Integration of neo-antigen vaccines and immune checkpoint therapy

新抗原疫苗与免疫检查点疗法的整合

基本信息

批准号：
10408081
负责人：
ELIZABETH M. JAFFEE
金额：
$ 38.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408081
关键词：
Adjuvant Affect Algorithms Amino Acids Antitumor Response B-Lymphocytes Back Binding CD8-Positive T-Lymphocytes CTLA4 gene Cancer Burden Cancer Patient Categories Cell Count Cell Death Cells Chronic Disease Clinical Clinical Trials Collaborations Combination immunotherapy Cytometry Data Epitopes FDA approved Flow Cytometry Future Gene Expression Genetically Engineered Mouse Glioblastoma Human Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immunologics Immunomodulators KPC model KRAS2 gene Lesion Ligands MADH4 gene MHC Class I Genes MHC Class II Genes Malignant Neoplasms Malignant neoplasm of pancreas Memory Metastatic Pancreatic Adenocarcinoma Modeling Mus Mutate Mutation Nivolumab Normal Cell Oncoproteins Outcome Pancreatic Adenocarcinoma Pathway interactions Patients Peptide Vaccines Peptides Point Mutation Prevention Proteins Publishing Reporting Resected Resistance Signal Transduction Somatic Mutation Stromal Cells T cell receptor repertoire sequencing T cell response T memory cell T-Lymphocyte TP53 gene Technology Testing Tumor Antigens Tumor Burden Tumor Immunity Tumor Tissue Tumor-associated macrophages Tumor-infiltrating immune cells Vaccines Work analytical tool cancer immunotherapy checkpoint therapy combinatorial cytokine effector T cell exhaustion exome sequencing immune activation immunocytochemistry immunogenicity improved inhibiting antibody ipilimumab melanoma monocyte mouse model mutant neoantigen vaccine neoantigens neoplastic cell nonsynonymous mutation novel novel strategies pancreatic cancer patients peripheral blood pre-clinical premalignant prevent programmed cell death ligand 1 programs response single-cell RNA sequencing synergism targeted agent targeted treatment transcriptome sequencing tumor tumor microenvironment tumor-immune system interactions tumorigenesis vaccine evaluation

项目摘要

Project 1 Summary Immune-checkpoint inhibitors (ICIs) are providing durable clinical responses in about 20% of cancer patients, but have minimal effect in cancers lacking intra-tumoral T cells. Approaches that turn T cell deplete cancers into ones that attract high quality T cells are needed to sensitize these unresponsive cancers to ICIs. Most tumors have somatic mutations that encode for mutant proteins that are tumor–specific and not expressed on normal cells (termed neoantigens). Cancers with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers, including pancreatic adenocarcinoma (PDA) have lower mutational loads, resulting in lower antigenicity, weaker endogenous T cell repertoires, and fewer T cells infiltrating the tumor. PDAs also have an immunosuppressive tumor microenvironment (TME) consisting of suppressive monocytes, B cells and T cells that express T cell inhibitory signals and exclude T cells or suppress them within the TME. However, we published data showing in genetically–engineered KPC mice expressing the oncoprotein mutated KRAS (mKRAS), that premalignant lesions can be prevented from progressing to PDA when a mKRAS vaccine is given with ICIs. More recently, we published in the murine Panc02 model that expresses about 50 neoantigens similar to human PDA, that a neoantigen targeted peptide vaccine (PancVAX) consisting of a mixture of 12 peptides each 20 amino acids long emulsed in adjuvant and given with ICIs, can treat PancO2 tumor-bearing mice. Thus, in this proposal we will test the hypothesis that peptide vaccines targeting shared (mKRAS) or personalized neoantigens will trigger high quality neoantigen–specific effector and effector memory T cells, which will become available for further activation by ICIs and result in tumor rejection. We will conduct two human clinical trials (Aims 1 and 2) to test vaccines targeting mKRAS and patient–tumor–specific neoantigens in combination with ipilimumab and nivolumab in patients with resected and metastatic PDA, respectively. Moving from the bedside back to the bench, in Aim 3, we will further develop our novel approaches arising from our current data to enhance the immunogenicity of the neoantigen vaccines. Our new preliminary data has shown that the inclusion of MHC Class II epitopes enhances CD8+ T cell response of our murine vaccine PancVAX (which is composed primarily of MHC Class I epitopes). We will also interrogate the otherwise immunosuppressive TME with targeted therapies that would potentially reprogram tumor-associated macrophages and stromal cells in collaboration with Projects 3 and 4. In all instances, we will assess the quality of T cells induced by each vaccine approach in combination with immune–modulatory agents. These studies will inform future combination immunotherapy approaches for testing in Project 3 patients with PDA.

项目1摘要免疫检查点抑制剂（ICI）在约20％的癌症患者中提供持久的临床反应，但是对缺乏肿瘤内T细胞的癌症的影响很小。将T细胞完全转化为需要吸引高质量T细胞的人会感觉到这些无反应性癌症对ICIS的感觉。大多数肿瘤具有编码肿瘤特异性突变蛋白的体细胞突变细胞（称为新抗原）。最高突变燃烧的癌症更有可能对单一做出反应代理ICIS。但是，大多数癌症，包括胰腺腺癌（PDA）的突变负荷较低，导致抗原性较低，内源性T细胞库板较弱，而T细胞浸润肿瘤较少。 PDA还具有由抑制性单核细胞组成的免疫抑制肿瘤微环境（TME）表达T细胞抑制信号并排除T细胞或抑制TME的B细胞和T细胞。但是，我们在表达癌蛋白突变的一般设计的KPC小鼠中发表了数据 KRAS（MKRA），当MKRAS疫苗时，可以防止这种前病变进展到PDA 用ICIS给出。最近，我们在鼠panc02模型中发表了大约50种新抗原的模型与人类PDA相似，新抗原针对的肽疫苗（pancvax）由12个混合物组成每20个氨基酸在调节中长期乳化并给予ICIS，可以治疗panco2肿瘤老鼠。在此提案中，我们将检验以下假设：靶向共享的胡椒疫苗（MKRA）或个性化的新抗原将触发高质量的新抗原特异性效应子和效应器记忆T细胞，它们 ICIS将用于进一步激活，并导致肿瘤排斥。我们将进行两个人临床试验（目标1和2）测试针对MKRAS和患者 - 肿瘤 - 特异性新抗原的疫苗切除和转移性PDA的患者中与ipilimumab和nivolumab结合。移动从床头回到板凳，在AIM 3中，我们将进一步发展我们的小说方法我们的新初步数据已显示 MHC II类表位的包含增强了我们鼠疫苗pancvax的CD8+ T细胞反应（主要由MHC I类表位组成）。我们还将审问其他具有靶向疗法的免疫抑制性TME，可能会重新编程肿瘤相关巨噬细胞和基质细胞与项目3和4合作。在所有情况下，我们都将评估质量每种疫苗方法诱导的T细胞与免疫调节剂结合使用。这些研究会为未来的组合免疫疗法用于测试PDA患者的测试。