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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：
10672943
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/10672943
关键词：
90Y Androgen Receptor Androgens Antigens Antitumor Response Binding Binding Sites Bioinformatics Brachytherapy CD8-Positive T-Lymphocytes Cancer Vaccines Castration Cells 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 checkpoint inhibitor Immunity Immunologics Immunotherapy Infiltration Interferon Type II Isotopes LNCaP 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 Predisposition Production Prostate Cancer therapy Prostatic Neoplasms Proteins Radiation Dose Unit Radiation therapy Radioimmunoconjugate Radiolabeled Radionuclide therapy Radium Recurrence Resistance Series T cell infiltration T-Cell Activation T-Lymphocyte Testing Time Tissues Toxic effect Transgenic Organisms Tumor Antigens Tumor Expansion Tumor-Infiltrating Lymphocytes Vaccination Vaccines Work Xenograft procedure advanced prostate cancer androgen deprivation therapy antitumor effect cancer infiltrating T cells cancer type cancer vaccination chelation deprivation design dosimetry immune cell infiltrate 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-项目四：前列腺癌是世界范围内的重大健康问题