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

分子靶向放射性核素治疗与肿瘤特异性疫苗刺激和扩大 T 细胞激活

基本信息

批准号：
10416048
负责人：
DOUGLAS G. MCNEEL
金额：
$ 31.91万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10416048
关键词：
90Y Androgen Receptor Androgens Antigens Antitumor Response Binding Binding Sites Bioinformatics Brachytherapy CD8-Positive T-Lymphocytes Cancer Vaccines Castration Cells Chelating Agents Clinical Treatment Clinical Trials Cytolysis DNA Vaccines Data Disease Dose Evaluation External Beam Radiation Therapy FDA approved FOLH1 gene Future Goals Health Human Image Immune Immune checkpoint inhibitor Immunity Immunologics Immunotherapy Infiltration Interferon Type II Isotopes LNCaP Lead Ligand Binding Domain Local Therapy Malignant Neoplasms Malignant neoplasm of prostate Metals Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Mission Modeling Molecular Target Mus Myeloid-derived suppressor cells National Cancer Institute Neoplasm Metastasis Normal Cell PC3 cell line Pathway interactions Patients Pattern Persons Phase I Clinical Trials Population Production Prostate Cancer therapy Prostatic Neoplasms Proteins Radiation Dose Unit Radiation therapy Radioimmunoconjugate Radiolabeled Radionuclide therapy Radium Recurrence Resistance Series T-Cell Activation T-Lymphocyte Testing Time Tissues Toxic effect Transgenic Organisms Tumor Antigens Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Vaccination Vaccines Work Xenograft procedure advanced prostate cancer androgen deprivation therapy antitumor effect base cancer type cancer vaccination deprivation design dosimetry immune function immunoregulation improved in vivo inhibitor interest lymph nodes male mouse model neoplastic cell next generation novel optimal treatments palliative programmed cell death ligand 1 prostate cancer cell line prostate cancer model prostate cancer progression research clinical testing response small molecule tumor tumor microenvironment tumor-immune system interactions vector

项目摘要

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.

项目摘要 - 项目4：前列腺癌是全球重大的健康问题需要治疗。放射疗法是针对局部前列腺癌的标准疗法，以任何一种外束放射治疗或近距离放射治疗。靶向放射线疗法（TRT）剂已经批准用于晚期前列腺癌和其他人正在临床测试中。迄今为止，大多数使用这些药物的研究重点是确定可以消除肿瘤细胞的最大剂量对正常细胞的影响最小。使用这些类型的代理来灌注肿瘤的概念免疫疗法的微环境相对出乎意料。该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一种手段。项目 2将评估TRT与T细胞检查点抑制剂治疗的结合，单独的治疗方法在治疗前列腺癌方面的成功较差。项目3将与肿瘤内评估TRT 用于免疫学“冷”肿瘤的免疫疗法递送，这种方法对于大多数前列腺不可行癌症给定转移扩散的模式。虽然前列腺癌通常被认为是免疫学上冷肿瘤，没有大量肿瘤浸润的T细胞，但它仍然是唯一的迄今能够引起肿瘤特异性T细胞的能力。当前的项目将着重于前列腺癌，并评估结合抗原特异性抗肿瘤疫苗接种。基于现有的假设初步数据是，TRT可以通过耗尽免疫抑制细胞来调节肿瘤微环境种群并促进活化的CD8+ T细胞的浸润，这可以通过使用不同的方式来调节 TRT载体，疫苗接种和雄激素剥夺疗法。这种方法对方是完整的项目和项目4将通过允许直接评估TRT对其他项目的信息肿瘤抗原特异性CD8+ T细胞的数量和功能，在其他项目中无法进行分析水平靶向肿瘤抗原尚不清楚。提议的工作将严重依赖RPR Core 1的 TRT矢量生产，用于剂量学研究的辅助核心和用于统计和生物信息学支持的BB Core 3。基本假设将以以下目的进行测试：1）确定不同TRT的影响鼠前列腺癌模型中免疫浸润细胞的组成和效应子功能的药物； 2）为了确定抗原特异性肿瘤疫苗接种是否与不同的TRT药物结合起来肿瘤特异性浸润CD8+ T细胞的数量越大; 3）确定CD8+ T细胞是否浸润和抗用抗原特异性肿瘤疫苗和TRT治疗引起的肿瘤效率通过雄激素增强剥夺。预计这些研究将为理性，新颖的未来临床的最佳设计和顺序提供信息对前列腺癌患者的试验，评估使用TRT与抗肿瘤疫苗结合使用的治疗方法。