Effective Anti-Tumor Vaccination - Targeting Checkpoint Regulation at the Time of T-cell Activation

有效的抗肿瘤疫苗——T细胞激活时的靶向检查点调节

基本信息

批准号：
9924259
负责人：
DOUGLAS G. MCNEEL
金额：
$ 35万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924259
关键词：
Active Immunotherapy Adjuvant Affect Agonist Androgen Receptor Animal Model Antibodies Antigen Presentation Antigens Antitumor Response Binding Blocking Antibodies CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Cells Clinical Trials DNA Vaccines Development Environment Epitopes Frequencies Goals Human Immunization Inferior Interferons Laboratories Lead Ligands Lytic MHC Class I Genes Malignant neoplasm of prostate Memory Methods Mission Modeling National Cancer Institute Nature OVA-8 Oncogenes Ovum PD-1 blockade PD-1/PD-L1 Patients Prostate Prostate Cancer therapy Prostatic Neoplasms Regulation Regulatory T-Lymphocyte Research Rodent Sampling Signaling Molecule T cell response T memory cell T-Cell Activation TLR1 gene TLR7 gene Testing Time Tissues Translating Tumor Antigens Up-Regulation Vaccination Vaccines antigen-specific T cells cancer therapy cancer vaccination design global health in vivo mouse model programmed cell death ligand 1 programmed cell death protein 1 prostatic fraction Acid phosphatase isoenzyme receptor resistance mechanism response tumor vaccine efficacy vector

项目摘要

Prostate cancer is a significant global health concern for which new treatments are needed. The long-range goal of our research for nearly two decades has been to develop active immunotherapies, and tumor vaccines in particular, as treatments for prostate cancer. We have focused on DNA vaccines as a simple method, and one specifically aimed at generating tumor antigen-specific CD8 T cells. A major effort in our laboratory over the last several years has been to evaluate the tumor response to immunization and identify mechanisms of resistance to immunization. We have found that PD-1 or LAG-3 are upregulated after T cell activation with vaccination, and that even the transient expression of PD-1 or LAG-3 following antigen-specific T-cell activation is sufficient to allow them to be regulated in the immunosuppressive tumor environment, and this can be abrogated using concurrent blockade of PD-1 or LAG-3. We have recently demonstrated that this is true in humans as well, as delivery of a PD-1 blocking antibody (pembrolizumab) at the time of immunization with a DNA vaccine, rather than beginning weeks after immunization, elicited objective anti-prostate tumor responses. This forms the basis of the hypothesis underlying this proposal, namely that given the dynamic nature of the expression of PD-1 or LAG-3 following anti-tumor immunization, blockade of the transient upregulation of regulatory T cell markers (including PD-1 and/or LAG-3) using either antibody blockade or using TLR agonists that reduce expression of these regulatory receptors at the time of T-cell activation via anti-tumor immunization will lead to greater effector CD8 T cells and greater anti-tumor efficacy.

前列腺癌是需要新疗法的重要全球健康问题。远程目标在我们的研究近二十年中，我们的研究一直是开发主动免疫疗法，并在特别是作为前列腺癌的治疗方法。我们专注于DNA疫苗作为一种简单的方法，一种特别旨在产生肿瘤抗原特异性CD8 T细胞。最后一项重大努力几年来评估肿瘤对免疫的反应并确定抗药性机制免疫。我们发现，通过疫苗接种T细胞激活后，PD-1或LAG-3上调，并且即使是抗原特异性T细胞激活后PD-1或LAG-3的瞬时表达也足以允许它们在免疫抑制性肿瘤环境中受到调节，并且可以使用同时封锁PD-1或LAG-3。我们最近证明，在人类中也是如此在用DNA疫苗免疫时，PD-1阻断抗体（Pembrolizumab）的递送与免疫后的几周开始，引起了客观的抗验证肿瘤反应。这形成了基础该提议的基础假设，即鉴于PD-1或表达的动态性质抗肿瘤免疫后的滞后3，阻断调节T细胞标记的瞬时上调（包括PD-1和/或LAG-3）使用抗体阻断或使用降低表达的TLR激动剂通过抗肿瘤免疫激活时，这些调节受体将导致更大的效应子 CD8 T细胞和更大的抗肿瘤功效。