Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 10⁶ CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19^dim or CD19^- B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22⁺ cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.

中文翻译：

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靶向CD22的CAR T细胞可诱导B-ALL的缓解，而B-ALL的天真性或对CD19靶向CAR免疫疗法有抵抗力。

靶向CD19的嵌合抗原受体（CAR）T细胞在复发和/或难治的前B细胞急性淋巴细胞白血病（B-ALL）中介导有效作用，但抗原丢失是对CD19靶向免疫疗法产生耐药性的常见原因。CD22在大多数B-ALL病例中也有表达，通常在CD19丢失后仍保留。我们报告了一项1期试验的结果，该试验在21名儿童和成人中测试了一种新型的针对CD22的CAR（CD22-CAR），其中包括17名先前接受过CD19定向免疫疗法治疗的儿童。观察到剂量依赖性抗白血病活性，接受每公斤体重≥1×10 ⁶ CD22-CAR T细胞的患者中有73％（11/15）的患者完全缓解，包括5名CD19 ^dim或CD19-患者中的5名^。球。中位缓解期为6个月。复发与CD22位点密度降低有关，这可能使CD22 ⁺细胞逃脱了CD22-CAR T细胞的杀伤。这些结果是第一个确立CD22-CAR在B-ALL中的临床活性的方法，包括对抗CD19免疫疗法有抗药性的白血病，证明了在生物活性剂量下与CD19-CAR相当的针对B-ALL的效力。我们的结果也突出了抗原密度在调节CAR功能中发挥的关键作用。