{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:37:37Z","timestamp":1785285457033,"version":"3.55.0"},"reference-count":35,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"unspecified","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,5,14]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.<\/jats:p>\n               <jats:p>This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.<\/jats:p>\n               <jats:p>This framework is informed by insights shared at the \u201cUnlocking Complex Cell-based Gene Therapies\u201d workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.<\/jats:p>","DOI":"10.1136\/jitc-2024-011301","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:05:19Z","timestamp":1749182719000},"page":"e011301","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9938-1331","authenticated-orcid":false,"given":"Christopher R","family":"Cabanski","sequence":"first","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1511-7511","authenticated-orcid":false,"given":"EnJun","family":"Yang","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-0736","authenticated-orcid":false,"given":"Mark D","family":"Stewart","sequence":"additional","affiliation":[{"name":"Friends of Cancer Research, Washington, District of Columbia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff D","family":"Allen","sequence":"additional","affiliation":[{"name":"Friends of Cancer Research, Washington, District of Columbia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E","family":"Connolly","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Dugan","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Parker Institute for Cancer Immunotherapy, San Francisco, California, USA"},{"name":"Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"},{"name":"Department of Immunology, University of Washington, Seattle, Washington, USA"},{"name":"Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal L","family":"Mackall","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Pediatric Hematology\/Oncology\/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Bone Marrow Transplant-Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Parker Institute for Cancer Immunotherapy at Stanford Medicine, Stanford Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl H","family":"June","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Marson","sequence":"additional","affiliation":[{"name":"Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes, San Francisco, California, USA"},{"name":"Department of Medicine, University of California San Francisco, San Francisco, California, USA"},{"name":"University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA"},{"name":"Parker Institute for Cancer Immunotherapy at Gladstone Institutes, Gladstone Institutes, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7578-0393","authenticated-orcid":false,"given":"Marcela V","family":"Maus","sequence":"additional","affiliation":[{"name":"Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Department of Medicine, Harvard 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