Eradication of Escaped Variant Tumor Cells for Cancer Immunotherapy

根除逃逸变异肿瘤细胞以进行癌症免疫治疗

基本信息

批准号：
10541139
负责人：
Yong Lu
金额：
$ 38.1万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541139
关键词：
Adenosine Adoptive Cell Transfers Adoptive Transfer Antigens Antitumor Response B-Lymphocytes CD19 Antigens CD19 gene CD22 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Lineage Cells Clinical Research Clinical Trials Color Darkness Data Disease remission Down-Regulation Endowment Extracellular Space Foundations Future Glioblastoma Growth Human Immune Immune response Immunotherapy Inflammatory Interferons Knock-out Leukocytes Lymphoma MS4A1 gene Malignant Neoplasms Mediating Melanins Modeling Multiple Myeloma Mus Mutation Myeloid Cells Pathway interactions Patients Production Purinoceptor Recurrence Recurrent tumor Relapse Resistance Role Site Solid Neoplasm Stress Surface T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Translating Tumor Immunity Tumor Tissue Tyrosinase related protein-1 Variant Work anti-tumor immune response antitumor effect cancer cell cancer immunotherapy cell injury chimeric antigen receptor T cells cost efficacy evaluation experience extracellular humanized mouse immunogenic in vivo innovation leukemia melanoma monocyte mouse model neoplastic cell novel pre-clinical prevent recruit response tumor tumor eradication

项目摘要

Project Summary Recently, we discovered that adoptive transfer of CD39KO tumor-specific (mixed CD4+ and CD8+) T cells, resulted in long-term survival of mice bearing large established tumors. Unexpectedly, we found that these T cells promoted killing of antigen-loss-variants (ALVs) in vivo and prevented tumor recurrence. Moreover, transfer of CD39KO, but not control KO, tumor-specific T cells eradicated large chimeric tumors that contained 10% of ALVs and resulted in long-term tumor-free survival and protection against rechallenge with ALV tumor cells. Based on these novel findings, we hypothesize that transfer of tumor-specific CD39KO T cells will eradicate large established tumors and prevent recurrence of ALV tumors, due to their ability to directly kill the tumor cells and induce anti-ALV responses. Aim 1 will determine the contribution of type I IFN production at the tumor site in preventing recurrence of ALV tumors. Aim 2 will determine the role of CD39KO T cells in the recruitment of inflammatory myeloid cells and the induction of type I IFN production for tumor clearance. Aim 3 will determine whether human tumor-specific CD39KO T cells are also endowed with these abilities to effectively eradicate human tumors in humanized mice. These innovative and mechanistic studies will shed light on the mechanisms underlying CD39KO T cell-mediated antitumor immunity and will thus establish a foundation for translating this discovery into more effective immunotherapies using tumor-specific T-cell subsets in human cancers.

项目摘要最近，我们发现CD39KO肿瘤特异性（混合CD4+和CD8+）T细胞的过继转移，导致具有大型肿瘤的小鼠长期存活。出乎意料的是，我们发现这些T 细胞促进体内杀死抗原损伤变异剂（ALV）并防止肿瘤复发。而且， CD39KO的转移，但不能控制KO，肿瘤特异性T细胞根除了包含的大嵌合肿瘤 10％的ALV，导致长期无肿瘤的生存率和防止ALV肿瘤的补给细胞。根据这些新发现的结果，我们假设肿瘤特异性CD39KO T细胞的转移将消除大型已建立的肿瘤并防止ALV肿瘤的复发，因为它们有能力直接杀死该肿瘤肿瘤细胞并诱导抗ALV反应。 AIM 1将确定I型IFN生产的贡献防止ALV肿瘤复发的肿瘤部位。 AIM 2将确定CD39KO T细胞在炎性髓样细胞的募集以及I型IFN产生肿瘤清除率的诱导。目标3 将确定人类肿瘤特异性CD39KO T细胞是否也具有这些能力有效地消除人源性小鼠的人类肿瘤。这些创新和机械研究将摆脱阐明CD39KO T细胞介导的抗肿瘤免疫的机制，因此将建立一个使用肿瘤特异性T细胞将该发现转化为更有效的免疫疗法的基础人类癌症中的子集。