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<p>CAR-T therapies targeting either CD19 or CD22 have shown significant promise for treating relapsed or refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, a common limitation is the high frequency of antigen loss, which leads to r/r B-ALL progression. To overcome progression caused by antigen loss, bi-specific CAR-T immunotherapies targeting both CD19 and CD22 may offer enhanced efficacy in eliminating r/r B-ALL and preventing relapse by hindering leukemia cell proliferation. In this study, we present both pre-clinical and clinical findings from an ongoing trial (NCT04303520) assessing the therapeutic efficacy of the CD19-CD22 bi-specific CAR-T therapy for r/r B-ALL patients. Pre-clinical data from animal models reveal that CD19-CD22 CAR-T cells effectively induce cytotoxicity, thus suppressing B-ALL cell proliferation. Notably, this dual-targeted approach outperforms single-target CAR-T treatments. From the Phase I trial encompassing 35 participants, 37.1% (13 out of 35 patients) experienced cytokine release syndrome, with only a single case of Grade&#xa0;III &#xa0; severity. Importantly, no neurotoxicity episodes were recorded post CD19-CD22 CAR-T administration. Common adverse events included hematological, gastrointestinal, and nutrition-related disturbances. B-ALL patients undergoing stem cell transplantation in tandem with CAR-T therapy exhibited a pronounced improvement in overall survival compared to those treated solely with CAR-T. The median overall survival duration was 21.49 ± 4.4&#xa0;months (95% CI: 14.31–31.40&#xa0;months), meanwhile one-year PFS and OS are 0.37 (95% CI, 0.21–0.49) and 0.62 (95% CI: 0.52–0.71), respectively. Clinical monitoring did not identify significant side effects associated with the CD19-CD22 regimen. To monitor the inflammation-associated factors accompanying CAR-T therapy, the peak value of CAR DNA copies was reached around Day 10, accompanied by a similar trend in the levels of inflammatory factors, including IFN-<i>γ</i>, Granzyme B, IL-6, and CRP. Collectively, our data advocate for the potential role of bi-specific CD19-CD22 CAR-T therapy in addressing r/r B-ALL. </p><p><i>Trial registration number</i> ClinicalTrials.gov (No. NCT04303520).</p>

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A bi-specific CAR-T cell therapy targeting CD19 and CD22 in relapsed or refractory B-ALL

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • Qiuling Ma,
  • Runhong Wei,
  • Qingming Wang,
  • Songfu Jiang,
  • Yi Wu,
  • Chao Min,
  • Shufang Guo,
  • Yu Zhang,
  • Xiaohong Sun,
  • Haigang Wu,
  • Xuedong Sun,
  • Fang Xiang,
  • Mingxing Xiao,
  • Zhi Cheng

摘要

CAR-T therapies targeting either CD19 or CD22 have shown significant promise for treating relapsed or refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, a common limitation is the high frequency of antigen loss, which leads to r/r B-ALL progression. To overcome progression caused by antigen loss, bi-specific CAR-T immunotherapies targeting both CD19 and CD22 may offer enhanced efficacy in eliminating r/r B-ALL and preventing relapse by hindering leukemia cell proliferation. In this study, we present both pre-clinical and clinical findings from an ongoing trial (NCT04303520) assessing the therapeutic efficacy of the CD19-CD22 bi-specific CAR-T therapy for r/r B-ALL patients. Pre-clinical data from animal models reveal that CD19-CD22 CAR-T cells effectively induce cytotoxicity, thus suppressing B-ALL cell proliferation. Notably, this dual-targeted approach outperforms single-target CAR-T treatments. From the Phase I trial encompassing 35 participants, 37.1% (13 out of 35 patients) experienced cytokine release syndrome, with only a single case of Grade III   severity. Importantly, no neurotoxicity episodes were recorded post CD19-CD22 CAR-T administration. Common adverse events included hematological, gastrointestinal, and nutrition-related disturbances. B-ALL patients undergoing stem cell transplantation in tandem with CAR-T therapy exhibited a pronounced improvement in overall survival compared to those treated solely with CAR-T. The median overall survival duration was 21.49 ± 4.4 months (95% CI: 14.31–31.40 months), meanwhile one-year PFS and OS are 0.37 (95% CI, 0.21–0.49) and 0.62 (95% CI: 0.52–0.71), respectively. Clinical monitoring did not identify significant side effects associated with the CD19-CD22 regimen. To monitor the inflammation-associated factors accompanying CAR-T therapy, the peak value of CAR DNA copies was reached around Day 10, accompanied by a similar trend in the levels of inflammatory factors, including IFN-γ, Granzyme B, IL-6, and CRP. Collectively, our data advocate for the potential role of bi-specific CD19-CD22 CAR-T therapy in addressing r/r B-ALL.

Trial registration number ClinicalTrials.gov (No. NCT04303520).