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：
10557758
负责人：
Yong Lu
金额：
$ 39.39万
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/10557758
关键词：
Adenosine Adoptive Cell Transfers Adoptive Transfer Antigens Antitumor Response B-Lymphocytes CD19 Antigens CD19 gene CD22 gene CD8-Positive T-Lymphocytes Cell Lineage Cells Clinical Research Clinical Trials Color Data Disease remission Down-Regulation Extracellular Space Foundations Future Human Immune Immune response Immunotherapy Inflammatory Interferons Knock-out Leukocytes Light Lymphoma MS4A1 gene Malignant Neoplasms Mediating Melanins Modeling Mus Mutation Myeloid Cells Pathway interactions Patients Production Purinoceptor Recurrence 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 base cancer cell cancer immunotherapy cell injury chimeric antigen receptor T cells cost experience extracellular humanized mouse immunogenic in vivo innovation melanoma monocyte mouse model neoplastic cell novel pre-clinical prevent recruit response tumor

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.

项目概要最近，我们发现 CD39KO 肿瘤特异性（混合 CD4+ 和 CD8+）T 细胞的过继转移，导致携带大肿瘤的小鼠长期存活。没想到我们发现这些T 细胞促进体内抗原丢失变体（ALV）的杀伤并防止肿瘤复发。而且， CD39KO 的转移，但不是对照 KO，肿瘤特异性 T 细胞根除含有 10% 的 ALV，可实现长期无瘤生存并防止 ALV 肿瘤再次攻击细胞。基于这些新发现，我们假设肿瘤特异性 CD39KO T 细胞的转移将根除已形成的大肿瘤并防止 ALV 肿瘤复发，因为它们能够直接杀死肿瘤细胞并诱导抗 ALV 反应。目标 1 将确定 I 型干扰素产量的贡献防止 ALV 肿瘤复发的肿瘤部位。目标 2 将确定 CD39KO T 细胞在募集炎性骨髓细胞并诱导 I 型干扰素产生以清除肿瘤。目标 3 将确定人类肿瘤特异性 CD39KO T 细胞是否也被赋予这些能力有效根除人源化小鼠体内的人类肿瘤。这些创新和机制研究将揭示阐明 CD39KO T 细胞介导的抗肿瘤免疫的潜在机制，从而建立一个为利用肿瘤特异性 T 细胞将这一发现转化为更有效的免疫疗法奠定了基础人类癌症的子集。