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：
10661795
负责人：
ELIZABETH M. JAFFEE
金额：
$ 38.33万
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/10661795
关键词：
Adjuvant Affect Algorithms Amino Acids Antigen Targeting 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 Exclusion FDA approved Flow Cytometry Future Gene Expression Genetically Engineered Mouse Glioblastoma Human Immune Immune System Diseases Immune checkpoint inhibitor Immune response Immunologics Infiltration 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 infiltration T cell receptor repertoire sequencing T cell response T memory cell T-Cell Depletion T-Lymphocyte TP53 gene Technology Testing Tumor Antigens Tumor Burden Tumor Immunity Tumor Tissue Tumor-associated macrophages Vaccines Work analytical tool antigen-specific T cells cancer immunotherapy cancer infiltrating T cells checkpoint therapy combinatorial cytokine effector T cell exhaustion exome sequencing immune activation immune modulating agents immunocytochemistry immunogenicity immunoregulation 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概要免疫检查点抑制剂 (ICIs) 为约 20% 的癌症患者提供持久的临床反应，但对肿瘤内缺乏 T 细胞的癌症效果甚微。大多数肿瘤需要吸引高质量 T 细胞来使这些无反应的癌症变得敏感。具有编码肿瘤特异性且在正常细胞上不表达的突变蛋白的体细胞突变突变负荷最高的癌症更有可能对单一细胞产生反应。然而，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 细胞库较弱以及浸润肿瘤的 T 细胞较少。 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)， B 细胞和 T 细胞表达 T 细胞抑制信号并排除 T 细胞或在 TME 内抑制它们。然而，我们发表的数据显示，基因工程 KPC 小鼠表达癌蛋白突变 KRAS (mKRAS)，当使用 mKRAS 疫苗时，可以防止癌前病变进展为 PDA 最近，我们发表了表达约 50 种新抗原的小鼠 Panc02 模型。与人类 PDA 类似，新抗原靶向肽疫苗 (PancVAX) 由 12 种成分的混合物组成每个 20 个氨基酸长的肽乳化在佐剂中并与 ICI 一起给药，可以治疗 PancO2 荷瘤因此，在本提案中，我们将测试针对共享（mKRAS）或小鼠的肽疫苗的假设。个性化新抗原将触发高质量的新抗原特异性效应和效应记忆 T 细胞，将可被 ICI 进一步激活并导致肿瘤排斥我们将对两个人进行研究。测试针对 mKRAS 和患者肿瘤特异性新抗原的疫苗的临床试验（目标 1 和 2）分别与 ipilimumab 和 nivolumab 联合用于切除和转移性 PDA 患者。从床边到工作台，在目标 3 中，我们将进一步开发我们的新颖方法我们新的初步数据显示，目前的数据可以增强新抗原疫苗的免疫原性。包含 MHC II 类表位可增强我们的鼠疫苗 PancVAX 的 CD8+ T 细胞反应（主要由 MHC I 类表位组成）我们还将询问其他情况。免疫抑制 TME 与靶向治疗可能会重新编程肿瘤相关细胞与项目 3 和 4 合作，研究巨噬细胞和基质细胞。在所有情况下，我们都会评估质量这些研究将结合每种疫苗方法与免疫调节剂诱导的 T 细胞。为未来在项目 3 的 PDA 患者中进行联合免疫治疗测试提供信息。