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: 7996015
• 负责人: Todd D Schell
• 金额: $ 37.44万
• 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/7996015
• 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 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. PUBLIC HEALTH RELEVANCE: The results of this study will further our understanding of how adoptive T cell-based immunotherapies can be applied to established cancers. The ability to apply this approach to multiple cancer types will be investigated and will provide insight for enhancement of this promising approach for the treatment of cancer.

描述（由申请人提供）：近年来已经开发了多种方法来募集CD 8 + T细胞用于控制癌症，因为它们具有破坏肿瘤细胞的公认效力。迄今为止最有希望的方法之一是使用过继性T细胞转移，在转移性黑色素瘤患者中特别成功。最近的进展是确定促进有效的基于过继性T细胞的癌症免疫治疗的机制。然而，决定成功与失败的变量，特别是对于黑色素瘤以外的癌症，仍然定义不清。该提案的主要目的是确定使用基于过继性T细胞的免疫疗法促进CD 8 + T细胞介导的已建立的自体肿瘤消除的机制。驱动本研究的假设是，基于T细胞的癌症过继免疫治疗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差异效应而靶向的CD 8 + T细胞表位而变化。将努力实现以下具体目标。具体目标1.明确放射增强过继免疫治疗后促进已建立的自体脑肿瘤消退的机制。具体目标2。评估来自独特组织来源的肿瘤对过继性T细胞免疫治疗的敏感性。具体目标3。确定针对弱肿瘤相关决定因素的过继性T细胞免疫治疗的关键机制。在这项研究中，从组织特异性启动子表达SV 40大T抗原癌蛋白的小鼠将被用于研究调节有效的过继性T细胞免疫疗法对不同组织中出现的肿瘤的机制。这将包括脑、胰腺和前列腺癌的模型。SV 40 T抗原系统提供了一个强大的模型来解决这些问题，因为有多种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CD 8 + T细胞对源自相同蛋白抗原的多种决定簇的应答。将定义与成功的T细胞介导的肿瘤消退相关的放射的局部效应与全身效应，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放射增强过继性T细胞转移控制独特组织学来源肿瘤的疗效。最后，我们将确定克服过继免疫治疗靶向弱肿瘤相关决定因素的局限性的方法，以扩大可用靶点的库。通过在抗原和效应T细胞群体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/或抑制成功的基于过继T细胞的免疫治疗的肿瘤特异性机制。这一新的知识应该为增加基于翻译过继性T细胞的免疫治疗方法对不同癌症的成功提供见解。 公共卫生相关性：这项研究的结果将进一步加深我们对基于过继性T细胞的免疫疗法如何应用于已建立的癌症的理解。将研究将这种方法应用于多种癌症类型的能力，并将为增强这种有前途的癌症治疗方法提供见解。