Background BCMA-targeted chimeric antigen receptor (CAR)T-cell therapy promotes transient recovery in patients with multiple myeloma, but relapses occurs commonly. GPRC5D, a surface receptor that is highly expressed in bone marrow samples of multiple myeloma patients, shows a promising potential as a specific CAR-T target. Its expression in MM cells is not dependent on BCMA, which makes it an ideal target for MM treatment, either alone or in combination with BCMA.
Methods In this study, we utilized an in-house phage display synthetic nanobody library to identify two VHHs with high affinity and specificity to GPRC5D.
Results We further demonstrated that GPRC5D CAR T-cells with tandem biepitopic VHHs (OriCAR-017) have superior MM cell lysis in vitro, low toxicity and high anti-tumor effects in vivo, compared to single VHH or bicistronic VHH structures (figures 1–5). A phase 1 trial (Clinical Trials.gov identifier: NCT05016778) with 10 MM patients, including 5 patients who had relapsed after BCMA CAR-T therapy, showed a 100% objective response rate without severe side effects with OriCAR-017 treatment, suggesting the safety and efficacy of OriCAR-017 therapy with best-in-class potential (figure 6).
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