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ASH 2025 | Improving CAR T-cell efficacy in myeloma: CRISPR engineering and dual-antigen targeting
Arun Wiita, MD, PhD, University of California, San Francisco, CA, discusses emerging strategies to improve CAR T-cell efficacy in multiple myeloma, including CRISPR-engineered CARs and dual-antigen targeting, to overcome antigen escape. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
One of the main things that we’re investigating at UCSF, a technology with our close collaborator there, Dr Justin Eyquem in the Department of Medicine, he developed, several years ago now has enhanced it further since coming to UCSF, where we can actually use CRISPR genome engineering technology to take a cell and edit T cells directly at the T cell receptor alpha chain locus. And what this enables us to do, all the other CAR T cells we have right now in multiple myeloma, essentially, they use a virus...
One of the main things that we’re investigating at UCSF, a technology with our close collaborator there, Dr Justin Eyquem in the Department of Medicine, he developed, several years ago now has enhanced it further since coming to UCSF, where we can actually use CRISPR genome engineering technology to take a cell and edit T cells directly at the T cell receptor alpha chain locus. And what this enables us to do, all the other CAR T cells we have right now in multiple myeloma, essentially, they use a virus. It’s basically an engineered version of the HIV virus where we actually can take that CAR gene, insert it in the T cells, and then they express the CAR, they’re able to kill tumor cells. What Justin has demonstrated, and we’ve actually recapitulated the CARs in our lab as well, and he’s shown for BCMA CARs, if you take that CAR and use CRISPR genome engineering to put it in a very precise location in the T cell, it’s under this really consistent control and downstream signaling where you can actually give 20-fold lower dose CAR T cells and still get the same outcomes, both in murine models and mouse models. And actually now we’re about to translate that to a clinical trial at UCSF. So we think this could potentially be one of the most powerful ways to avoid potential toxicities of current CAR T cells. We actually get much greater T cell expansion. So we think this could do a better job of avoiding those low antigen escape-based clones because you think there could be more sensitivity to low antigen. So we think that’s a really important potential strategy. And another one is really thinking about dual targeting CAR T-cells. So something that we’ve developed in our lab are CD70 targeting CAR T-cells against high-risk multiple myeloma. We’ve demonstrated proof of principle. We can take CD70 and pair it with BCMA. And then by having two different antigens you’re going after, this can make it harder for the tumors to escape by only losing one of them, for example. So these are two different strategies that we think, especially if we combine those technologies, really can make a difference in improving CAR T’s for myeloma and avoiding antigen escape.
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