Deniger Drew C, Kwong Mei Li M, Pasetto Anna, Dudley Mark E, Wunderlich John R, Langhan Michelle M, Lee Chyi-Chia Richard, Rosenberg Steven A
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Cell and Gene Therapy, Novartis, Cambridge, Massachusetts.
Clin Cancer Res. 2017 Jan 15;23(2):351-362. doi: 10.1158/1078-0432.CCR-16-0906. Epub 2016 Oct 7.
This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma.
A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor.
The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases.
Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351-62. ©2016 AACRSee related commentary by Cogdill et al., p. 327.
本初步可行性临床试验评估了BRAF突变小分子拮抗剂维莫非尼与肿瘤浸润淋巴细胞（TIL）联合应用于转移性黑色素瘤治疗的效果。
切除转移性肿瘤以培养TIL，患者接受维莫非尼治疗2周，随后切除第二个病灶。然后患者接受非清髓性预处理方案、自体TIL输注及大剂量白细胞介素-2给药。维莫非尼在TIL输注时重新开始使用，并持续2年或直至疾病进展。采用实体瘤疗效评价标准（RECIST）1.0评估临床反应。使用TCRB深度测序、免疫组织化学、增殖及对自体肿瘤的识别，比较维莫非尼治疗2周前后切除的转移灶。
该治疗耐受性良好，安全性与单独使用TIL或维莫非尼相似。11例患者中有7例（64%）出现客观临床反应，2例患者（18%）完全缓解达3年（1例反应持续至46个月）。当接近维莫非尼的最大血清浓度时，研究级维莫非尼（PLX4032）在体外抑制了输注袋TIL和外周血T细胞的增殖及活力。维莫非尼治疗前后的病灶之间，TCRB库（克隆型数量、克隆性及频率）无显著变化。从维莫非尼治疗前后的转移灶培养的TIL对自体肿瘤的识别相似。
在这项小型初步临床试验中，维莫非尼与TIL联合应用安全可行，并产生了客观临床反应。《临床癌症研究》；23(2)；351 - 62。©2016美国癌症研究协会。见Cogdill等人的相关评论，第327页。
