Center for Cancer Immune Therapy, Department of Hematology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; Department of Oncology, University of Copenhagen, Copenhagen, Denmark.
Center for Cancer Immune Therapy, Department of Hematology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.
Ann Oncol. 2018 Jul 1;29(7):1575-1581. doi: 10.1093/annonc/mdy139.
Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses.
Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells.
TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing.
Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.
几乎一半的转移性黑色素瘤患者接受检查点抑制剂 (CPI) 免疫治疗后仅获得短期或无获益。在这项研究中，我们研究了在 CPI 治疗后进展的患者的免疫系统是否能够产生针对肿瘤的功能性免疫反应。
从接受抗程序性死亡蛋白 1 (PD-1) 和抗细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 治疗后进展的转移性黑色素瘤病灶中分离和扩增肿瘤浸润淋巴细胞 (TIL)。通过 TIL 与自体肿瘤细胞共培养评估肿瘤特异性免疫反应。
可评估 23 名患者 23 个转移灶的 T 细胞对自体肿瘤细胞的识别。所有转移灶均在抗 PD-1（23/23，100%）治疗期间或之后进展，且大多数在抗 CTLA-4 （17/23，74%）治疗后进展。在 23 名患者中的 19 名（83%）检测到功能性抗肿瘤免疫反应。CD8+（23/23 名患者，78%）和 CD4+（23/23 名患者，70%）TIL 均能够识别自体肿瘤。大量 CD8+TIL（中位数 23%，范围 1.0%-84%）能够识别肿瘤细胞。这与之前研究中呈现的未经选择的转移性黑色素瘤患者队列相似。肿瘤内免疫浸润的定位在样本之间存在异质性。在一项 I/II 期临床试验中，12 名 CPI 耐药黑色素瘤患者接受了 TIL 联合淋巴细胞耗竭化疗、聚乙二醇干扰素 α2b 和白细胞介素-2的治疗。在 12 名先前 CPI 治疗失败的患者中，TIL 治疗导致 2 例部分缓解，其中 1 例仍在进行中。
在先前接受 CPI 治疗失败的患者中，肿瘤反应性 T 细胞似乎大量浸润肿瘤微环境。这些患者仍可对未经选择的自体 TIL 输注产生反应。我们的结果证明，在接受多次 CPI 治疗失败的黑色素瘤患者中，需要进一步测试新的免疫再激活策略。
