Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

摘要 本申请是为了回应特别利益通知（NOSI）而提交的，该通知被确定为不- CA-21-083在我们的癌症Moonshot IOTN U 01奖中，我们正在开发一种联合治疗方法， 根除免疫学上“冷”且对免疫应答无反应的转移性癌症的方法 检查点抑制（ICI）。推进该奖项的目标，并广泛定义辐射敏感性 和免疫放射生物学的免疫细胞谱系，我们将使用先进的免疫测定，以确定 辐射剂量、剂量率和分次对免疫细胞谱系存活和表型的影响 从血液骨髓和肿瘤浸润免疫细胞中提取我们假设不同的免疫效应 放射治疗的剂量将具有不同的剂量反应曲线，因此无法定义单一剂量的放射治疗。 而是不同剂量的辐射将最能激活有效的抗肿瘤药物 通过在单个肿瘤微环境中最佳地接合不同的机制来产生免疫应答。的 在这些研究中开发的见解和治疗方案应该能够使更有效的临床 将联合收割机和免疫疗法结合起来治疗 转移性癌症

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-21-083. In our Cancer Moonshot IOTN U01 award, we are developing a combined modality therapeutic approach to eradicating metastatic cancers that are immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). To advance the objectives of that award and to broadly define the radiosensitivity and immuno-radiobiology of immune cell lineages, we will use advanced immune assays to determine the effects of radiation dose, dose rate, and fractionation on the survival and phenotype of immune cell lineages from blood, bone marrow, and tumor infiltrating immune cells. We hypothesize that diverse immunologic effects of radiation will have distinct dose-response profiles, such that no single dose of radiotherapy can be defined as “optimal” but rather that a heterogeneous dose of radiation will be best able to activate a potent anti-tumor immune response by optimally engaging distinct mechanisms within a single tumor microenvironment. The insights and treatment regimens developed in these studies should enable more effective clinical translation of therapeutic approaches that combine radiation and immunotherapies in patients with metastatic cancer.