Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19⁻ or CD19^lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19^−/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22^−/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

尽管取得了令人瞩目的进展，但超过 50% 的接受 CD19 靶向嵌合抗原受体 T 细胞 (CAR19) 治疗的患者会出现病情进展。 16 名大 B 细胞淋巴瘤 (LBCL) 患者在 CAR19 治疗后疾病进展，其中 10 名患者 CD19 缺失或较低。较低表面 CD19 密度预处理与疾病进展相关。为了预防 CD19 ^-或 CD19 ^lo疾病复发，我们在针对患有复发/难治性 B 细胞的成人的 I 期临床试验 (NCT03233854) 中测试了靶向 CD19 和/或 CD22 的双特异性 CAR (CD19-22.BB.z-CAR)急性淋巴细胞白血病 (B-ALL) 和 LBCL。主要终点是生产可行性和安全性，次要终点是疗效终点。达到主要终点； 97% 的产品符合方案规定的剂量，并且在剂量递增期间没有发生剂量限制性毒性。在 B-ALL ( n = 17) 中，100% 的患者有缓解，88% 的微小残留病阴性完全缓解 (CR)；在 LBCL（ n = 21）中，62% 的患者获得 29% CR 的缓解。 50%（10 名中的 5 名）B-ALL 患者和 29%（14 名中的 4 名）LBCL 患者出现 CD19 ^-/lo复发，但与 CD22 ^-/lo疾病无关。 CD19/22-CAR 产品显示，与 CD19 相比，CD22 刺激时细胞因子的产生减少。我们的结果进一步表明抗原丢失是 CAR T 细胞耐药性的主要原因，强调了设计跨靶点具有同等效力的多特异性 CAR T 细胞的挑战，并将细胞因子的产生确定为 CAR T 细胞效力的重要质量指标。