A new framework developed in partnership with Friends of Cancer Research (Friends) and the Parker Institute for Cancer Immunotherapy was published in The Journal for ImmunoTherapy of Cancer, “Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.” This pertinent collaborative manuscript emphasizes the need for flexible approaches to efficiently characterize and advance new cell therapies.
Advances in genome editing technologies have led to the discovery of numerous gene edits that can enhance T-cell functionality in preclinical models. However, translating these discoveries into clinical benefit remains limited by the impracticality of testing each of the individual edits in a traditional clinical trial, emphasizing the need for new strategies to improve efficiency. The proposed trial framework enables the intentional inclusion of heterogeneous, genetically modified T-cell subpopulations within a single product, allowing internally controlled evaluation of multiple edits in parallel. This approach will enable rapid prioritization of enhanced T-cell constructs, a process that would otherwise take years to evaluate each candidate individually.
The manuscript provides a technical foundation for this approach, including a detailed review of in vitro and in vivo genome-wide screens, clinical trial design principles, and key Chemistry, Manufacturing, and Controls (CMC), non-clinical, and clinical considerations. With a strong emphasis on patient safety, the publication outlines how these complex designs can be operationalized in ethically sound and scientifically rigorous ways.
Click to read the publication: https://jitc.bmj.com/content/13/6/e011301
The proposed framework was informed by insights shared at the “Unlocking Complex Cell-based Gene Therapies” public meeting held on May 6, 2024. This event brought together leaders from academia, the U.S. Food and Drug Administration, and patient advocacy groups to discuss innovative solutions for expediting access to next-generation therapies.
To learn more about Friends’ Cell & Gene Therapies portfolio and the projects, events, and findings that have led to this important publication, click here.
Manuscript Authors
Christopher R Cabanski, EnJun Yang, Mark D Stewart, Jeff D Allen, John E Connolly, Ute Dugan, Philip D Greenberg, Crystal L Mackall, Carl H June, Alexander Marson, Marcela V Maus, Antoni Ribas.
Author Affiliations
Parker Institute for Cancer Immunotherapy, Friends of Cancer Research, Fred Hutchinson Cancer Center, Stanford University School of Medicine, Gladstone Institute, University of California San Francisco, Massachusetts General Hospital, University of California Los Angeles.
Acknowledgements
We extend our gratitude to the FDA Center for Biologics Evaluation and Research (CBER) staff, including Asha Das, Anna Kwilas, Nicole Verdun, Iwen Wu, and Peter Marks, for their valuable feedback and participation as panelists in the workshop. We also thank patient advocates Rick Bangs, Desirée Walker, Chris White, and Tom Whitehead for sharing their perspectives and insights, which were instrumental in shaping the discussion.
