Selecting Donor T Cells for CAR T Therapy, With Mark B. Leick, MD

Findings from a germline genetics study of CAR T cell therapy could help guide how researchers select donor T cells for allogeneic, "off the shelf" CAR T products. The results also point to a new way to identify genes that could improve future CAR T cell designs.

Mark B. Leick, MD, a medical oncologist and physician scientist at Massachusetts General Hospital who led the study, spoke with HCPLive about the clinical and translational implications of the findings, which linked germline variants in STXBP2 to CAR T cell toxicity and variants in PTPN22 to greater CAR T cell expansion.

Rethinking How Donor T Cells Are Chosen

"I think the places where it can become relevant [is that] there's a shift now to do, rather than sort of autologous CAR T cells, where we generate CAR T cells from each patient for themselves, allogeneic CAR T cells, where we take T cells from one healthy person," Leick told HCPLive.

Leick pointed to several advantages of allogeneic, or donor derived, CAR T cell products over the autologous approach, in which a patient's own T cells are used to manufacture their therapy. Chemotherapy can leave a cancer patient's own T cells less fit and less able to kill target cells, and the cancer itself can further suppress T cell function. Manufacturing autologous CAR T cells from a sick patient's own cells can also take weeks to months, whereas healthy donor cells could theoretically be manufactured in advance and kept frozen and ready to use.

"Up until now, there's been relatively little thought put into how do you choose those donor T cells," Leick said. He noted that although some functional assays are used, a single donor's T cells can be used to manufacture CAR T products for dozens or hundreds of patients, raising the stakes of that selection process. Leick said the study's findings suggest researchers developing allogeneic CAR T products should factor genetic variants like those identified in the study into how they screen and choose donor T cells.

Natural Human Variation as an Alternative to CRISPR Screening

Beyond donor selection, Leick said the findings offer a new strategy for identifying genes that could be engineered into future CAR T cell products to improve their efficacy. Historically, the field has leaned on synthetic screening approaches, generally using CRISPR-Cas9, in which a gene is knocked out in a pool of CAR T cells before the cells are tested in a mouse model or in vitro to see whether the edit improves CAR T cell function.

"This has yielded some interesting results, but the problem is we don't actually know what happens when you put that in a human," Leick said.

Leick said the advantage of his team's approach is that it draws on natural variation that already exists within the human population. Because all of the patients in the ZUMA-1 and ZUMA-7 trials reached adulthood, the variants identified in the study are known to be compatible with survival, unlike CRISPR edited genes with unknown effects in humans. That allowed investigators to use real clinical outcomes, rather than a mouse model or in vitro system, to evaluate the effects of specific genetic variants on CAR T cell activity.

Leick's team is now pursuing the PTPN22 variants identified in the study as a target for engineering into other CAR T cell products. Two patients in ZUMA-1 who carried the same PTPN22 mutation had the highest CAR T cell expansion of the roughly 100 patients in the trial, which Leick said suggests the variant confers a gain of function advantage in the context of CAR T cell therapy.

Limitations Tied to Ancestry and a Single CAR T Product

Leick said the study carries 2 notable limitations. Germline genetics analyses require comparing genetic variation among patients of comparable ancestry, and because clinical trial accrual in the United States skews toward patients of European ancestry, the study's population was limited mostly to that group. Too few non-European patients were enrolled to support a meaningful analysis, and Leick said his team would like to extend the work to more diverse populations.

The study also focused on a single CAR T cell product, axicabtagene ciloleucel, in patients with lymphoma, so the findings may not generalize to other CAR T cell products or disease types. Leick said his lab is now working to determine whether the findings extend to other diseases and CAR T cell contexts.

Editor’s Note: Leick reports relevant disclosures with BioNTech, Cabaletta Bio, and Adaptimmune.

Reference

1. Leick MB, Sun B, Birocchi F, et al. Genomic correlates of clinical CAR T cell activity. Sci Immunol. 2026;11(121). doi:10.1126/sciimmunol.aef4134

2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.