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

前列腺癌是一个重要的全球健康问题，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方法。我们把DNA疫苗作为一种简单的方法， 特异性地旨在产生肿瘤抗原特异性CD8 T细胞。我们实验室在过去的一个主要努力 几年来一直在评估肿瘤对免疫的反应并确定耐药机制， 免疫接种。我们已经发现，PD-1或LAG-3在接种疫苗的T细胞活化后上调， 即使在抗原特异性T细胞活化后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，并且这可以通过使用 同时阻断PD-1或LAG-3。我们最近证明，这在人类中也是如此， 在用DNA疫苗免疫时递送PD-1阻断抗体（派姆单抗），而不是 与免疫后开始数周相比，引起了客观的抗前列腺肿瘤应答。这构成了 这一提议的假设，即鉴于PD-1表达的动态性质， 抗肿瘤免疫后LAG-3阻断调节性T细胞标志物的瞬时上调 使用抗体阻断或使用TLR激动剂降低PD-I和/或LAG-3的表达， 这些调节受体在T细胞活化时通过抗肿瘤免疫将导致更大的效应子 CD8 T细胞和更大的抗肿瘤功效。

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.