Clinical responses with T lymphocytes targeting malignancy-associated κ light chains
Clinical responses with T lymphocytes targeting malignancy-associated κ light chains
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DOI：
10.1172/jci86000
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
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作者：
Ramos, Carlos A.;Savoldo, Barbara;Dotti, Gianpietro
背景。通过过继转移带有 CD19 特异性嵌合抗原受体 (CAR) 的 T 细胞来治疗 B 细胞恶性肿瘤显示出显着的临床疗效。然而，针对 CD19（一种泛 B 细胞标记物）的 T 细胞的长期持续存在也会消耗正常 B 细胞并导致严重的低丙种球蛋白血症。在这里，我们开发了一种利用 B 细胞轻 Ig 链限制更有选择性地靶向 B 细胞恶性肿瘤的策略。我们生成了一种针对 kappa 轻链 (kappa.CAR) 特异的 CAR，因此可以识别 kappa 限制性细胞并保留表达非靶向 lambda 轻链的正常 B 细胞，从而有可能最大限度地减少体液免疫损伤。方法。我们进行了一项 1 期临床试验，用经过基因改造表达 kappa.CAR (kappa.CARTs) 的自体 T 细胞治疗了 16 名复发或难治性 kappa(+) 非霍奇金淋巴瘤/慢性淋巴细胞白血病 (NHL/CLL) 或多发性骨髓瘤 (MM) 患者。 16 名患者中有 11 名在 T 细胞输注前至少 4 周停止了其他治疗。六名无淋巴细胞减少症的患者在 kappa.CART 输注前 4 天接受 12.5 mg/kg 环磷酰胺（0.2 x 10(8) 至 2 x 10(8) kappa.CARTs/m(2)）。没有使用其他淋巴细胞清除方法。结果。 kappa.CART 扩增在输注后 1-2 周达到峰值，并且细胞在超过 6 周内保持可检测。在 9 名复发 NHL 或 CLL 患者中，2 名患者在 2 次和 3 次输注 kappa.CART 后进入完全缓解，1 名患者出现部分缓解。 7 名 MM 患者中，4 名病情稳定，持续 2-17 个月。没有观察到可归因于 kappa.CART 的毒性。结论。 kappa.CART输注是可行且安全的，并且可以产生完全的临床反应。
BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the kappa light chain (kappa.CAR) and therefore recognizes kappa-restricted cells and spares the normal B cells expressing the nontargeted lambda light chain, thus potentially minimizing humoral immunity impairment.METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractoryr kappa(+) non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express kappa.CAR (kappa.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before kappa.CART infusion (0.2 x 10(8) to 2 x 10(8) kappa.CARTs/m(2)). No other lymphodepletion was used.RESULTS. kappa.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of kappa.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to kappa.CARTs were observed.CONCLUSION. kappa.CART infusion is feasible and safe and can lead to complete clinical responses.