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

• 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
• 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

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.

项目摘要 免疫检查点抑制剂（ICI）在约20%的癌症患者中提供了持久的临床反应， 在缺乏肿瘤内T细胞的癌症中效果最小。将T细胞耗尽的癌症转化为 需要吸引高质量T细胞的细胞来使这些无反应的癌症对ICI敏感。肿瘤含有 编码肿瘤特异性的突变蛋白质且不在正常细胞上表达的体细胞突变 （称为新抗原）。具有最高突变负担的癌症，如黑色素瘤，更有可能 对单剂ICI作出反应。然而，大多数癌症，包括胰腺导管腺癌（PDAC）， 具有较低的突变负荷，导致较低的抗原性，较弱的内源性T细胞库，以及较少的T 细胞浸润肿瘤PDAC还具有免疫抑制性肿瘤微环境（TME）， 表达T细胞抑制信号的单核细胞、B细胞和T细胞。临床前研究表明， KRAS（mKRAS）疫苗与ICI一起给予过表达mKRASG 12 D的基因工程小鼠（KPC小鼠） 抑制癌前病变进展为PDAC（PMID：24607504）。我对Panc 02细胞的研究表明， 一种新抗原靶向疫苗PancVAX，一种12种20聚体新抗原肽的混合物，当配对时， IC调节剂清除了携带Panc 02的小鼠中的肿瘤，具有存活益处（PMID：30333318）。在这 我们将测试靶向“共享”mKRAS新抗原的肽疫苗，或 “个性化”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物， 效应记忆T细胞，然后可被ICI进一步激活并导致肿瘤 排斥反应因此，我们将进行两项早期临床试验，以测试靶向mKRAS（特异性目的1）或 患者肿瘤特异性新抗原（特异性Aim 2）与ICI伊匹单抗和纳武单抗联合治疗 分别为切除和转移性PDAC患者。在这两种情况下，我们将评估三重的安全性 组合，进行外周血的深入免疫表型分析，包括T细胞数量，质量和 剧目，并研究TME的细胞结构。最先进技术的补充 包括单细胞RNA-Seq和TCR-Seq，并将利用多光谱免疫荧光。从长远 长期而言，这些研究应该为PDAC患者未来的联合免疫治疗方法提供信息， 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的重要新技能 设计我的顾问团队的杰出指导，约翰霍普金斯丰富的科学环境， 大量的可用资源应该使我能够实现我的目标，成为一个有资金的，独立的， 研究员在转化肿瘤学在此资助期结束。