Cell Therapy: Novel Signaling Strategies for CAR-T therapies Solid Tumors

Presented by: Greg Allen, MD/PhD, Assistant Professor, University of California San Francisco

Covered by: Hannah Abrams, MD

Dr. Greg Allen, assistant professor at the University of California San Francisco, delves into the challenge of appropriately targeting CAR-T cells to distinguish tumor from its surrounding tissue. Almost all potential CAR T-cell antigen targets, he describes, are also expressed on healthy tissue, which causes dose-limiting “on-target, off tumor” toxicity and has been a major barrier for solid tumor CAR T-cell therapy. [1, 2]

Dr. Allen describes broad strategies currently under development requiring two-antigen signaling to make CAR T-cell targeting more specific to tumor tissue, which he likens to “two factor identification” in modern software engineering. [3] One mechanism he describes is NOT gate recognition program in which, for example, a CAR T-cell might target colorectal cancer cells which express CEA but have lost their HLA-A*02 expression. This strategy allows the CAR T-cell to spare nonmalignant tissue which has normal HLA expression, while targeting tumor tissue. [4] The same logic can be applied to AND gate recognition programs, where a CAR T-cell requires recognition of two antigens more commonly co-expressed on tumor cells to improve its specificity. [5] While the current generation, single-antigen CAR T-cells have had dose limiting toxicity in solid tumors, Dr. Allen describes the next generation of dually targeted CAR Ts ready to widen the therapeutic window for CAR T.

1. Thistlethwaite et al Cancer Immunol 2017
2. Hinrichs and Restifo Nature Biotechnology 2013
3. Roybal et al 2016 Cell
4. Rafiq et al 2019 Nat Rev Clin Onc
5. Dannenfelser et al Cell Systems 2020