Project 1: Personalized Adjuvant Immunotherapy for High-risk Colorectal Cancer.

项目1：总结/摘要 在个体癌症患者中鉴定肿瘤相关的突变靶抗原可以促进新的肿瘤治疗。 和潜在有效的治疗方法，其中针对多种相关肿瘤的免疫应答 可以使用个性化的疫苗接种方法产生抗原。突变肽的鉴定 个体患者的表位靶点仍然是一个艰巨的技术挑战， 第二代基因测序为开展这些工作提供了坚实的基础。这 该方法有望成为一种更加个性化和有效的激活抗肿瘤免疫的方法， 而没有与许多替代方法相关的毒性。然而，许多基本问题 关于选择最佳肿瘤抗原和免疫刺激佐剂以用于产生 通过疫苗接种，癌症患者获得最佳的抗肿瘤免疫力。 这项建议的具体目标是产生一种有效的、个性化的疫苗治疗方法 转移性结直肠癌（CRC）患者。我们将检验一个假设，即针对 多个突变的CRC肿瘤抗原沿着免疫佐剂的特定组合将能够 预防肝切除术后CRC患者微小残留病复发。我们的初步 数据显示，提出的个性化疫苗接种策略是可行的，因为一些CRC患者现在已经 在目前的临床试验中接种疫苗。此外，我们的临床前小鼠模型已经清楚地表明， Toll样受体配体、抗CD 40和检查点阻断剂可以是以下药物的高效组合： 体内佐剂。然而，了解用于疫苗接种的药剂的最佳组合至关重要 以便将这些发现转化为针对我们的CRC患者的更有效的疫苗策略。因此，我们计划 我们的努力集中在以下具体目标上： 目的1：设计并免疫20例肝切除术后转移性结直肠癌患者， 与TLR 7激动剂和抗PD 1或抗CD 40组合的抗原肽疫苗。 目的2：开发免疫和系统性免疫调节的新组合， 使用鼠CRC肿瘤疫苗模型的有效性。 这些研究将提供指导未来癌症疫苗设计的关键信息， 在低发病率情况下测试疫苗接种效力。该方法有望使 在复发可能性高且治疗有限的疾病环境中产生显著的积极影响 选项.此外，这些研究有很大的潜力对许多其他癌症类型产生影响。

PROJECT 1: Summary/Abstract Identification of tumor-associated mutated target antigens in individual cancer patients can facilitate a novel and potentially effective treatment approach in which an immune response against multiple relevant tumor antigens can be generated using a personalized vaccination approach. While identification of mutated peptide epitope targets in individual patients remains a daunting technical challenge, recent advances in next generation genetic sequencing has provided a strong foundation on which to build these efforts. This approach holds the promise of a more personalized and effective method of activating anti-tumor immunity, without the toxicities associated with many alternate approaches. However, many fundamental questions remain regarding choice of optimal tumor antigens and immunostimulatory adjuvants to use for generating optimal antitumor immunity in cancer patients through vaccination. The specific objective of this proposal is to generate an effective, personalized vaccine approach for treatment of metastatic colorectal cancer (CRC) patients. We will test the hypothesis that a vaccination strategy targeting multiple mutated CRC tumor antigens along with specific combinations of immune adjuvants will be capable of preventing recurrence of minimal residual disease in post-hepatectomy CRC patients. Our Preliminary Data shows that the proposed personalized vaccination strategy is feasible, as several CRC patients have now undergone vaccination in a current clinical trial. In addition, our pre-clinical mouse models have clearly shown that Toll-like receptor ligands, anti-CD40, and checkpoint blockade can be highly effective combinations of adjuvants in vivo. However, it is critical to understand the optimal combination of agents to use for vaccination in order to translate these findings into more effective vaccine strategies for our CRC patients. We thus plan to focus our efforts on the following Specific Aims: Aim 1: Design and immunize 20 post-hepatectomy metastatic CRC patients with personalized, neo- antigen peptide vaccines combined with a TLR7 agonist and either anti-PD1 or anti-CD40. Aim 2: Develop novel combinations of immunization and systemic immunomodulation with improved efficacy using murine CRC tumor vaccine models. These studies will provide critical information that will guide the future of cancer vaccine design and allow for testing of vaccination efficacy in a setting of low volume disease. The approach promises to make a significant positive impact in a disease setting that shows high likelihood of recurrence and limited treatment options. Furthermore, these studies have a strong potential to make an impact in many other cancer types.