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.

总结/摘要 影像引导放射治疗（IGRT）或全身给予放射性核素治疗是有吸引力的方法 它可以扰乱肿瘤微环境（TME），使靶向免疫治疗可以在很大程度上转化肿瘤微环境。 免疫抗性转化为免疫敏感性肿瘤。虽然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疗法，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。在本申请中，我们 我提出了三个目标来检验我们的假设，即IGRT和/或靶向α治疗（达特）立即 通过免疫细胞因子（ICK），一种靶向免疫疗法，将导致IFN γ +的肿瘤浸润增加 CD 8 s（Teff）和Foxp 3 + CD 4s（Treg）减少。这一假设得到了两项针对CEA的研究的支持， 实体瘤恶性肿瘤的主要标志物（例如，结肠和乳腺），在CEA转基因小鼠中， 具有免疫活性，在正常组织中表达CEA，并对CEA耐受。我们现在建议对此进行测试 在两项临床试验中假设，目标1（IGRT + ICK）和2（达特），并进行免疫相关性研究， Teff和Treg细胞等，在治疗前和治疗后活检。目的2是一项仅作为前奏的达特研究 第三个临床试验结合达特加ICK，这将在项目结束时启动。在目标3中，我们 将完善我们的动物研究，以确定IGRT和IGRT序贯治疗后即刻的TME变化。 加ICK或达特加ICK，通过成纤维细胞对CEA、CD 8和基质细胞进行PET成像的组合 活化蛋白（FAPI），沿着肿瘤、LN和脾的流动和IHC分析。我们期待着 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 癌胚抗原阳性恶性肿瘤中达特加ICK。