SITC 2021 | Key mechanisms of resistance to CAR T-cell therapy
Crystal Mackall, MD, Stanford University, Stanford, CA, outlines the two main causes of resistance to chimeric antigen receptor (CAR) T-cell therapy, CAR T-cell failure and antigen modulation, a mechanism by which a tumor escapes immune destruction by CAR T-cells. Whilst CAR T-cell failure has been extensively studied, there has been less focus on overcoming antigen escape. Prof. Mackall underlines the importance of understanding how to modulate antigen expression and measure target expression levels more quantitatively in order to detect antigen downregulation more accurately. This interview took place during the 36th Society for Immunotherapy of Cancer (SITC) Annual Meeting in Washington, D.C.
Transcript (edited for clarity)
We have been studying the basis of resistance to CAR T-cells very intensely at Stanford in the last five years, since I launched the center there, focusing on CAR T-cell therapies. And it really falls into two major buckets, either the tumor escapes because it evolves to downregulate or lose the target that the CAR T-cell is going after, or the T-cell fails. And those problems are very different and will be solved in different ways...
We have been studying the basis of resistance to CAR T-cells very intensely at Stanford in the last five years, since I launched the center there, focusing on CAR T-cell therapies. And it really falls into two major buckets, either the tumor escapes because it evolves to downregulate or lose the target that the CAR T-cell is going after, or the T-cell fails. And those problems are very different and will be solved in different ways. I think that the issues around antigen modulation are areas where we need greater focus. I think that the community is well recognizing the challenges of T-cell failure, but the issue around antigen modulation isn’t one that maybe we’ve looked at as closely. I think there’s a lot more we can learn about how we can drive antigen expression. We need to learn how to measure target expression levels more quantitatively. So that rather than just looking for loss of an antigen, we can determine whether it’s been downregulated because downregulation may be enough to escape a CAR-T. So I think that’s two major buckets, antigen modulation, T-cell failure, and we need to work on both in parallel.
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