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Neoantigen-Targeted Vaccines in Combination with Immune Checkpoint Inhibitors for Pancreatic Cancer

新抗原靶向疫苗联合免疫检查点抑制剂治疗胰腺癌

基本信息

批准号：
10301252
负责人：
Neeha Zaidi
金额：
$ 22.17万
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301252
关键词：
Advisory Committees Affect Algorithms Antibodies Antitumor Response Architecture B-Lymphocytes Binding Bioinformatics Biopsy CD8-Positive T-Lymphocytes CTLA4 gene Cancer Burden Cancer Patient Categories Cell Count Cell Death Cells Chronic Disease Clinical Clinical Trials Clinical Trials Design Combination immunotherapy Complement Data Enrollment Environment Epitope spreading FDA approved Flow Cytometry Funding Future Gene Expression Genetic Engineering Genetically Engineered Mouse Glioblastoma Goals Grant Human Immune Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunology Immunotherapy KPC model KRAS2 gene KRASG12D Lesion Ligands Longitudinal Studies MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Measures Memory Mentorship Mus Mutate Mutation Nivolumab Normal Cell Oncology Pancreatic Ductal Adenocarcinoma Pathologic Pathway interactions Patients Peptide Vaccines Peptides Phenotype Point Mutation Prevention Proteins Reporting Research Personnel Resected Resistance Resources Safety Signal Transduction Somatic Mutation T cell receptor repertoire sequencing T cell response T memory cell T-Lymphocyte TP53 gene Technology Testing Tumor Tissue Up-Regulation Vaccines Work anti-tumor immune response base cancer immunotherapy cytokine early phase clinical trial effector T cell exhaustion exome sequencing immune activation immunogenicity inhibiting antibody ipilimumab melanoma monocyte mutant neoantigen vaccine neoantigens neoplastic cell nonsynonymous mutation novel vaccines overexpression pancreatic ductal adenocarcinoma model peripheral blood pre-clinical preclinical study premalignant prevent programmed cell death ligand 1 programs response single cell analysis single-cell RNA sequencing trafficking transcriptome transcriptome sequencing tumor tumor microenvironment tumor-immune system interactions vaccine evaluation

项目摘要

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) provide durable clinical responses in about 20% of cancer patients, but have minimal effects 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. Tumors contain somatic mutations that encode for mutant proteins that are tumor–specific and not expressed on normal cells (termed neoantigens). Cancers, such as melanoma, with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers, including pancreatic ductal adenocarcinoma (PDAC), have lower mutational loads, resulting in lower antigenicity, weaker endogenous T cell repertoires, and fewer T cells infiltrating the tumor. PDACs also have an immunosuppressive tumor microenvironment (TME) consisting of monocytes, B cells and T cells that express T cell inhibitory signals. Preclinical studies show that a mutated KRAS (mKRAS) vaccine given with ICIs to genetically–engineered mice overexpressing mKRASG12D (KPC mice) inhibits premalignant lesions from progressing to PDAC (PMID: 24607504). My work with Panc02 cells showed that a neoantigen–targeted vaccine, PancVAX, a mixture of twelve 20–mer neoantigen peptides, when paired with IC modulators cleared tumors in Panc02–bearing mice with a survival benefit (PMID: 30333318). In this proposal we will test the hypothesis that peptide vaccines targeting ‘shared’ mKRAS neoantigens, or ‘personalized’ patient–tumor–specific neoantigens will trigger high–quality neoantigen–specific effector and effector memory T cells, which will then become available for further activation by ICIs and result in tumor rejection. We will thus conduct two early clinical trials to test vaccines targeting mKRAS (Specific Aim 1) or patient–tumor–specific neoantigens (Specific Aim 2) in combination with the ICIs ipilimumab and nivolumab in patients with resected and metastatic PDAC, respectively. In both instances, we will assess safety of the triple combinations, perform in–depth immune phenotyping of peripheral blood to include T cell number, quality and repertoire, and study the cellular architecture of the TME. A complement of state–of–the–art technologies including single cell RNA–Seq and TCR–Seq, and multispectral immunofluorescence will be utilized. In the long term, these studies should inform future combination immunotherapy approaches in PDAC patients, and, in the short term, will provide me with vital new skillsets in bioinformatics, human immunology, and early clinical trial design. The outstanding mentorship of my Advisory Team, the rich scientific environment at Johns Hopkins, and the vast array of available resources should poise me to achieve my goal of becoming a funded, independent investigator in translational oncology by the end of this grant period.

项目总结