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

项目1：摘要/摘要 在单个癌症患者中识别与肿瘤相关的突变靶抗原可以促进一种新的 和潜在有效的治疗方法，其中针对多种相关肿瘤的免疫反应 可以使用个性化的疫苗接种方法产生抗原。同时对突变多肽进行鉴定 单个患者的表位靶标仍然是一个令人望而生畏的技术挑战，Next的最新进展 世代基因测序为建立这些努力提供了坚实的基础。这 Approach有望提供一种更个性化、更有效的抗肿瘤免疫激活方法， 没有与许多替代方法相关的毒性。然而，许多根本性的问题 关于选择最佳的肿瘤抗原和免疫刺激佐剂用于产生 通过接种疫苗优化癌症患者的抗肿瘤免疫。 这项提议的具体目标是产生一种有效的、个性化的治疗疫苗方法。 转移性结直肠癌(CRC)患者的比例。我们将检验这样一种假设，即疫苗接种策略针对 多个突变的结直肠癌肿瘤抗原与特定的免疫佐剂组合将能够 预防肝切除术后微小残留病的复发。我们的预赛 数据表明，建议的个性化疫苗接种策略是可行的，就像几名结直肠癌患者现在所做的那样。 在目前的临床试验中接受了疫苗接种。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CD40抗体和检查点阻断可以是高效的组合 体内佐剂。然而，了解用于疫苗接种的最佳制剂组合是至关重要的。 以便将这些发现转化为我们的结直肠癌患者更有效的疫苗策略。因此，我们计划 集中力量抓好以下具体目标： 目的1：设计并免疫20例肝切除术后转移性结直肠癌患者。 结合TLR7激动剂和抗PD1或抗CD40的抗原肽疫苗。 目标2：发展免疫和系统免疫调节的新组合 使用小鼠结直肠癌肿瘤疫苗模型的疗效。 这些研究将提供关键信息，指导未来的癌症疫苗设计，并允许 在低发病率环境下的疫苗接种效果测试。这一方法有望使 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 选择。此外，这些研究有很大的潜力对许多其他类型的癌症产生影响。

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.