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IRP-3

基本信息

批准号：
10473682
负责人：
Pawel Kalinski
金额：
$ 32.31万
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/10473682
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 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 vaccination strategy

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：尽管标准治疗卵巢癌（OvCa）的疗效增加，但总体5年 OvCa患者的存活率仅为47.6%。针对多种癌症和患者的多克隆T细胞应答特异性抗原是有效的癌症免疫和产生的结果的关键要素。项目3开发和测试一种新的免疫策略，以增强细胞毒性淋巴细胞的诱导通过靶向癌细胞、内源性树突状细胞（DC），和离体产生的DC。我们将比较OvCa细胞和两个群体的特异性CTL诱导的DC：离体产生的α 1型极化（α DC 1）和内源性常规DC（cDC 1），其具有炎性BATF 3/IRF 8表型，并且具有升高的将多种癌细胞相关抗原交叉呈递给CD 8 + T细胞。结合我们独特的体外致敏（IVS）和生物信息学方法，我们将测试整体假设OvCa细胞和DC呈递抗原的免疫肽段之间的错配限制了自发性和疫苗诱导的CTL的治疗效果应答我们进一步假设，α DC 1装载了合成的患者特异性新抗原肽，将绕过这种错配，诱导CTL特别有效地杀死OvCa肿瘤。我们建议三个目标：特异性目的1：比较负载人CD 8 + T细胞的DC诱导的人CD 8 + T细胞的抗原特异性，自体OvCa细胞、肿瘤洗脱肽和患者特异性新抗原肽，计算机模拟方法。我们假设，自体癌细胞负载的CD 4DC 1或 cDC 1含有大量与肿瘤识别无关的CTL，其缺陷可以是通过用对每个患者的OvCa细胞特异性的合成新抗原肽加载DC来校正。具体目标2：评价OvCa细胞和肿瘤负载的 α DC 1 s和内源性cDC 1 s，并检验其调节的可行性。我们假设免疫佐剂和炎症介质可用于调节APM模式， DC和OvCa细胞的免疫肽段，以增强产生的CTL之间的抗原匹配，自体OvCa细胞。具体目标3：确定负载α DC 1疫苗的可行性、安全性和临床有效性患者特异性新抗原肽与PD-1阻断的组合。每位患者将接受8个疗程负载有患者特异性新抗原和派姆单抗的PDC 1疫苗。以目标的结果为指导 2、患者还可接受全身免疫调节，以增加自身OvCa的可见性。细胞抑制DC 1诱导的CTL并减少免疫抑制。将通过iORR监测临床疗效。预测影响：项目3的结果将转化为新型治疗性疫苗的开发，前瞻性地进入免疫检查点抑制和过继性T细胞疗法的新模式。