肿瘤细胞治疗研究
英文原题：Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.
Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.
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在 4-1BB 和 CD3 激动作用的辅助下制备的 TIL 是可行的，且治疗未伴随新的安全性信号。
TIL（肿瘤浸润淋巴细胞）疗法已在转移性黑色素瘤、非小细胞肺癌及其他实体瘤中显示疗效。我们的临床前研究显示，在TIL早期体外培养中加入激动性抗4-1BB和抗CD3抗体，可产生更强、以CD8细胞为主的TIL。
难治性转移性结直肠癌（CRC）、胰腺癌（PDAC）和卵巢癌（OVCA）患者符合入组条件。患者先接受淋巴细胞清除化疗，随后输注在MD Anderson癌症中心制备的体外扩增TIL；培养中使用IL-2并激动CD3和4-1BB（urelumab）。TIL输注后，患者最多接受6剂大剂量IL-2。主要终点为按实体瘤疗效评价标准1.1版评估的12周客观缓解率；次要终点包括疾病控制率（DCR）、缓解持续时间、无进展生存期（PFS）、总生存期（OS）和安全性。
17例患者接受TIL采集，16例按方案接受治疗（NCT03610490），包括8例CRC、5例PDAC和3例OVCA患者。中位年龄为57.5岁（范围33至70岁），女性占50%。既往治疗中位线数为2线（范围1至8线）。12周时未观察到缓解。10名受试者至少有一次疾病稳定（SD）评估，DCR为62.5%（95% CI：35.4%至84.8%）。最佳疗效包括一例PDAC患者持续17个月的SD。各队列中位PFS为2.53个月（95% CI：1.54至4.11），中位OS为18.86个月（95% CI：4.86至未达到）。14名受试者（87.5%；95% CI：61.7%至98.4%）出现3级或以上、归因于治疗的毒性。输注产品分析显示，无论肿瘤类型如何，均存在高表达CD39的效应记忆细胞，而检查点标志物表达较低。
在4-1BB和CD3激动作用辅助下制备TIL具有可行性，治疗未出现新的安全性信号。尽管未观察到客观缓解，但相当一部分患者达到SD，提示存在早期或部分免疫学效应。仍需进一步研究耐药相关因素并从功能上增强T细胞，以提高治疗效果。
Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.
Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety.
17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers.
TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.
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