CLINICAL STUDY OF LOCOREGIONAL ADOPTIVE CELLULAR IMMUNOTHERAPY FOR THE CANCER OF DIGESTIVE TRACT

在前2年，为了开发一种新的肿瘤特异性过继细胞免疫疗法，我们对难治性晚期或复发性食管癌患者进行了I/II期临床试验。肿瘤细胞刺激的T细胞（AuTL）通过与自体肿瘤细胞和外周血淋巴细胞混合培养体外增殖。11例中有5例（45%）的AuTLs对自体肿瘤细胞和其他肿瘤细胞系表现出HLA-I类分子限制性的细胞毒作用<51>。这些AuTL通过重复直接或内窥镜注射局部施用到肿瘤中。观察到1例CR、3例PR、2例SD和5例PD的临床反应，不良事件均可耐受。本研究还提示，所给细胞的CTL活性和外周血中CD 16 ^+细胞的百分比可能是预测临床反应的实验室标志物。去年，为了研究一种新的调节剂来增强这种免疫疗法的效果，我们专注于蛋白酶体抑制剂（PS-341）与细胞毒性蛋白质TRAIL组合在诱导人肿瘤细胞凋亡中的协同作用。单独高剂量的PS-341对大多数人类肿瘤细胞系具有毒性。然而，在存在TRAIL的情况下，中等剂量的PS-341将大大增强凋亡。蛋白酶体抑制剂有望成为肿瘤免疫治疗的一种新的调节剂。

In first 2 years, to develop a novel tumor-specific adoptive cellular immunotherapy, we conducted a phase I/II clinical trial for patients with refractory advanced or recurrent esophageal cancer. The tumor cell-stimulated T cells (AuTL) were propagated ex vivo by a mixed culture with autologous tumor cell and peripheral blood lymphocytes. In 5 of 11 cases (45%), the AuTLs showed a specific cytotoxicity against autologous tumor cell and other tumor cells lines in an HLA- class I molecular restricted manner tested by ^<51>Cr release assay and IFN-g production assay. These AuTLs were administrated into the tumor locoregionally by repeated direct or endoscopic injections. The clinical response was observed with 1 CR, 3 PRs, 2 SDs and 5 PDs and adverse events were all tolerable. This study also suggested CTL activity in the administrated cells and percentages of CD16^+ cells in the peripheral blood might be laboratory markers for prediction of clinical response. In last year, in order to investigate a new modulator to enhance effects of this immunotherapy, we focused on a synergistic effect in inducing human tumor cell apoptosis between the proteasome inhibitor (PS-341) in combination with the cytotoxic protein TRAIL. High doses of PS-341 alone were toxic to the most human tumor cell lines. However, in presence of TRAIL the apoptosis would be greatly enhanced by intermediate doses of PS-341. Proteasome inhibitor might be a novel modulator for cancer immunotherapy.