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 4：前列腺癌是世界范围内的一个重大健康问题，新的研究需要进行放射治疗，这是局部前列腺癌的标准治疗方法。外束放射治疗或近距离放射治疗（TRT）已被采用。已被批准用于晚期转移性前列腺癌，而其他药物目前正处于临床测试阶段。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，同时对正常细胞影响最小的概念是使用这些类型的药物来引发肿瘤。免疫治疗的微环境相对尚未被探索。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治疗项目的一种手段。 2 将评估 TRT 与 T 细胞检查点抑制剂治疗的结合，单独治疗已被证实项目 3 将评估 TRT 与瘤内治疗的结合，但在治疗前列腺癌方面不太成功。针对免疫学“冷”肿瘤提供免疫疗法，这种方法对大多数前列腺来说不可行考虑到转移扩散的模式，前列腺癌通常被认为是一种癌症。免疫冷肿瘤，缺乏大量肿瘤浸润 T 细胞，但它仍然是唯一的迄今为止，FDA 已批准抗肿瘤疫苗的人类癌症类型，可能是基于其目前的项目将重点关注前列腺癌并评估 TRT 的治疗效果。结合抗原特异性抗肿瘤疫苗接种待检验的假设基于现有的。初步数据显示，TRT 可以通过消耗免疫抑制细胞来调节肿瘤微环境群体并促进活化的 CD8+ T 细胞的浸润，这可以通过使用不同的 TRT 载体、疫苗接种和雄激素剥夺疗法是其他方法的补充。项目和项目 4 将通过允许直接评估 TRT 对肿瘤抗原特异性 CD8+ T 细胞的数量和功能，这是其他项目不可能达到的分析水平所提议的工作将在很大程度上依赖于 RPR Core 1。 TRT 向量生成、用于剂量测定研究的 AID Core 2 和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测试：1）确定不同 TRT 的效果对小鼠前列腺癌模型中免疫浸润细胞的组成和效应功能的影响；2) 确定抗原特异性肿瘤疫苗接种与不同的 TRT 药物联合使用时是否会引起更大数量的肿瘤特异性浸润 CD8+ T 细胞；3) 确定 CD8+ T 细胞浸润和抗- 雄激素可增强抗原特异性肿瘤疫苗接种和 TRT 治疗带来的肿瘤疗效预计这些研究将为合理、新颖的未来临床的最佳设计和顺序提供信息。针对前列腺癌患者的试验，评估 TRT 与抗肿瘤疫苗联合治疗的效果。