IRP-3

基本信息

批准号：
10171149
负责人：
Pawel Kalinski
金额：
$ 33.65万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10171149
关键词：
Alternative Therapies Antigen Targeting Antigen-Presenting Cells Antigenic Specificity Antigens Autologous Bioinformatics Bypass CD8-Positive T-Lymphocytes Cancer Patient Cells Cross Presentation Data Dendritic Cell Vaccine Dendritic Cells Development Elements Epitopes Generations Human Immunization Immunologic Adjuvants Immunosuppression Immunotherapy In Vitro Individual Inflammation Mediators Inflammatory Lesion Lymphocyte Malignant Neoplasms Malignant neoplasm of ovary Monitor Mutate Operative Surgical Procedures Outcome PD-1 blockade Patients Pattern Peptides Phenotype Platinum Population Regulation Role Safety T cell response T cell therapy Testing Translating Tumor Antigens Tumor Burden Tumor Immunity Vaccination Vaccines antigen processing antigen-specific T cells cancer cell cancer diagnosis cancer therapy checkpoint inhibition chemotherapy clinical application clinical efficacy cytotoxic feasibility testing immunoregulation in silico individual patient multiple omics neoantigens novel novel therapeutics pembrolizumab prospective response standard care standard of care taxane therapeutic effectiveness therapeutic vaccine therapeutically effective tumor

项目摘要

ABSTRACT: Despite increasing efficacy for standard of care of ovarian cancer (OvCa), the overall five-year survival of OvCa patients is only 47.6%. Polyclonal T cell responses against multiple cancer- and patient- specific antigens are the key element of effective cancer immunity and resulting outcomes. Project 3 develops and tests a new immunization strategy to enhance the induction of cytotoxic lymphocytes (CTLs) against multiple patient-specific epitopes, by targeting cancer cells, endogenous dendritic cells (DCs) and ex vivo generated DCs. We will compare the immunopeptidomes on OvCa cells and two populations of DC specialized in CTL induction: ex-vivo generated alpha-type-1-polarized (αDC1s) and endogenous conventional DCs (cDC1s) which share the inflammatory BATF3/IRF8 phenotype and elevated ability to cross-present multiple cancer-cell-associated antigens to CD8+ T cells. Combining our unique in vitro sensitization (IVS) and bioinformatics approaches, we will test the overall hypothesis that the mismatch between immunopeptidomes of OvCa cells and DCs presenting antigens from cancer cells limits the therapeutic effectiveness of spontaneous and vaccination-induced CTL responses. We further hypothesize that αDC1s loaded with synthetic patient-specific neoantigen peptides will bypass such mismatch, inducing CTLs particularly effective in killing OvCa tumors. We propose the following three Aims: Specific Aim 1: Compare the antigenic specificity of human CD8+ T cells induced by DCs loaded with autologous OvCa cells, tumor-eluted peptides and patient-specific neoantigen peptides identified by in-silico approaches. We hypothesize that CTLs induced by autologous cancer cell-loaded DC1s or cDC1s contain large number of CTLs which are irrelevant for tumor recognition, which deficit can be corrected by loading DCs with synthetic neoantigen peptides specific to each patient's OvCa cells. Specific Aim 2: Evaluate the immunopeptidome differences between OvCa cells and tumor-loaded αDC1s and endogenous cDC1s and test the feasibility of their adjustment. We hypothesize that immune adjuvants and inflammatory mediators can be used to modulate APM patterns and immunopeptidomes of DCs and OvCa cells, to enhance the antigenic match between arising CTLs and autologous OvCa cells. Specific Aim 3: Determine the feasibility, safety and clinical efficacy of αDC1 vaccines loaded with patient-specific neoantigen peptides combined with PD-1 blockade. Each patient will receive 8 courses of DC1 vaccines loaded with patient-specific neoantigens and pembrolizumab. Guided by the results of Aim 2, the patients may also receive systemic immune modulation to increase the visibility of their own OvCa cells to DC1-induced CTLs and reduce immune suppression. Clinical efficacy will be monitored by iORR. Predicted Impact: Results of Project 3 will be translated into development of novel therapeutic vaccines and prospectively into new modes of immune checkpoint inhibition and adoptive T cell therapies.

摘要：尽管卵巢癌标准的效率提高了（OVCA），但总五年 OVCA患者的生存率仅为47.6％。多克隆T细胞反应针对多个癌症和患者特异性抗原是有效的癌症免疫学和结果结果的关键要素。项目3的发展和测试一种新的免疫抑制策略，以增强细胞毒性淋巴细胞的诱导（CTL）针对多个患者特异性表位，通过靶向癌细胞，内源性树突状细胞（DCS）和实体生成的DC。我们将比较OVCA细胞和两个种群的免疫肽组 DC专门从事CTL诱导：Ex-Vivo产生的α-1偏振（αDC1）和内源性具有炎症性BATF3/IRF8表型的常规DC（CDC1）和升高的能力与CD8+ T细胞相关的多个癌细胞相关抗原。结合我们独特的体外灵敏度（IVS）和生物信息学方法，我们将测试整体假设OVCA细胞的免疫肽和呈现抗原的DC之间的不匹配从癌细胞中限制了赞助商和疫苗接种引起的CTL的治疗效果回答。我们进一步假设αDC1装有合成患者特异性的新抗原肽将绕过这种不匹配，引起的CTL在杀死OVCA肿瘤方面特别有效。我们建议以下三个目标：特定目标1：比较由加载的DC诱导的人CD8+ T细胞的抗原特异性自体OVCA细胞，肿瘤洗脱的肽和患者特异性的新抗原肽塞里科的方法。我们假设自体癌细胞诱导的ctls是dc1或 CDC1包含大量与肿瘤识别无关的CTL，赤字可能是通过用特定于每个患者的OVCA细胞的合成新抗原辣椒加载DC来纠正DC。特定目标2：评估OVCA细胞和肿瘤负载之间的免疫肽组差异 αDC1和内源性CDC1并测试其调整的可行性。我们假设这一点免疫调节器和炎症介质可用于调节APM模式和 DC和OVCA细胞的免疫肽组，以增强CTL和CTL之间的抗原匹配自体OVCA细胞。特定目标3：确定带有αDC1疫苗的可行性，安全性和临床效率患者特异性的新抗原Petides结合了PD-1封锁。每个患者将接受8门课程装有患者特异性新抗原和pembrolizumab的DC1疫苗的疫苗。在目标结果的指导下 2，患者还可以接受全身免疫调节以提高自己的OVCA的可见性细胞至DC1诱导的CTL并减少免疫抑制。临床效率将由IORR监测。预测的影响：项目3的结果将转化为新型治疗疫苗的发展和前瞻性地进入免疫切除点抑制和适应性T细胞疗法的新模式。