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.

前列腺癌是一个重大的全球健康问题，需要新的治疗方法。长远目标近二十年来，我们的研究重点是开发主动免疫疗法和肿瘤疫苗特别是作为前列腺癌的治疗。我们专注于 DNA 疫苗作为一种简单的方法，并且专门针对产生肿瘤抗原特异性 CD8 T 细胞。我们实验室过去的一项重大努力多年来一直在评估肿瘤对免疫的反应并确定耐药机制到免疫接种。我们发现，通过疫苗接种激活 T 细胞后，PD-1 或 LAG-3 的表达上调，并且即使抗原特异性 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肿瘤环境中受到调节，这可以通过使用消除同时阻断 PD-1 或 LAG-3。我们最近证明，这对于人类来说也是如此，因为在 DNA 疫苗免疫时递送 PD-1 阻断抗体（pembrolizumab），而不是与免疫接种后几周相比，引发了客观的抗前列腺肿瘤反应。这构成了基础该提议所依据的假设，即考虑到 PD-1 表达的动态性质或抗肿瘤免疫后的 LAG-3，阻断调节性 T 细胞标记物的瞬时上调（包括 PD-1 和/或 LAG-3）使用抗体阻断或使用 TLR 激动剂来减少这些调节受体在通过抗肿瘤免疫激活T细胞时将产生更大的效应 CD8 T细胞具有更强的抗肿瘤功效。