Combination immunotherapy using autologous tumor-stimulated lymphocytes and conventional chemotherapy for the patients with refractory recurrent cancer

实验研究：肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过与死亡受体DR 4/DR 5结合诱导癌细胞凋亡。功能性TRAIL蛋白的表达似乎相当局限于免疫细胞，包括T细胞，NK细胞，树突状细胞（DCs）等。我们研究了人类癌细胞系中的TRAIL敏感性，并评估了EGFR酪氨酸激酶抑制剂吉非替尼和蛋白酶体抑制剂Bortez作为可能的联合治疗新方法的TRAIL疗效。我们的研究表明，吉非替尼和硼替佐米可用于增强部分细胞系对TRAIL的敏感性，这表明Akt和NFkB途径可能是联合免疫化疗的靶点。临床研究：自体肿瘤细胞刺激T淋巴细胞（AuTL）是从外周血淋巴细胞中体外产生的经过两周的与自体肿瘤细胞共培养过程。这些AuTLs能够溶解已建立的肿瘤细胞， ...更多信息 在晚期和转移性难治性癌症患者（pts）中可能具有过继免疫疗法（IT）的功效。我们研究了在常规预处理方案的基础上联合应用AuTL转移和化疗（ChT）的可行性，以利用两者的抗癌效应和抗肿瘤免疫重建。19例患者入组了一项初步临床试验。常规ChT方案以标准剂量为基础。中位治疗时间超过11.5个月，中位生存时间为14.8个月。在所有剂量下，与ChT和AuTL转移相关的不良事件都很小。在本研究中，13例患者中有4例实现了主要肿瘤缓解（2例CR：完全消退，2例PR：部分消退）。3例患者显示疾病进展，6例患者疾病稳定超过90天。3次治疗后，4例CR/PR患者中分别有2例和1例PBMC产生IFN-γ和TNF-α，但无TGF-β1反应。治疗后病情稳定的6例患者中有2例IFN-γ和TNF-α应答较高，无TGF-β1或IL-4应答。3/3例进展性疾病患者TGF-β1和IL-4分泌平行增加。这些数据显示，AuTL转移和非清髓性ChT的组合疗法对于患有难治性晚期癌症的患者是可行的选择，而不降低大多数对治疗有反应的患者的外周血中的Thl细胞因子应答。根据IT和ChT各自的作用机制，应更严格地评估AuTL转移联合非清髓性ChT对各种癌症的治疗效果，以管理患者的免疫缺陷。少

Experimental research : Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) induces apoptosis in cancer cells by binding to death receptors DR4/DR5. The expression of functional TRAIL protein appears to be rather restricted to immune cells, including T cells, NK cells, dendric cells (DCs) etc. We examined TRAIL sensitivity in the human cancer cell lines and also assessed TRAIL efficacy with EGFR tyrosine kinase inhibitor Gefitinib, and proteasome inhibitor Bortezomib as possible new approach of combination therapy. Our studies demonstrate that Gefitinib and Bortezomib were useful for enhancement of TRAIL sensitivity in part of cell lines suggesting Akt and NFkB pathways as possible target of combining immuno-chemotherapy.Clinical research : Autologous tumor cells stimulated T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell l … More ines and may have potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on conventional conditioning regimen in order to take advantage by both the anticancer effects reconstruction of antitumor immune. 19 patients were enrolled in a pilot clinical trial. The conventional ChT regimen was based on standard dose. The median period of treatment was over 11.5 months and median survival time is 14.8 months. Adverse events related to both of the ChT and AuTL transfer at all doses was minimal. 4 of 13 pts achieved major tumor responses (2 CR : complete regression and 2 PR : partial regression) in this study. 3 pts showed progressive disease and 6 pts had stable disease for over 90 days. Two and one of 4 CR/PR pts had increased IFN-γ and TNF-α production no TGF-β1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after treatment had high IFN-γ and TNF-α responses and no TGF-β1 or IL-4 response. TGF-β1 and IL-4 secretion increased parallaly in 3/3 pts that experienced progressive disease. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without reducing Thl cytokine responses in peripheral blood of most pts responded to the treatment. According each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with nonmyeloablative ChT for various cancer should be performed to manage the immunodeficiency in pts. Less