虽然嵌合抗原受体 T 细胞 (CAR-T) 疗法彻底改变了 B 细胞恶性肿瘤的治疗，但许多患者会复发，因此需要提高抗肿瘤免疫力的策略。我们之前设计了一种针对 CD19 和 CD22 的新型自体双特异性 CAR (CAR19-22)，其耐受性良好且反应率高，但复发很常见。白细胞介素 15 (IL15) 可诱导多种免疫细胞增殖，并可增强淋巴细胞运输。在这里，我们报告了新型重组聚合物偶联 IL15 受体激动剂 (NKTR-255) 与 CAR19-22 的首次组合治疗成人复发/难治性 B 细胞急性淋巴细胞白血病的 1 期临床试验结果。共有 11 名患者入组，其中 9 名患者成功接受了 CAR19-22，随后又接受了 NKTR-255。没有剂量限制性毒性，短暂发热和骨髓抑制是最常见的可能相关毒性。我们观察到良好的疗效，九名患者中有八名 (89%) 实现了可测量的残留疾病阴性缓解。 12 个月时，NKTR-255 的无进展生存期是历史对照的两倍（67% vs 38%）。我们进行了相关分析来研究 IL15 受体激动的影响。细胞因子分析显示 IL15 以及趋化因子 CXCL9 和 CXCL10 显着增加。趋化因子的增加与血液中绝对淋巴细胞计数和 CD8 CAR-T 细胞的减少以及脑脊液 CAR-T 细胞增加十倍相关，表明淋巴细胞向组织转运。将 NKTR-255 与 CAR19-22 组合是安全、可行的，并且与高持久反应率相关 (NCT03233854)。版权所有 © 2024 美国血液学会。

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).Copyright © 2024 American Society of Hematology.