Poch Michael, Hall MacLean, Joerger Autumn, Kodumudi Krithika, Beatty Matthew, Innamarato Pasquale P, Bunch Brittany L, Fishman Mayer N, Zhang Jingsong, Sexton Wade J, Pow-Sang Julio M, Gilbert Scott M, Spiess Philippe E, Dhillon Jasreman, Kelley Linda, Mullinax John, Sarnaik Amod A, Pilon-Thomas Shari
Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, USA.
Immunology, Moffitt Cancer Center and Research Institute, Tampa, USA.
Oncoimmunology. 2018 Jul 23;7(9):e1476816. doi: 10.1080/2162402X.2018.1476816. eCollection 2018.
Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3 (median 63%, range 10-87%) with a median of 30% CD8 + T cells (range 5-70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.
晚期膀胱癌患者的治疗选择有限，中位总生存期（OS）在12至15个月之间。使用肿瘤浸润淋巴细胞（TIL）的过继性细胞疗法（ACT）已成功用于治疗转移性黑色素瘤患者，中位OS为52个月。在本研究中，我们调查了从膀胱癌患者肿瘤中扩增TIL的可行性。收集原发性膀胱肿瘤和淋巴结（LN）转移灶。将肿瘤标本切碎成碎片，置于24孔板的各个孔中，并在高剂量白细胞介素-2中培养四周。通过流式细胞术对扩增的TIL进行表型分析，并在与自体肿瘤消化物共培养和干扰素-γ酶联免疫吸附测定后评估抗肿瘤反应性。在收集的28例移行细胞膀胱癌或LN肿瘤中，14/20（70%）原发性肿瘤和所有LN转移灶均显示TIL扩增。扩增的TIL主要为CD3（中位值63%，范围10-87%），CD8 + T细胞中位值为30%（范围5-70%）。TIL对自体肿瘤分泌干扰素-γ。添加激动性4-1BB抗体可改善原发性膀胱肿瘤的TIL扩增，无论是否接受过化疗预处理。本研究为膀胱癌患者的自体TIL治疗测试建立了迈向治疗过程的实际第一步。
