Immunotherapy of pancreatic ductal adenocarcinoma with human gammadelta T lymphocytes

人γδT淋巴细胞对胰腺导管腺癌的免疫治疗

• 批准号: 191998266
• 负责人: Professorin Dr. Daniela Wesch
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/191998266?language=en
• 关键词: Immunotherapy; pancreatic; ductal; adenocarcinoma; human

Circulating as well as tumor-infiltrating human γδ T cells kill various tumor cells in a MHC-non-restricted fashion. The dominant subset of human Vγ9Vδ2 γδ T cells recognizes isopentenyl pyrophosphate (IPP), an intermediate of the mevalonate pathway, which is increased in tumor cells. The augmented production of IPP in transformed cells can be further increased by therapeutically administered nitrogen-containing-bisphosphonates (n-BPs). We have shown the efficacy of human Vγ9Vδ2 γδ T cells against pancreatic ductal adenocarcinoma (PDAC) in vitro as well as in vivo after adoptive transfer of γδ T cells and n-BPs/IL-2 into SCID mice. Several pilot studies published by others reported a selective activation of γδ T cells and a partial reduction of tumor growth in renal or prostate cancer patients after treatment with n-BPs and low dose IL-2. To promote γδ T cell-based immunotherapy, the following issues will be addressed: (i) optimization of in vitro expansion and cytotoxic effector activity of tumor-reactive γδ T cells; (ii) characterization of cytotoxicity against PDAC cell lines including direct effects of n-BPs, regulation of interacting molecules and tumor escape mechanisms in the interplay of γδ T cells and PDAC cells; (iii) use of an adoptive transfer model in SCID-Beige mice for further preclinical characterization of PDAC-reactive γδ T cells and anti-tumor effects of n-BPs; (iv) γδ T cell focused immune-monitoring in proof-of-principle studies in patients with advanced PDAC treated with n-BPs plus low dose IL-2; and (v) establishment of GMP protocols for ultimate adoptive transfer of γδ T cells into patients.

循环以及肿瘤浸润的人γδ Τ细胞以MHC非限制性方式杀死各种肿瘤细胞。人Vγ 9VS 2 γδ T细胞的优势亚群识别异戊烯焦磷酸（IPP），其是甲羟戊酸途径的中间体，在肿瘤细胞中增加。通过治疗性施用含氮双膦酸盐（n-BP），可以进一步增加转化细胞中IPP的增加的产生。我们已经显示了在γδ T细胞和n-BP/IL-2过继转移到SCID小鼠中后，人Vγ 9VS 2 γδ T细胞在体外以及体内针对胰腺导管腺癌（PDAC）的功效。其他人发表的几项初步研究报告了在用n-BP和低剂量IL-2治疗后，肾癌或前列腺癌患者中γδ T细胞的选择性活化和肿瘤生长的部分减少。为了促进基于γδ T细胞的免疫治疗，将解决以下问题：（i）肿瘤反应性γδ T细胞的体外扩增和细胞毒性效应器活性的优化;（ii）针对PDAC细胞系的细胞毒性的表征，包括n-BP的直接作用、相互作用分子的调节以及γδ T细胞和PDAC细胞相互作用中的肿瘤逃逸机制;（iv）在用n-BP加低剂量IL-2治疗的晚期PDAC患者中的原理验证研究中的γδ T细胞聚焦免疫监测;以及（v）建立用于γδ T细胞最终过继转移到患者体内的GMP方案。