Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR T cells Available to Purchase

• CD70 is an upregulated cell surface antigen and a promising therapeutic target in high-risk myeloma tumors.

• Structure-optimized CD27-based CAR-Ts targeting CD70 outperform single-chain variable fragment–based CARs, leading to improved CAR-T expansion in vivo.

Despite the success of B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor (CAR) T cells (CAR-Ts) in multiple myeloma, patients with high-risk cytogenetic features continue to relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high-risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested single-chain variable fragment–based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high-risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape–mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.