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：
10438927
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/10438927
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 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 translational oncology 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.

项目摘要免疫检查点抑制剂（ICI）可在约20％的癌症患者中提供持久的临床反应，但缺乏肿瘤内T细胞的癌症的影响最小。将T – cell – Deplete Cancers变成的方法需要吸引高质量的T细胞的癌症来感知这些无反应的癌症。肿瘤包含编码肿瘤特异性且未在正常细胞上表达的突变蛋白的体细胞突变（称为新抗原）。癌症（例如黑色素瘤）具有最高的突变伯良响应单个代理ICI。但是，大多数癌症，包括胰腺导管腺癌（PDAC），具有较低的突变载荷，导致抗原性较低，内源性T细胞库板较弱，而T较少T 细胞浸润肿瘤。 PDAC还具有包含的免疫抑制肿瘤微环境（TME）表达T细胞抑制性信号的单核细胞，B细胞和T细胞。临床前研究表明突变 Kras（MKRAS）疫苗用ICI给予过表达Mkrasg12d（KPC小鼠）的基因工程的小鼠（KPC小鼠）抑制从进展到PDAC的预先病变（PMID：24607504）。我在显示的Panc02细胞的工作成对时，新抗原靶向的疫苗，pancvax，十二个20 – mer Neoantigen Pepperides的混合物 IC调节剂清除了具有生存益处的panc02-伴随小鼠（PMID：30333318）。在这个提案我们将检验以下假设，即针对“共享” Mkras新抗原的胡椒疫苗或 “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子和效应子记忆T细胞，然后将通过ICIS进一步激活并导致肿瘤拒绝。因此，我们将进行两项早期临床试验，以测试针对MKRA的疫苗（特定目标1）或患者 - 肿瘤 - 特异性新抗原（特定目标2）与ICIS ipilimumab和Nivolumab结合切除和转移性PDAC的患者。在这两种情况下，我们都将评估三重的安全组合，进行周围血液的深入免疫表型，包括T细胞数，质量和曲目，研究TME的细胞结构。完整的状态 - 艺术技术将使用包括单细胞RNA -SEQ和TCR -SEQ，以及多光谱免疫荧光。长时间术语，这些研究应告知PDAC患者的未来组合免疫疗法方法，并在短期，将为我提供生物信息学，人类免疫学和早期临床试验的重要新技能设计。我的咨询团队，约翰·霍普金斯（Johns Hopkins）丰富的科学环境和各种各样的可用资源应该毒死我，以实现成为一名资助的独立的目标在本赠款期结束时，转化肿瘤学的研究者。