sanofi, Sun Pharma, Instil Bio, Iovance Biotherapeutics, Pfizer, Medison, LaRoche Possey, and Regeneron; is on safety review committee of Adaptimmune and GlaxoSmithKline; and receiving honoraria from Sanofi, Bristol Myers Squibb, Merck, and Novartis. JH received compensation for advisory roles for Achilles Therapeutics, AstraZeneca, BioNTech, Bristol Myers Squibb, CureVac, Gadeta, Imcyse, Immunocore, Iovance Biotherapeutics, Instil Bio, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, Seattle Genetics, Third Rock Ventures, and T-Knife; and has received grants from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, and Sastra Cell Therapy. SN reports ad hoc advisory board representation for Kite/Gilead, GlaxoSmithKline, Iovance, SmartImmune, A2 Bio, and Sobi, and honoraria from Oncologia Clinica Brazil, Stamford Hospital, CT, Mass Assoc of Blood Bankers, and AcCELLerate meeting. IP owns stock in Ideaya, Inc; research funding from NIH/NCI P30CA016056, Cancer Center Support Grant, Program Leader, 1.2 Calendar Months; and has consulted for Nouscom, Iovance, Nektar, and Regeneron. ASarnaik is a co-inventor on a patent application with Provectus Biopharmaceuticals. Moffitt Cancer Center has licensed Intellectual Property (IP) related to the proliferation and expansion of tumor infiltrating lymphocytes (TILs) to Iovance Biotherapeutics. ASarnaik is a coinventor on such Intellectual Property. ASarnaik has received Ad hoc consulting fees from Iovance Biotherapeutics, Guidepoint, Defined Health, Boxer Capital, Huron Consulting Group, KeyQuest Health Inc, Istari, Rising Tide, Second City Science, Market Access, and Gerson Lehrman Group. ASchoenfeld has received speaker fees from the Society for Immunotherapy of Cancer, Physicians’ Educational Resource (PER), Medscape, WebMD, and Medstar Health. Research funding and other support from Iovance Biotherapeutics, Provectus, Prometheus and Bristol Myers Squibb. MRB Membership on a Advisory Board or Consultant: KITE/Gilead, Novartis, BMS, CRISPR Therapeutics, OptumHealth, Autolus, In8bio, Sana Biotechnology, Chimeric Therapeutics, Arcellx, Achieve ClinicsHonoraria: BMS, Kite/Gilead, Novartis, Agios, Incyte, Servier, Sanofi, ADC TherapeuticsSpeakers Bureau: BMS, Kite/Gilead, Agios, Incyte, Servier, Sanofi, ADC TherapeuticsAJS reports consulting/advising role and participation in a Data Safety Monitoring Board or Advisory Board with Johnson & Johnson, KSQ therapeutics, Bristol Myers Squibb, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Lyell Immunopharma, Amgen, and Heat Biologics; research funding from GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst), and Amgen (Inst)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cancer is one of the most devastating complications of kidney transplantation and constitutes one of the leading causes of morbidity and mortality among solid organ transplantation (SOT) recipients. Immunosuppression, although effective in preventing allograft rejection, inherently inhibits immune surveillance against oncogenic viral infections and malignancy. Adoptive cell therapy, particularly immune effector cell therapy, has long been a modality of interest in both cancer and transplantation, though has only recently stepped into the spotlight with the development of virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. Although these modalities are best described in hematopoietic cell transplantation and hematologic malignancies, their potential application in the SOT setting may hold tremendous promise for those with limited therapeutic options. In this review, we provide a brief overview of the development of adoptive cell therapies with a focus on virus-specific T-cell therapy and chimeric antigen receptor T-cell therapy. We also describe the current experience of these therapies in the SOT setting as well as the challenges in their application and future directions in their development., (Copyright © 2024. Published by Elsevier Inc.)

Background Aims: Cell therapies are an emerging treatment option for a variety of diseases, especially with the success of chimeric antigen receptor T-cell therapies. With 18 FDA-approved cell therapy products as of December 2020 and a growing number in clinical trials, standards for most aspects of the cell therapy lifecycle are well-established by professional organizations like AABB and FACT; however, there are limited standardized protocols regarding the day-of infusion., Methods: Infusions were observed at three academic medical centers in the United States, and the workflows were analyzed and compared based on factors including facility layout, product verification processes, cryobag design, timing restrictions, and use of electronic medical records., Results: Variations between the facilities were identified with product thawing location and cell therapy lab location being the most important factors in time from thaw to infusion., Conclusions: Based on this analysis, opportunities were identified for standardization and streamlining the infusion workflow which may help facilitate adoption of new and existing cell therapies at a wider range of hospitals., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Since the first genetically-engineered clinical trial was posted to clinicaltrials.gov in 2003 (NCT00019136), chimeric antigen receptor (CAR) and T-cell receptor (TCR) therapies have exhibited unprecedented growth. USA, China, and Europe have emerged as major sites of investigation as many new biotechnology and established pharmaceutical companies invest in this rapidly evolving field. Although initial studies focused primarily on CD19 as a target antigen, many novel targets are now being evaluated. Next-generation genetic constructs, starting materials, and manufacturing strategies are also being applied to enhance efficacy and safety and to treat solid tumors as well as hematologic malignancies. Fueled by dramatic clinical efficacy and recent regulatory approvals of CD19-targeted CAR cell therapies, the field of engineered cell therapeutics continues to expand. Here, we review all 745 genetically modified CAR and TCR clinical trials with anticipated accrual of over 28,000 patients posted to clinicaltrials.gov until 31 st of December 2019. We analyze projected patient enrollment, geographic distribution and phase of studies, target antigens and diseases, current strategies for optimizing efficacy and safety, and trials expected to yield important clinical data in the coming 6-12 months., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pinte, Cunningham, Trébéden-Negre, Nikiforow and Ritz.)

Importance: Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion., Objective: To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk., Design, Setting, and Participants: This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion., Main Outcomes and Measures: The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria., Results: Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26)., Conclusions and Relevance: The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials., (© 2020 by The American Society of Hematology.)

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 10 6 -3 × 10 7 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3 + T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro , but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity., (©2018 American Association for Cancer Research.)

Background Aims: Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor (CAR)-modified T cells has demonstrated preclinical efficacy in several model systems, including hematological and solid tumors. We present comprehensive data on manufacturing development and clinical production of autologous NKG2D CAR T cells for treatment of acute myeloid leukemia and multiple myeloma (ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates with native costimulatory molecule DAP10, effectively generating a second-generation CAR against multiple ligands upregulated during malignant transformation including MIC-A, MIC-B and the UL-16 binding proteins., Methods: CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells were genetically modified with replication-defective gamma-retroviral vector and expanded ex vivo for 5 days with recombinant human interleukin-2., Results: Despite sizable interpatient variation in originally collected cells, release criteria, including T-cell expansion and purity (median 98%), T-cell transduction (median 66% CD8 + T cells), and functional activity against NKG2D ligand-positive cells, were met for 100% of healthy donors and patients enrolled and collected. There was minimal carryover of non-T cells, particularly malignant cells; both effector memory and central memory cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated., Conclusions: The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing., (Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)