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1 默克尔细胞癌（MCC）是高度侵略性的皮肤癌诊断，每年> 2500人美国。〜80％的MCC是由Merkel细胞多瘤病毒（MCPYV）引起的，这些肿瘤依赖于持续表达的细胞周期促进癌症（T-抗原）。这些病毒抗原是理想的靶标对于免疫疗法：它们是高度表达的，不容易丢失，独有的肿瘤组织，非人类序列（降低靶标风险）和高度免疫原性。最近的研究表明，减少内源性T细胞在MCC中的功能障碍是有效的，因为一半的患者对PD-1轴具有持久的反应封锁。但是，许多患者没有反应，代表未满足的临床需求。我们假设这一点肿瘤对PD-1无反应的患者没有足够或狂热的MCPYV响应性T 细胞，并且可以通过多种方法来提高治疗效率。在R01资助的试验中，我们使用“三重治疗”来治疗MCC转移性疾病的患者，其中我们将单分数辐射组合在一起，以反向MCC特异性下调I类，输注自体外扩展的MCPYV特异性CD8+ T细胞，以补充缺乏有效的MCPYV特异性 T细胞和AVELUMAB（PD-L1检查点抑制剂）以增强抗原特异性反应。这些治疗方法耐受性良好，令人鼓舞的有效（有3名患者中有3例完全缓解，2个耐用在> 2年），我们已经证明了注入T细胞的持久性，功能和肿瘤定位。但是，该策略受到内源性MCPYV特异性T细胞的罕见性和低相关的限制大多数患者，面对快速进行性，生成T细胞产品所需的2-3个月疾病。为了避免遇到的挑战，我们现在提出了一种转基因T细胞疗法。我们将1）使用新开发的高通量策略来识别安全的高亲和力HLA限制性T细胞受体（TCR）为了确保所有患者都可以接受高度狂热，有效的MCPYV特异性T细胞。我们已经成功使用这种方法来识别MCPYV特异性HLA A*0201限制的TCR（TCRA2-MCC1），现在将采用这些策略来确定3个其他规格的TCR。 2）在针对PD-患者的I/II期试验中 1胃浪费性转移性MCC，评估自体CD8+ T细胞翻译的安全性和效率表达经过验证的TCRA2-MCC1与MHC上调和PD-1轴封锁相结合，3）使用在患者样品上的尖端工具套件，以表征注入的T细胞，MCC细胞和其他特征的其他特征肿瘤微环境，确定与治疗反应和/或失败相关的参数。我们相信拟议的研究将为下一代T细胞疗法的设计提供关键见解 MCC患者，对其他免疫原性恶性肿瘤有影响。