Pei Shu, Fuchun Guo, Diyuan Qin, Liqun Zou, Qizhi Ma, Benxia Zhang, Ge Gao, Yue Chen, Xia He, Ming Jiang, Ning Liu, Kexun Zhou, Jian Zhao, Yanna Lei, Yu Gao, Yugu Zhang, Yao Zeng, Mingyang Feng, Xiaoyu Li, Dan Li, Yongsheng Wang
These findings support the use of CXCR4 modification as a strategy to improve CAR-T cell efficacy in treating hematologic B cell malignancies, warranting further clinical investigation.
Hematological malignancies of B cell origin are characterized by frequent expression of CXCR4. The CXCR4-CXCL12 axis facilitates the in vivo dissemination of B cell lymphoma and multiple myeloma (MM). It is also a pivotal regulator in the migration and bone marrow homing of T cells. Herein, we hypothesized that engineering CAR-T cells to overexpress CXCR4 could utilize the CXCR4-CXCL12 axis to enhance their therapeutic efficacy by increasing tumor tracking and bone marrow accumulation. In this study, we found that lentiviral transduction caused significant CXCR4 downregulation on T cells, leading to impaired CAR-T cell migration to CXCL12. By contrast, CXCR4 overexpressing (CXCR4 hi ) CD19 CAR-T cells and BCMA CAR-T cells showed superior in vivo tumor tracking and clearance capacities in the localized and systemically disseminated models of B cell lymphoma and MM, respectively. Notably, CXCR4 modification significantly facilitated the bone marrow homing and accumulation of CAR-T cells, which further promoted memory T cell differentiation, persistence and prolonged antitumor activity. Building on these findings, an investigator-initiated clinical trial (IIT) evaluating CXCR4 hi CD19 CAR-T cells in patients with relapsed/refractory B cell malignancies (NCT04684472) achieved encouraging efficacy: the low-dose cohort yielded 3 complete responses (CRs) and 1 partial response (PR) within the first month post-infusion. These findings support the use of CXCR4 modification as a strategy to improve CAR-T cell efficacy in treating hematologic B cell malignancies, warranting further clinical investigation.