ASH 2025 | CD70-targeted CAR T-cells for high-risk myeloma after BCMA CAR-T relapse

The story that we recently published in Blood, we’re really trying to investigate this concept that we know for BCMA targeting CAR-T cells. Some patients now have been demonstrated can have very long-term remissions, even out to five years. But those other 65, 70% of patients who don’t achieve long-term remissions with the current BCMA CAR-T cells, of those patients, we know that many of them tend to have what we call these high-risk genotypes. So the genome, the DNA within their tumor, shows certain features that are associated with poor prognosis, with prior therapies, and even with CAR-T cells, they tend to relapse more quickly. And so these are the patients that we need additional therapeutic solutions for. What we found through our bioinformatic analysis of myeloma patient samples is that many of these high-risk tumor cells express this other protein called CD70 on their cell surface. We were excited about CD70 because others had previously found it to be an immunotherapy target in AML, in renal cell carcinoma. It hadn’t really been explored in multiple myeloma, but we actually had clinical data to suggest it’s a safe target, could be useful from these other cancers. And so what we were able to do here was we could demonstrate not only CD70 is a promising target for these high-risk patients that were relapsing on BCMA CAR-T, so now we can make a new therapy for them if they receive BCMA CAR-T, if they do relapse, this can be a new option. But then also what we did in that paper was we took a protein engineering strategy where we tested many different types of CARs against CD70, including ones based on antibody fragments, which is the most common type of CAR. We actually took advantage of CD70’s natural interaction partner in T cells and B cells and dendritic cells called CD27. And we basically found a minimal fragment of CD27 we could turn into the CAR binding element that recognizes CD70. And by using this natural binder instead of an antibody fragment, we got much greater expansion of the CAR-T cells when we put them into mouse models. And we know this expansion and persistence correlates with good outcomes in patients. So we think we made this optimized CD70 CAR construct that can specifically address these high-risk patients who are not always well served by BCMA CAR-T.

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