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

项目概要-项目4：前列腺癌是全球范围内的重大健康问题， 需要治疗。放射治疗是局限性前列腺癌的标准治疗， 外部射束放射治疗或近距离放射治疗。靶向放射性核素治疗（TRT）剂已经被广泛应用于临床。 已被批准用于晚期转移性前列腺癌，其他正在进行临床试验。迄今为止，大多数 使用这些药剂的研究集中在确定可以消除肿瘤细胞的最大剂量， 对正常细胞的影响很小。使用这些类型的药物来引发肿瘤的概念 免疫治疗的微环境相对未被探索。本P01的总体目标是 评估TRT作为调节肿瘤微环境以实现免疫疗法治疗的手段。项目 2将评估TRT与T细胞检查点抑制剂治疗的组合， 在前列腺癌的治疗上不太成功。项目3将评价TRT联合瘤内 为免疫学上的“冷”肿瘤提供免疫治疗，这是一种对大多数前列腺不可行的方法。 癌症的转移扩散模式。虽然前列腺癌通常被认为是一种 免疫冷肿瘤，缺乏大量的肿瘤浸润性T细胞，但它仍然是唯一的 迄今为止，抗肿瘤疫苗已被FDA批准的人类癌症类型，可能是基于其 引发肿瘤特异性T细胞的能力。目前的项目将集中在前列腺癌和评价TRT在 与抗原特异性抗肿瘤疫苗接种的组合。待检验的假设，基于现有的 初步数据表明，TRT可以通过消耗免疫抑制细胞来调节肿瘤微环境， 细胞群并促进活化的CD 8 + T细胞的浸润，并且这可以通过使用不同的免疫调节剂来调节。 TRT载体、疫苗接种和雄激素剥夺治疗。这种方法是对另一种方法的补充 项目和项目4将通过允许直接评估TRT对 肿瘤抗原特异性CD 8 + T细胞的数量和功能，这一分析水平在其他项目中是不可能的。 其靶向的肿瘤抗原是未知的。建议的工作将在很大程度上依赖于RPR核心1， TRT载体生产，AID Core 2用于剂量测定研究，BB Core 3用于统计和生物信息学支持。 将按照以下目的检验基本假设：1）确定不同TRT的影响 药物对鼠前列腺癌模型中免疫浸润细胞的组成和效应子功能的影响; 2） 为了确定抗原特异性肿瘤疫苗接种与不同的TRT剂联合使用时是否能增强肿瘤细胞的增殖， 更大数量的肿瘤特异性浸润性CD 8 + T细胞;和3）确定CD 8 + T细胞浸润和抗-CD 8 + T细胞浸润是否与肿瘤特异性浸润性CD 8 + T细胞相关。 抗原特异性肿瘤疫苗接种和TRT治疗引起的肿瘤疗效可通过雄激素增强 剥夺预计这些研究将为合理的、新颖的未来临床研究提供最佳设计和顺序。 前列腺癌患者的试验，评估TRT联合抗肿瘤疫苗的治疗。

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.