Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials
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 bar...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-06-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e011301.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849434049407352832 |
|---|---|
| author | Antoni Ribas Carl H June Philip D Greenberg Crystal L Mackall Marcela V Maus John E Connolly Christopher R Cabanski Ute Dugan Mark D Stewart Jeff D Allen EnJun Yang Alexander Marson |
| author_facet | Antoni Ribas Carl H June Philip D Greenberg Crystal L Mackall Marcela V Maus John E Connolly Christopher R Cabanski Ute Dugan Mark D Stewart Jeff D Allen EnJun Yang Alexander Marson |
| author_sort | Antoni Ribas |
| collection | DOAJ |
| description | 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.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.This framework is informed by insights shared at the “Unlocking Complex Cell-based Gene Therapies” 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. |
| format | Article |
| id | doaj-art-5335452ae1b24c848b9a6ac47ed4cd08 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5335452ae1b24c848b9a6ac47ed4cd082025-08-20T03:26:48ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2024-011301Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trialsAntoni Ribas0Carl H June1Philip D Greenberg2Crystal L Mackall3Marcela V Maus4John E Connolly5Christopher R Cabanski6Ute Dugan7Mark D Stewart8Jeff D Allen9EnJun Yang10Alexander Marson11Parker Institute for Cancer Immunotherapy at UCLA, University of California Los Angeles, Los Angeles, California, USACenter for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USAParker Institute for Cancer Immunotherapy, San Francisco, California, USAParker Institute for Cancer Immunotherapy at Stanford Medicine, Stanford Medicine, Stanford, California, USACellular Immunotherapy Program, Massachusetts General Hospital, Boston, Massachusetts, USAParker Institute for Cancer Immunotherapy, San Francisco, California, USAParker Institute for Cancer Immunotherapy, San Francisco, California, USAParker Institute for Cancer Immunotherapy, San Francisco, California, USAFriends of Cancer Research, Washington, District of Columbia, USAFriends of Cancer Research, Washington, District of Columbia, USAParker Institute for Cancer Immunotherapy, San Francisco, California, USAGladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes, San Francisco, California, USACell-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.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.This framework is informed by insights shared at the “Unlocking Complex Cell-based Gene Therapies” 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.https://jitc.bmj.com/content/13/6/e011301.full |
| spellingShingle | Antoni Ribas Carl H June Philip D Greenberg Crystal L Mackall Marcela V Maus John E Connolly Christopher R Cabanski Ute Dugan Mark D Stewart Jeff D Allen EnJun Yang Alexander Marson Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials Journal for ImmunoTherapy of Cancer |
| title | Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials |
| title_full | Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials |
| title_fullStr | Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials |
| title_full_unstemmed | Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials |
| title_short | Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials |
| title_sort | intentional heterogeneity in autologous cell based gene therapies strategic considerations for first in human trials |
| url | https://jitc.bmj.com/content/13/6/e011301.full |
| work_keys_str_mv | AT antoniribas intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT carlhjune intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT philipdgreenberg intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT crystallmackall intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT marcelavmaus intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT johneconnolly intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT christopherrcabanski intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT utedugan intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT markdstewart intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT jeffdallen intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT enjunyang intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials AT alexandermarson intentionalheterogeneityinautologouscellbasedgenetherapiesstrategicconsiderationsforfirstinhumantrials |