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Project 1: Transgenic TCR-mediated tumor therapy

项目一：转基因TCR介导的肿瘤治疗

基本信息

批准号：
10629190
负责人：
PHILIP D GREENBERG
金额：
$ 57.96万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-04 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629190
关键词：
Address Adoptive Transfer Affect Affinity Alleles Antigens Antitumor Response Autoimmune Autologous Avidity Biopsy Blood Blood donor CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Cycle Cell physiology Cells Characteristics Clinical Clinical Trials Cytolysis Data Disease Disease Progression Disease remission Dose Down-Regulation Ensure Epitope spreading Epitopes Exhibits Failure Functional disorder Funding Future Genome HLA A*0201 antigen HLA-A gene Immune Immune checkpoint inhibitor Immune system Immunobiology Immunohistochemistry Immunotherapy In Vitro Individual Infusion procedures Laboratory Study Ligation Link Low Dose Radiation MHC Class I Genes Macrophage Malignant Epithelial Cell Malignant Neoplasms Measurable Mediating Merkel Cells Merkel cell carcinoma Neurosecretory Systems Oncoproteins PD-1 blockade PDL1 inhibitors Partial Remission Patients Persons Phase I/II Trial Polyomavirus Predisposition Progressive Disease Proliferating Refractory Resistance Risk Safety Sampling Simian virus 40 Site Skin Skin Cancer Specificity T cell therapy T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Therapeutic Thymus Gland Time Transgenic Organisms Translating Treatment Efficacy Treatment Failure Treatment outcome Tumor Tissue United States National Institutes of Health Up-Regulation Viral Viral Proteins Viral Tumor Antigens Virus anti-PD-L1 anti-tumor immune response antigen-specific T cells cancer diagnosis cell mediated immune response cellular transduction clinical efficacy clinical translation design epidemiologic data immune checkpoint blockade immunogenic improved insight model development mortality neoplastic cell next generation pressure programmed cell death ligand 1 programmed cell death protein 1 receptor binding response single fraction radiation single-cell RNA sequencing success tool treatment response treatment strategy tumor tumor microenvironment

项目摘要

Summary – Project 1 Merkel cell carcinoma (MCC) is a highly aggressive skin cancer diagnosed in >2,500 persons per year in the US. ~80% of MCCs are caused by the Merkel cell polyomavirus (MCPyV), and these tumors rely on persistently-expressed cell cycle promoting oncoproteins (T-Antigens). These viral T antigens are ideal targets for immunotherapies: they are highly expressed, not readily lost, exclusive to tumor tissue, non-human in sequence (reducing off-target risk), and highly immunogenic. Recent studies have shown that reducing dysfunction of endogenous T cells in MCC is effective, as half of patients have durable responses to PD-1 axis blockade. However, many patients do not respond, representing an unmet clinical need. We hypothesize that patients whose tumors do not respond to PD-1 blockade have insufficient or poorly avid MCPyV-responsive T cells, and that therapeutic efficacy can be improved with a combination of approaches. In an R01-funded trial, we have used “Triple Therapy” to treat MCC patients with metastatic disease, where we combined single-fraction radiation to reverse MCC-specific downregulation of MHC class I, infusion of autologous ex vivo-expanded MCPyV specific CD8+ T cells to supplement the lack of effective MCPyV-specific T cells and avelumab (a PD-L1 checkpoint inhibitor) to boost antigen-specific responses. These treatments have been well tolerated, encouragingly effective (with 3 of 6 patients achieving complete remission, 2 durable at >2 years), and we have demonstrated persistence, function, and tumor localization of infused T cells. However, this strategy was limited by the rarity and low avidity of the endogenous MCPyV-specific T cells in most patients, and the 2-3 months required to generate T cell products in the face of rapidly progressive disease. To circumvent the challenges encountered, we now propose a transgenic T cell therapy approach. We will 1) use a newly developed high-throughput strategy to identify safe, high-affinity HLA-restricted T cell receptors (TCRs) to ensure all patients can receive highly avid, effective MCPyV-specific T cells. We have successfully used this approach to identify an MCPyV-specific HLA A*0201-restricted TCR (TCRA2-MCC1) and will now employ these strategies to identify TCRs of 3 additional specificities. 2) in a Phase I/II trial for patients with PD- 1 blockade-refractory metastatic MCC, evaluate the safety and efficacy of autologous CD8+ T cells transduced to express the validated TCRA2-MCC1 combined with MHC upregulation and PD-1 axis blockade, and 3) use a suite of cutting-edge tools on patient samples to characterize infused T cells, MCC cells and other features of the tumor microenvironment, identify parameters associated with treatment responses and/or failures. We believe the proposed studies will provide critical insights into the design of next-generation T cell therapies for MCC patients, with implications for other immunogenic malignancies.

摘要-项目一