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缓解，但对缺乏肿瘤内 T 细胞的癌症的影响微乎其微。需要吸引高质量 T 细胞来使这些无反应的癌症对肿瘤所含的 ICI 敏感。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（称为新抗原），例如黑色素瘤，突变负担最高的癌症更有可能发生。然而，大多数癌症，包括胰腺导管腺癌 (PDAC)，突变负荷较低，导致抗原性较低、内源性 T 细胞库较弱、T 细胞较少浸润肿瘤的细胞还具有免疫抑制肿瘤微环境（TME），其中包括：临床前研究表明，单核细胞、B 细胞和 T 细胞表达 T 细胞抑制信号。将 KRAS (mKRAS) 疫苗与 ICI 一起给予过度表达 mKRASG12D 的基因工程小鼠（KPC 小鼠）抑制癌前病变进展为 PDAC (PMID: 24607504) 我对 Panc02 细胞的研究表明。新抗原靶向疫苗 PancVAX 是 12 个 20 聚体新抗原肽的混合物，配对后使用 IC 调节剂可以清除携带 Panc02 的小鼠的肿瘤，并具有生存益处（PMID：30333318）。建议我们将测试针对“共享”mKRAS 新抗原的肽疫苗的假设，或者 “个性化”的患者肿瘤特异性新抗原将触发高质量的新抗原特异性效应器和效应记忆 T 细胞，随后可被 ICI 进一步激活并导致肿瘤因此，我们将进行两项早期临床试验来测试针对 mKRAS（具体目标 1）或患者肿瘤特异性新抗原（具体目标 2）与 ICI 伊匹单抗和纳武单抗联合治疗在这两种情况下，我们将分别评估三联疗法的安全性。组合，对外周血进行深入的免疫表型分析，包括 T 细胞数量、质量和曲目，并研究 TME 的细胞架构。包括单细胞RNA-Seq和TCR-Seq，并且长期将使用多光谱免疫荧光。从长远来看，这些研究应该为未来 PDAC 患者的联合免疫治疗方法提供信息，并且，短期内，将为我提供生物信息学、人类免疫学和早期临床试验方面重要的新技能我的顾问团队的出色指导、约翰·霍普金斯大学丰富的科学环境以及大量的可用资源应该使我能够实现成为一个有资金的、独立的在此资助期结束时，担任转化肿瘤学研究者。