Targeted radiation and immunocytokine therapy for CEA positive malignancies

CEA 阳性恶性肿瘤的靶向放疗和免疫细胞因子治疗

• 批准号: 10720201
• 负责人: John Ernest Shively
• 金额: $ 67.63万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720201
• 关键词: Animal Model; Animals; Antibodies; Antigen Targeting; Beta Particle; Biopsy; Blocking Antibodies; Blood Platelets; Body Weight decreased; Breast; CD8-Positive T-Lymphocytes; CD8B1 gene; Carcinoembryonic Antigen; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Colon; Colonic Neoplasms; Combined Modality Therapy; Correlative Study; Data; Dose; Environment; Eragrostis; FDA approved; FOXP3 gene; Fibroblasts; Funding; Future; Hematology; IL2 gene; Image; Immune; Immune Targeting; Immune response; Immunize; Immunocompetent; Immunologics; Immunotherapy; Infiltration; Interleukin-2; Length; Linear Energy Transfer; Lymphocyte; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Mental Depression; Modeling; Monitor; Mus; Myelogenous; Neoplasm Metastasis; Normal tissue morphology; Patients; Phase; Phenotype; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Property; Proteins; Radiation; Radiation therapy; Radionuclide therapy; Regimen; Regulatory T-Lymphocyte; Resistance; Safety; Shapes; Site; Solid Neoplasm; Spleen; Stromal Cells; Stromal Neoplasm; Study models; Testing; Therapeutic; Therapy trial; Time; Tissues; Toxic effect; Transgenic Mice; Tumor Immunity; checkpoint therapy; clinically relevant; comparative; cytokine; data modeling; design; dosimetry; effector T cell; fibroblast-activating factor; image guided radiation therapy; immune activation; immune cell infiltrate; immunoregulation; improved; man; pre-clinical; predictive marker; response; side effect; subcutaneous; systemic toxicity; targeted therapy trials; treatment response; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions; wound healing

SUMMARY/ABSTRACT Image guided radiotherapy (IGRT) or systemically administered radionuclide therapy are attractive approaches that can perturb the tumor microenvironment (TME) so that targeted immunotherapy can convert a largely immunoresistant into an immunosusceptible tumor. Although this approach has been clinically explored using high or low or high plus low dose IGRT plus untargeted checkpoint immunotherapy, further improvements are warranted and require testing in appropriate clinical studies and preclinical models. In this application we propose three aims to test our hypothesis that IGRT and or targeted alpha therapy (TAT) followed immediately by immunocytokine (ICK), a form of targeted immunotherapy, will lead to increased tumor infiltration of IFN+ CD8s (Teff) and decreased Foxp3+ CD4s (Treg). This hypothesis is supported by two studies targeting CEA, a major marker of solid tumor malignancies (eg. colon and breast), in CEA transgenic mice that are immunocompetent, express CEA in normal tissues, and are tolerant to CEA. We now propose to test this hypothesis in two clinical trials, aims 1 (IGRT + ICK) and 2 (TAT), and perform immunocorrelate studies for Teff and Treg cells, among others, on pre- and post-therapy biopsies. Aim 2 is a TAT only study as a prelude to a third clinical trial combining TAT plus ICK, that will be initiated at the end of the project period. In aim 3, we will refine our animal studies to determine TME changes immediately after sequential therapy for both IGRT plus ICK or TAT plus ICK, by a combination of PET imaging for CEA, CD8s and stromal cells by fibroblast activated protein (FAPI), along with flow and IHC analysis of tumors, LNs and spleen. We expect the results of aims 1 and 2 to further guide aim 3, and the results of aim 3 to guide future trials that incorporate IGRT and/or TAT plus ICK in CEA positive malignancies.

摘要/摘要 图像引导放射治疗 (IGRT) 或全身性放射性核素治疗是有吸引力的方法 可以扰乱肿瘤微环境（TME），从而使靶向免疫疗法可以在很大程度上转化 免疫抵抗性转化为免疫敏感肿瘤。尽管这种方法已经在临床上进行了探索 高或低或高加低剂量IGRT加非靶向检查点免疫治疗，进一步的改进是 需要在适当的临床研究和临床前模型中进行测试。在这个应用程序中我们 提出三个目标来检验我们的假设，即立即进行 IGRT 和/或靶向 α 疗法 (TAT) 免疫细胞因子 (ICK)（一种靶向免疫疗法）将导致 IFN-+ 的肿瘤浸润增加 CD8 (Teff) 和 Foxp3+ CD4 (Treg) 减少。这一假设得到了两项针对 CEA 的研究的支持， 实体瘤恶性肿瘤（例如结肠癌和乳腺癌）的主要标志物，在 CEA 转基因小鼠中 具有免疫功能，在正常组织中表达 CEA，并且对 CEA 具有耐受性。我们现在建议对此进行测试 两项临床试验中的假设，目标 1 (IGRT + ICK) 和 2 (TAT)，并进行免疫相关研究 Teff 和 Treg 细胞等在治疗前和治疗后活检中。目标 2 是一项仅作为前奏的 TAT 研究 第三项临床试验结合了 TAT 和 ICK，该试验将在项目期结束时启动。在目标 3 中，我们 将完善我们的动物研究，以确定 IGRT 序贯治疗后立即发生的 TME 变化 加 ICK 或 TAT 加 ICK，通过成纤维细胞对 CEA、CD8 和基质细胞进行 PET 成像的组合 激活蛋白 (FAPI)，以及肿瘤、淋巴结和脾脏的流式分析和 IHC 分析。我们期望的结果是 目标 1 和 2 进一步指导目标 3，目标 3 的结果指导未来纳入 IGRT 和/或 CEA 阳性恶性肿瘤中 TAT 联合 ICK。