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<p>The chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of hematological and solid tumors. Although CAR-T cells targeting PSMA showed robust antitumor efficacy for prostate cancer in preclinical studies, the clinical benefits of PSMA CAR-T cells are unsatisfactory. To maximize the efficacy of this immunotherapy, we combined zoledronic acid (ZOL), a first-line prophylactic drug against skeletal-related events (SREs) and for bone pain management in patients with advanced prostate cancer, with PSMA CAR-T cells for the treatment of prostate cancer. In mice with intratibial inoculation of 22Rv1 prostate tumor, ZOL treatment after PSMA CAR-T cells infusion inhibited growth of the primary intratibial tumor, while it increased the extraskeletal metastasis, demonstrating that ZOL impedes the long-term immunosurveillance, albeit it enhances the short-term antitumor capability of the CAR-T cells. Mechanistically, ZOL showed no increase in the frequency of γδT cell phenotype. Finally, we found that ZOL induced hyperactivation and eventually led to exhaustion of the PSMA CAR-T cells, elucidating the impediment clues of ZOL on the T cell therapy. Our study demonstrates the necessity to balance the contribution of ZOL when combined with CAR-T cell therapy for prostate cancer.</p>

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Zoledronic acid enhances the antitumor efficacy of the PSMA CAR-T cells for bone tumors, but impedes the ability to control metastases of prostate cancer in mice

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Dan Li,
  • Xinyu Gu,
  • Jing Li,
  • Yong Huang,
  • Wei-Lin Zhou,
  • Jiaqian Li,
  • Fengling Wang,
  • Feiyang Yan,
  • Haozhan Gao,
  • Xue Ying,
  • Yikun Li,
  • Shimao Qi,
  • Yueting Zhu,
  • Jiyan Liu,
  • Wei Wang

摘要

The chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of hematological and solid tumors. Although CAR-T cells targeting PSMA showed robust antitumor efficacy for prostate cancer in preclinical studies, the clinical benefits of PSMA CAR-T cells are unsatisfactory. To maximize the efficacy of this immunotherapy, we combined zoledronic acid (ZOL), a first-line prophylactic drug against skeletal-related events (SREs) and for bone pain management in patients with advanced prostate cancer, with PSMA CAR-T cells for the treatment of prostate cancer. In mice with intratibial inoculation of 22Rv1 prostate tumor, ZOL treatment after PSMA CAR-T cells infusion inhibited growth of the primary intratibial tumor, while it increased the extraskeletal metastasis, demonstrating that ZOL impedes the long-term immunosurveillance, albeit it enhances the short-term antitumor capability of the CAR-T cells. Mechanistically, ZOL showed no increase in the frequency of γδT cell phenotype. Finally, we found that ZOL induced hyperactivation and eventually led to exhaustion of the PSMA CAR-T cells, elucidating the impediment clues of ZOL on the T cell therapy. Our study demonstrates the necessity to balance the contribution of ZOL when combined with CAR-T cell therapy for prostate cancer.