P38 MAPK is a molecular switch that controls the acquired resistance in adoptive cell therapy

P38 MAPK 是一种分子开关，可控制过继性细胞疗法中的获得性耐药

基本信息

批准号：
10640871
负责人：
Yong Lu
金额：
$ 36.11万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640871
关键词：
Adoptive Cell Transfers Antigen Presentation Antigens Automobile Driving Bone Marrow CD19 gene Cancer Patient Cancer Relapse Cell Differentiation process Cell Lineage Cells Characteristics Clinical Clinical Trials Data Dendritic Cells Development Drug resistance Foundations Future Generations Genetic Transcription Glioblastoma Granulocyte-Macrophage Colony-Stimulating Factor Immune Immunity Immunotherapy In Vitro Infiltration Interferons Lead Lymphoma MAP Kinase Gene Macrophage Malignant neoplasm of pancreas Mediating Modeling Molecular Multiple Myeloma Mus Myeloid Cells Nature PPAR Pathway Pathway interactions Patients Population Process Production Recurrence Relapse Reporting Repression Resistance Role Signal Repression Signal Transduction Solid Neoplasm Somatic Mutation T cell therapy T-Lymphocyte TNFRSF5 gene TNFSF4 gene Testing Tumor Antigens Tumor Immunity Viral Work cancer cell cancer immunotherapy chimeric antigen receptor T cells genetic signature immunogenic in vivo inhibitor leukemia/lymphoma melanoma mimicry neoplastic cell novel p38 Mitogen Activated Protein Kinase prevent programs response tumor tumor microenvironment tumor-immune system interactions

项目摘要

Project Summary A major obstacle to successful adoptive cell therapy (ACT) is the development of acquired resistance, which can occur due to cancer cells become invisible to tumor-specific T cells when cancer cells downregulate or lost the antigen(s) (refers to antigen-low/loss resistant tumor cells, or ALRs). In this proposal, we will explore the role of reprogramming of tumor microenvironment (TME) by p38 MAPK inhibition to promote a robust dendritic cell (DC)-driving anti-ALR immunity to prevent acquired resistance in ACT. In our in vivo preliminary studies, co-treatment with CAR T cells and Ralimetinib (a potent and selective inhibitor of p38 MAPK developed for cancer patients) confers immunogenic DC signature characteristics within TME. Strikingly, CAR T cell+Ralimetinib-treatment eradicated established tumors and resulted in long-term tumor-free survival by triggering a robust host anti-ALR immunity, whereas CAR T cell ACT alone recapitulated the clinical scenario of cancer relapse mediated by ALRs. Based on these novel findings, we hypothesize that p38 MAPK is a critical molecular switch that controls DC differentiation, where p38 inhibition promotes an immunogenic DC transcriptional program and induces potent anti-ALR immunity to prevent the acquired resistance in T cell therapy. Aim 1 will determine the role of NFB/Stat5 signaling by repression of PPAR in the molecular mechanisms of Ralimetinib-mediated DC enrichment. Aim 2 will determine the role of NFB (p50)-dependent viral mimicry in DCs for ALR clearance after p38 inhibitor-treatment in vivo. This study may uncover a novel mechanism for preventing tumor relapse in ACT. Data from our proposed Aims may yield critically needed evidence that repurposing the clinically tested Ralimetinib from targeting p38 MAPK in tumor cells toward that of immune cells may induce a complete and durable response in ACT. This translationally relevant work could then lay the foundation for future clinical trials.

项目概要成功的过继细胞疗法（ACT）的一个主要障碍是获得性耐药的发展，这会导致可能是由于当癌细胞下调或丢失时，癌细胞对肿瘤特异性 T 细胞来说变得不可见。抗原（指抗原低/丢失抗性肿瘤细胞，或 ALR）在本提案中，我们将探讨通过抑制 p38 MAPK 重新编程肿瘤微环境（TME）以促进强健的树突状细胞的作用细胞 (DC) 驱动抗 ALR 免疫，以防止 ACT 获得性耐药。与 CAR T 细胞和 Ralimetinib（一种有效的选择性 p38 MAPK 抑制剂，为癌症患者）在 TME 中赋予免疫原性 DC 特征，CAR T 引人注目。细胞+雷美替尼治疗根除已形成的肿瘤并导致长期无肿瘤生存触发强大的宿主抗 ALR 免疫力，而 CAR T 细胞 ACT 单独概括了临床情况基于这些新发现，我们认为 p38 MAPK 是一种 ALR 介导的癌症复发的机制。控制 DC 分化的关键分子开关，其中 p38 抑制可促进免疫原性 DC 转录程序并诱导有效的抗 ALR 免疫，以防止 T 细胞获得性耐药目标 1 将通过抑制 PPAR- 来确定 NF-B/Stat5 信号传导在分子生物学中的作用。 Ralimetinib 介导的 DC 富集机制目标 2 将确定 NFκB (p50) 依赖性的作用。 p38 抑制剂体内治疗后 DC 中 ALR 清除的病毒拟态性这项研究可能会揭示一种新的机制。我们提出的目标中的数据可能会产生急需的预防肿瘤复发的机制。有证据表明，将经过临床测试的 Ralimetinib 的用途从靶向肿瘤细胞中的 p38 MAPK 转向：免疫细胞的作用可能会在 ACT 中诱导完整且持久的反应。进而为以后的临床试验奠定基础。