CD8+ T Cell-Mediated Immunotherapy of Autochthonous SV40 T Antigen-Induced Tumors

CD8 T 细胞介导的本地 SV40 T 抗原诱导肿瘤的免疫治疗

• 批准号: 8387758
• 负责人: Todd D Schell
• 金额: $ 35.19万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-06-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387758
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Antigen Targeting; Antigens; Antineoplastic Agents; Autoantigens; Automobile Driving; Brain; Brain Neoplasms; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Control; Cells; Characteristics; Clinical Research; Coupled; Dependence; Development; Effectiveness; Epitopes; Event; Failure; Goals; ITGAM gene; ITGAX gene; Immune response; Immunization; Immunotherapeutic agent; Immunotherapy; In Vitro; Knowledge; Large T Antigen; Life; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Metastatic Melanoma; Modeling; Monitor; Mus; Oncogene Proteins; Patients; Phenotype; Population; Positioning Attribute; Property; Prostate; Proteins; Radiation; Radiation Tolerance; Reagent; Recruitment Activity; Relative (related person); Research; Simian virus 40; Site; System; T cell anergy; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; TNFRSF5 gene; Target Populations; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Viral Tumor Antigens; base; cancer immunotherapy; cancer therapy; cancer type; design; experience; improved; insight; irradiation; killings; melanoma; neoplastic cell; novel; pancreatic neoplasm; promoter; public health relevance; radiation effect; response; success; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): A variety of approaches have been developed in recent years to recruit CD8+ T cells for the control of cancer due to their recognized potency to destroy tumor cells. One of the most promising approaches to date is the use of adoptive T cell transfer, with particular success in metastatic melanoma patients. Recent progress has been made toward defining the mechanisms that promote effective adoptive T cell-based immunotherapy of cancer. However, the variables that determine success versus failure, particularly for cancers beyond melanoma, remain poorly defined. The broad objective of this proposal is to identify mechanisms that promote CD8+ T cell-mediated elimination of established autochthonous tumors using adoptive T cell-based immunotherapies. The hypothesis driving this study is that the effectiveness of T cell- based adoptive immunotherapy of cancer will vary with the distinct histological origin of the tumor and the CD8+ T cell epitope targeted due to differential effects on the tumor microenvironment. The following specific aims will be pursued. Specific Aim 1. Define the mechanisms that promote regression of established autochthonous brain tumors following radiation-enhanced adoptive immunotherapy. Specific Aim 2. Evaluate the sensitivity of tumors from unique tissue origins to adoptive T cell immunotherapy. Specific Aim 3. Identify mechanisms critical for adoptive T cell immunotherapy targeting a weak tumor-associated determinant. In this study, mice that express the SV40 large T antigen oncoprotein from tissue-specific promoters will be used to investigate mechanisms that regulate effective adoptive T cell immunotherapy toward tumors that arise in distinct tissues. This will include models of brain, pancreas and prostate cancer. The SV40 T antigen system provides a powerful model to address these issues due to the availability of multiple well-established transgenic mouse tumor models and the large array of reagents available to monitor T antigen-specific CD8+ T cell responses to multiple determinants derived from the same protein antigen. Localized versus systemic effects of radiation associated with successful T cell-mediated tumor regression will be defined in order to more specifically design immunotherapies for established tumors. In addition, the efficacy of radiation-enhanced adoptive T cell transfer to control tumors of unique histological origin will be assessed by defining changes in the T cell phenotype and tumor microenvironments that are associated with successful immunotherapy. Finally, we will identify approaches that overcome the limitations of targeting a weak tumor-associated determinant by adoptive immunotherapy in order to broaden the repertoire of available targets. By testing these approaches in a tumor system where the antigen and the effectors' T cell population are held constant, the results of these studies should reveal tumor-specific mechanisms that promote and/or inhibit successful adoptive T cell-based immunotherapy. This new knowledge should provide insight for increasing the success of translational adoptive T cell-based immunotherapy approaches against diverse cancers.

描述（由申请人提供）：近年来，人们开发了多种方法来招募 CD8+ T 细胞来控制癌症，因为它们具有公认的破坏肿瘤细胞的功效。迄今为止最有前途的方法之一是使用过继性 T 细胞移植，在转移性黑色素瘤患者中取得了特别成功。最近在确定促进基于 T 细胞的有效过继性癌症免疫疗法的机制方面取得了进展。然而，决定成功与失败的变量，尤其是黑色素瘤以外的癌症，仍然不明确。该提案的主要目标是确定使用基于 T 细胞的过继免疫疗法促进 CD8+ T 细胞介导的消除已建立的原发肿瘤的机制。推动这项研究的假设是，基于 T 细胞的癌症过继免疫疗法的有效性将随着肿瘤的不同组织学起源和由于对肿瘤微环境的不同影响而靶向的 CD8+ T 细胞表位而变化。将追求以下具体目标。具体目标 1. 明确放射增强过继免疫治疗后促进已形成的原发性脑肿瘤消退的机制。具体目标 2. 评估独特组织来源的肿瘤对过继性 T 细胞免疫疗法的敏感性。具体目标 3. 确定针对弱肿瘤相关决定簇的过继性 T 细胞免疫疗法的关键机制。在这项研究中，通过组织特异性启动子表达 SV40 大 T 抗原癌蛋白的小鼠将用于研究调节针对不同组织中出现的肿瘤的有效过继性 T 细胞免疫治疗的机制。这将包括脑癌、胰腺癌和前列腺癌模型。 SV40 T 抗原系统提供了一个强大的模型来解决这些问题，因为有多个成熟的转基因小鼠肿瘤模型和大量试剂可用于监测 T 抗原特异性 CD8+ T 细胞对源自相同蛋白抗原的多个决定簇的反应。将定义与 T 细胞介导的肿瘤消退成功相关的放射的局部效应和全身效应，以便更具体地设计针对已建立肿瘤的免疫疗法。此外，将通过定义与成功免疫治疗相关的 T 细胞表型和肿瘤微环境的变化来评估辐射增强过继性 T 细胞转移控制独特组织学起源肿瘤的功效。最后，我们将确定克服通过过继免疫疗法靶向弱肿瘤相关决定簇的局限性的方法，以扩大可用靶点的范围。通过在抗原和效应 T 细胞群保持恒定的肿瘤系统中测试这些方法，这些研究的结果应该揭示促进和/或抑制成功的过继 T 细胞免疫疗法的肿瘤特异性机制。这一新知识将为提高基于转化过继 T 细胞的免疫疗法针对不同癌症的成功率提供见解。