Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2019-000166.
Adoptive cell therapy (ACT) with tumor-reactive T cells has shown consistent clinical efficacy. We evaluated the response to ACT in combination with interferon alpha (IFNa) preconditioning in patients with stage IV metastatic melanoma, most of which were progressive on cytotoxic T-lymphocyte-associated protein 4 and/or programmed cell death protein 1 checkpoint blockade therapy.
Thirty-four patients were treated with ex vivo expanded tumor reactive T cells, derived from mixed lymphocyte autologous tumor cultures, or with autologous tumor-infiltrating lymphocytes and evaluated for clinical response. Clinical and immunological parameters associated with response were also evaluated.
Best overall response defined as clinical benefit, comprising either complete response, partial response or stable disease >6 months, was observed in 29% of the patients. Forty-three per cent of the 14 immunotherapy-naïve patients and 20% of the 20 patients progressive on prior immunotherapy benefited from ACT. The overall survival (OS) was 90% versus 28.6% at 1 year and 46.7% versus 0% at 3 years follow-up, of responder and non-responder patients, respectively. Median OS was 36 versus 7 months, respectively. IFNa pretreatment resulted in leukopenia, neutropenia and lymphopenia, which was sustained during the treatment in clinical responders and associated with response. Differences in antigen specificity, but not in phenotype, cytokine profile or CD8+ T cell number of the ACT products correlated with clinical response. Cross-reactivity of the ACT products to one or more allogeneic human leukocyte antigen-matched melanoma cell lines was associated with short OS after treatment while the ACT products of very long-term survivors showed no cross-reactivity but recognized patient-specific neoantigens.
This study demonstrates that ACT in combination with a mild IFNa preconditioning regimen can induce clinical benefit even in immunotherapy pretreated patients, although with lower success than in immunotherapy-naïve patients. ACT products comprising neoantigen reactivity may be more effective.
过继性细胞疗法（ACT）与肿瘤反应性 T 细胞联合应用显示出一致的临床疗效。我们评估了 ACT 联合干扰素 α（IFNa）预处理在 IV 期转移性黑色素瘤患者中的反应，其中大多数患者在细胞毒性 T 淋巴细胞相关蛋白 4 和/或程序性细胞死亡蛋白 1 检查点阻断治疗后进展。
34 例患者接受了体外扩增的肿瘤反应性 T 细胞治疗，这些细胞来自混合淋巴细胞自体肿瘤培养物，或接受自体肿瘤浸润淋巴细胞治疗，并评估了临床反应。还评估了与反应相关的临床和免疫参数。
定义为临床获益的最佳总体反应，包括完全缓解、部分缓解或稳定疾病>6 个月，在 29%的患者中观察到。在 14 例免疫治疗初治患者中，43%和在 20 例先前免疫治疗进展的患者中，20%的患者受益于 ACT。应答者和无应答者的总生存率（OS）分别为 90%和 28.6%，在 1 年时，46.7%和 0%，在 3 年时。中位 OS 分别为 36 个月和 7 个月。IFNa 预处理导致白细胞减少、中性粒细胞减少和淋巴细胞减少，在临床应答者中持续存在，并与反应相关。ACT 产品的抗原特异性差异，但不是表型、细胞因子谱或 CD8+T 细胞数量差异，与临床反应相关。ACT 产品对一个或多个同种异体 HLA 匹配的黑色素瘤细胞系的交叉反应性与治疗后短 OS 相关，而长期存活者的 ACT 产品无交叉反应性，但识别患者特异性新生抗原。
这项研究表明，即使在免疫治疗预处理的患者中，ACT 联合轻度 IFNa 预处理方案也可以诱导临床获益，尽管成功率低于免疫治疗初治患者。包含新抗原反应性的 ACT 产品可能更有效。
