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<p>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<sup>hi</sup>) 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, <i>CXCR4</i> 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<sup>hi</sup> 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 <i>CXCR4</i> modification as a strategy to improve CAR-T cell efficacy in treating hematologic B cell malignancies, warranting further clinical investigation.</p>

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CXCR4-modification enhances CAR-T efficacy by improving tumor tracking and bone marrow homing in B-cell malignancies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月28日

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  • 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

摘要

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 (CXCR4hi) 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 CXCR4hi 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.