Molecular Targeted Radionuclide Therapy with Tumor-Specific Vaccine to Stimulate and Expand T-cell Activation

项目摘要-项目4：前列腺癌是一个严重的全球健康问题 治疗是必要的。放射治疗是局限性前列腺癌的标准治疗方法，治疗方式为 外照射或近距离放射治疗。靶向放射性核素治疗(TRT)试剂已被 已被批准用于晚期转移性前列腺癌，其他正在进行临床测试。迄今为止，大多数 使用这些药物的研究集中在确定可以消除肿瘤细胞的最大剂量，同时 对正常细胞的影响最小。使用这些类型的药物来启动肿瘤的概念 免疫治疗的微环境相对来说还没有被探索。这个P01的首要目标是 评价TRT作为一种调节肿瘤微环境以进行免疫治疗的手段。项目 2将评估TRT与T细胞检查点抑制剂治疗的结合，这些治疗单独是 前列腺癌的治疗不太成功。项目3将结合肿瘤内评估TRT 为免疫“冷”肿瘤提供免疫疗法，这对大多数前列腺癌来说是不可行的 癌症的转移扩散模式。虽然前列腺癌通常被认为是一种 免疫寒冷肿瘤，缺乏大量肿瘤浸润性T细胞，但它仍然是唯一 到目前为止，抗肿瘤疫苗已经获得FDA批准的人类癌症类型，可能是基于其 诱导肿瘤特异性T细胞的能力。目前的项目将集中在前列腺癌和评估TRT在 与抗原特异性抗肿瘤疫苗联合接种。要检验的假设，基于现有的 初步资料表明，TRT可以通过消耗免疫抑制细胞来调节肿瘤微环境。 并促进活化的CD8+T细胞的渗透，这可能通过使用不同的 TRT载体、疫苗接种和雄激素剥夺疗法。这种方法与另一种方法相辅相成 项目和项目4将通知其他项目，允许直接评估TRT对 肿瘤抗原特异性CD8+T细胞的数量和功能，这是在 哪些靶向肿瘤抗原是未知的。拟议的工作将在很大程度上依赖于RPR Core 1 TRT载体生产，用于剂量学研究的AID Core 2，以及用于统计和生物信息学支持的BB Core 3。 基本假设将通过以下目的进行检验：1)确定不同TRT的效果 药物对小鼠前列腺癌模型免疫浸润性细胞组成和效应功能的影响 为了确定抗原特异性肿瘤疫苗在与不同的TRT试剂结合时是否会引起 肿瘤特异性CD8+T细胞的大量浸润性；3)确定CD8+T细胞的侵袭性和抗肿瘤 雄激素增强抗原特异性肿瘤疫苗和TRT治疗的肿瘤疗效 剥夺。预计这些研究将为合理、新颖的未来临床提供最佳设计和序列 前列腺癌患者评估联合使用TRT和抗肿瘤疫苗治疗的试验。

PROJECT SUMMARY – PROJECT 4: Prostate cancer is a significant health problem worldwide for which new treatments are needed. Radiation therapy is a standard therapy for localized prostate cancer, delivered as either external beam radiation therapy or brachytherapy. Targeted radionuclide therapy (TRT) agents have been approved for advanced, metastatic prostate cancer, and others are in clinical testing. To date, the majority of studies using these agents have focused on identifying maximum doses that can eliminate tumor cells while having minimal effects on normal cells. The concept of using these types of agents to prime the tumor microenvironment for immunotherapy has been relatively unexplored. The overarching goal of this P01 is to evaluate TRT as a means to modulate the tumor microenvironment to enable immunotherapy treatments. Project 2 will evaluate TRT in combination with T-cell checkpoint inhibitor treatments, treatments which alone have been less successful in the treatment of prostate cancer. Project 3 will evaluate TRT in combination with intratumoral delivery of immune therapies for immunologically “cold” tumors, an approach not feasible for most prostate cancers given the patterns of metastatic spread. While prostate cancer is generally considered to be an immunologically cold tumor, devoid of large numbers of tumor-infiltrating T cells, it nonetheless remains the only human cancer type to date for which an anti-tumor vaccine has been FDA-approved, likely on the basis of its ability to elicit tumor-specific T cells. This current Project will focus on prostate cancer and evaluate TRT in combination with antigen-specific anti-tumor vaccination. The hypothesis to be tested, based on existing preliminary data, is that TRT can modulate the tumor microenvironment by depleting immunosuppressive cell populations and promote infiltration of activated CD8+ T cells, and this may be modulated by the use of different TRT vectors, vaccination, and androgen deprivation therapy. This approach is complementary to the other Projects and Project 4 will inform the other Projects by permitting the direct evaluation of effects of TRT on the number and function of tumor antigen-specific CD8+ T cells, a level of analysis not possible in other Projects in which the targeted tumor antigens are not known. The work proposed will rely heavily on the RPR Core 1 for TRT vector production, AID Core 2 for dosimetry studies, and BB Core 3 for statistical and bioinformatics support. The underlying hypothesis will be tested with the following Aims: 1) to determine the effects of different TRT agents on the composition and effector function of immune infiltrating cells in murine prostate cancer models; 2) to determine whether antigen-specific tumor vaccination, when combined with different TRT agents, elicits greater numbers of tumor-specific infiltrating CD8+ T cells; and 3) to determine if CD8+ T cell infiltration and anti- tumor efficacy elicited with antigen-specific tumor vaccination and TRT treatment are augmented with androgen deprivation. It is expected these studies will inform the best design and sequence of rational, novel future clinical trials for patients with prostate cancer evaluating treatments using TRT in combination with anti-tumor vaccines.