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

摘要 本申请是为回应特别利益通知(NOSI)而提出的，该通知被确认为非- CA-21-083。在我们的癌症登月IOTN U01奖中，我们正在开发一种综合疗法 根除免疫“冷”和免疫无效的转移性癌症的方法 检查点抑制(ICI)。以推进该奖项的目标并广泛地定义辐射敏感性 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分析来确定 辐射剂量、剂量率和分割对免疫细胞系存活和表型的影响 来自血液、骨髓和肿瘤浸润性免疫细胞。我们假设不同的免疫效应 将有不同的剂量-反应曲线，因此不能定义单一剂量的放射治疗 但不同剂量的辐射将最能激活一种有效的抗肿瘤 通过在单个肿瘤微环境中以最佳方式接触不同的机制来实现免疫反应。这个 在这些研究中开发的洞察力和治疗方案应该能够使临床更有效 将放射治疗和免疫治疗相结合的治疗方法在慢性阻塞性肺疾病患者中的翻译 转移性癌。

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.