Lowery Frank J, Goff Stephanie L, Gasmi Billel, Parkhurst Maria R, Ratnam Nivedita M, Halas Hyunmi K, Shelton Thomas E, Langhan Michelle M, Bhasin Aarushi, Dinerman Aaron J, Dulemba Victoria, Goldlust Ian S, Gustafson Alexandra M, Hakim Abraham A, Hitscherich Kyle J, Kenney Lisa M, Levy Lior, Rault-Wang Juliette G, Bera Alakesh, Ray Satyajit, Seavey Courtney D, Hoang Chuong D, Hernandez Jonathan M, Gartner Jared J, Sindiri Sivasish, Prickett Todd D, McIntyre Lori S, Krishna Sri, Robbins Paul F, Klemen Nicholas D, Kwong Mei Li M, Yang James C, Rosenberg Steven A
National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA.
National Cancer Institute, Center for Cancer Research, Thoracic Surgery Branch, Bethesda, MD, USA.
Nat Med. 2025 Apr 1. doi: 10.1038/s41591-025-03627-5.
Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7-20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4-40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4 neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121 .
未选择的自体肿瘤浸润淋巴细胞（TILs）的过继性转移已在转移性黑色素瘤患者中介导了有意义的临床反应，但在胃肠道上皮起源的癌症中却没有。在一项不断发展的单臂2期试验设计中，TILs来源于91例难治性错配修复 proficient转移性胃肠道癌症患者，并在淋巴细胞清除化疗和高剂量白细胞介素-2的方案中给予这些患者（一项正在进行的试验的三个队列）。本研究的主要终点是使用实体瘤疗效评价标准1.0测量的客观缓解率；安全性是描述性次要终点。在试点阶段，18例患者接受大量未选择的TILs后未观察到临床反应；然而，当筛选并选择TILs用于新抗原识别（SEL-TIL）时，39例患者中有3例出现反应（7.7%（95%置信区间（CI）：2.7-20.3））。基于输注的TILs中高水平的程序性细胞死亡蛋白1，将帕博利珠单抗添加到方案中（SEL-TIL + P），34例患者中有8例出现客观反应（23.5%（95%CI：12.4-40.0））。所有患者均经历了化疗引起的短暂严重血液学毒性。7例（10%）患者需要重症监护支持。对SEL-TIL和SEL-TIL + P治疗组进行了反应的实验室和临床相关性的探索性分析。反应与识别更多靶向新抗原和给予更多CD4新抗原反应性TILs相关。当前策略（SEL-TIL + P）超出了结肠癌患者试验设计的参数，正在进行扩展阶段。这些结果可能为传统上预期对免疫疗法无反应的人群提供一种基于细胞的治疗方法。ClinicalTrials.gov标识符：NCT01174121 。
