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

项目1：高危结直肠癌的个体化辅助免疫治疗。

基本信息

批准号：
10226087
负责人：
Michael J Overman
金额：
$ 24.84万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226087
关键词：
Adjuvant Agonist Anti-CD40 Antibodies Antigen Targeting Antigens Biological Assay CT26 CTLA4 gene Cancer Center Cancer Patient Cancer Vaccines Cell surface Clinical Clinical Trials Colorectal Cancer Combined Vaccines Cytotoxic T-Lymphocytes DNA Data Disease Epitopes Foundations Future Genetic Hepatectomy Immune Immune checkpoint inhibitor Immune response Immunity Immunization Immunize Immunologic Adjuvants Immunologic Markers Immunologics Immunotherapeutic agent Immunotherapy Individual Ligands Lung Adenocarcinoma MC38 Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Methods Microsatellite Instability Modeling Monitor Mus Mutate Mutation OX40 Operative Surgical Procedures Patients Peptide Vaccines Peptides Recurrence Residual Neoplasm T cell response T-Lymphocyte TLR7 gene Testing Time Toll-like receptors Toxic effect Translating Tumor Antigens Tumor Immunity Tumor-Derived University of Texas M D Anderson Cancer Center Vaccination Vaccine Design Vaccine Therapy Vaccines anti-PD-1 anti-PD1 therapy cancer therapy cancer type cancer vaccination clinical practice colon cancer patients colorectal cancer risk combinatorial design effective therapy efficacy clinical trial high risk immune checkpoint immune checkpoint blockade immunogenic immunoregulation improved in vivo individual patient liquid biopsy melanoma metastatic colorectal mouse model neoantigens neoplastic cell next generation next generation sequencing novel peptide based vaccine peptide vaccination personalized immunotherapy pre-clinical preclinical evaluation prevent programmed cell death protein 1 response response biomarker success tumor tumor-immune system interactions vaccination strategy

项目摘要

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.

项目1：摘要/摘要鉴定单个癌症患者中与肿瘤相关的突变靶抗原可以促进新型以及潜在有效的治疗方法，其中免疫反应针对多个相关肿瘤可以使用个性化疫苗接种方法生成抗原。同时鉴定突变的肽个别患者的表位目标仍然是一个艰巨的技术挑战，下一步的最新进展一代遗传测序为建立这些努力提供了坚实的基础。这方法有一种更个性化和有效的方法激活抗肿瘤免疫的承诺，没有与许多其他方法相关的毒性。但是，许多基本问题关于选择最佳肿瘤抗原和免疫刺激佐剂的选择通过疫苗接种癌症患者的最佳抗肿瘤免疫力。该提案的具体目标是生成一种有效的个性化疫苗治疗方法转移性结直肠癌（CRC）患者的患者。我们将检验以下疫苗接种策略的假设多种突变的CRC肿瘤抗原以及免疫佐剂的特定组合将能够防止肝后切除术CRC患者的最小残留疾病复发。我们的初步数据表明，拟议的个性化疫苗接种策略是可行的，因为几名CRC患者现在已经在当前的临床试验中进行了疫苗接种。此外，我们的临床前鼠标模型已清楚地显示了 Toll样受体配体，抗CD40和检查点封锁可以是高效的组合体内佐剂。但是，了解用于疫苗接种的代理的最佳组合至关重要为了将这些发现转化为CRC患者更有效的疫苗策略。因此，我们计划将我们的精力集中在以下具体目标上： AIM 1：设计和免疫20个肝后切除术转移性CRC患者，具有个性化的，新的抗原肽疫苗与TLR7激动剂和抗PD1或抗CD40结合。目的2：通过改善使用鼠CRC肿瘤疫苗模型的功效。这些研究将提供关键信息，以指导癌症疫苗设计的未来，并允许在低容量疾病的情况下测试疫苗接种功效。该方法有望做一个在表现出很高复发性和有限治疗可能性的疾病环境中的重大积极影响选项。此外，这些研究具有对许多其他癌症类型产生影响的强大潜力。