Development of a new immunotherapeutic approach for the treatment of pancreatic adenocarcinoma by combining tumor-specific CAR-T cells with tumour-persistent immunostimulating bacteria.

通过将肿瘤特异性 CAR-T 细胞与肿瘤持久性免疫刺激细菌相结合，开发治疗胰腺腺癌的新免疫治疗方法。

• 批准号: 435414693
• 负责人: Dr. Markus Chmielewski
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/435414693?language=en
• 关键词: Development; new; immunotherapeutic; approach; treatment

The diagnosis of pancreatic carcinoma means for most of the affected persons no possibility of a cure and an extremely unfavorable relative five-year survival rate. The curative possibilities with the help of conventional forms of therapy are often limited by the advanced stage of the disease at the time of diagnosis. Therefore, it is of great social importance to develop new treatment options against this malignant tumor disease. Adoptive T-cell therapy is a promising, targeted strategy in the treatment of tumor diseases. The expression of a chimeric antigen receptor (CAR) gives T cells new specificity against tumor-associated antigens (TAA) expressed on the surface of tumor cells. The binding of such a CAR leads to T-cell-mediated lysis of the affected tumor cells. While CAR T-cell mediated immunotherapy has enjoyed great success in the treatment of malignant hematological diseases, the hopes raised in it have not yet been fulfilled in the treatment of solid tumors. This research aims to extend CAR T-cell therapy to the treatment of solid tumors, in particular pancreatic cancer. This goal is to be achieved by developing a new combination therapy of CAR T cells and immunomodulating bacteria. Genetically modified gram-negative E. coli bacteria of the strain Nissle1917 with inducible expression of an immune-activating cytokine on the surface, will be administered orally to pancreas tumor-bearing, immunocompetent mice. As a rule, such bacteria in healthy tissue will be completely eliminated by the endogenous immune system. However, the pancreatic tumor represents an immune-privileged area where such bacteria can survive and persist in the long term. The aim is to actively exploit this phenomenon through the inducible expression of a proinflammatory cytokine limited to tumor tissue in order to modulate the tumor stroma permanently and thus recruit CAR T cells as well as endogenous immune cells, in particular tumor-associated macrophages (TAMs), natural killer cells (NK), NK T cells (NKT) for the elimination of the tumor. The testing of the following candidates is intended: TNF-ɑ, IFN-γ, IL-18, IL-21 and GM-CSF. It is planned that inducible cytokine expression on the surface of tumor-persistent bacteria will establish an acute inflammation in the area of the pancreatic tumor. In the second part of this combination therapy, tumor-specific CAR T cells will be injected intravenously to completely eliminate the tumors favored by bacterial-mediated immune modulation of the tumor microenvironment. We expect from this combination therapy that the often incurable pancreatic tumor disease will receive a new immunotherapeutic option with the prospect of cure.

胰腺癌的诊断意味着对大多数受影响的人来说，没有治愈的可能性，并且相对五年生存率极差。在确诊时，疾病的晚期往往限制了常规治疗方式的治愈可能性。因此，针对这种恶性肿瘤开发新的治疗方案具有重要的社会意义。在肿瘤疾病的治疗中，过继T细胞治疗是一种很有前途的靶向策略。嵌合抗原受体(CAR)的表达使T细胞对肿瘤细胞表面表达的肿瘤相关抗原(TAA)具有新的特异性。这种CAR的结合导致T细胞介导的受影响肿瘤细胞的裂解。虽然CAR T细胞介导的免疫治疗在恶性血液病的治疗中取得了巨大的成功，但它在实体瘤的治疗中所带来的希望还没有实现。这项研究旨在将CAR T细胞疗法扩展到实体瘤的治疗，特别是胰腺癌。这一目标是通过开发一种新的CAR T细胞和免疫调节细菌的联合疗法来实现的。Nissle1917菌株的转基因革兰氏阴性大肠杆菌表面可诱导表达一种免疫激活细胞因子，将被口服给带胰腺肿瘤、免疫能力强的小鼠。一般来说，健康组织中的这种细菌将被内源性免疫系统完全消除。然而，胰腺肿瘤代表了一个免疫特权区，在那里这些细菌可以长期存活和生存。其目的是通过诱导肿瘤组织中致炎细胞因子的诱导表达来积极利用这一现象，从而永久性地调节肿瘤间质，从而招募CAR T细胞和内源性免疫细胞，特别是肿瘤相关巨噬细胞(TAMs)、自然杀伤细胞(NK)、NK T细胞(NKT)以消除肿瘤。对以下候选抗体进行检测：肿瘤坏死因子-ɑ、干扰素-γ、白介素18、白介素21和粒-巨细胞集落刺激因子。据计划，可诱导的细胞因子在肿瘤持久性细菌表面的表达将在胰腺肿瘤区域建立急性炎症。在这种联合治疗的第二部分，肿瘤特异性CAR T细胞将被静脉注射，以完全消除肿瘤的细菌介导的免疫调节肿瘤微环境的有利条件。我们期待通过这种联合疗法，这种通常无法治愈的胰腺肿瘤疾病将获得一种新的免疫治疗选择，具有治愈的前景。