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

前列腺癌是一个重大的全球健康问题，需要新的治疗方法。远景目标 近二十年来，我们的研究重点一直是开发主动免疫疗法，以及 尤其是前列腺癌的治疗。我们已经将DNA疫苗作为一种简单的方法进行了重点研究， 专门针对产生肿瘤抗原特异性的CD8 T细胞。在过去的几年里，我们实验室的一项重大努力 几年来，人们一直在评估肿瘤对免疫的反应并确定其耐药机制 到免疫接种。我们发现，在接种疫苗后，T细胞活化后PD-1或LAG-3表达上调，并且 即使在抗原特异性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的肿瘤环境中受到调节，这可以通过使用 同时封锁PD-1或LAG-3。我们最近证明，这在人类身上也是如此，就像 在DNA疫苗免疫时传递PD-1封闭抗体(Pembrolizumab)，而不是 比免疫后开始数周，引起了客观的抗前列腺癌反应。这构成了基础 这一提议背后的假设，即考虑到PD-1或 抗肿瘤免疫后的LAG-3阻断调节性T细胞标志物的瞬时上调 (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T细胞通过抗肿瘤免疫激活时会产生更大的效应 CD8T细胞和更大的抗肿瘤效果。

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.