rPIV5- and AVLP-vectored vaccine development with public tumor-specific neoantigens

使用公共肿瘤特异性新抗原开发 rPIV5 和 AVLP 载体疫苗

• 批准号: 10831315
• 负责人: William Hildebrand
• 金额: $ 14.67万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-11 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831315
• 关键词: Acceleration; Alleles; Antigen Presentation; Award; Binding; Biological Assay; Breeding; Cancer Vaccine Related Development; Cancer Vaccines; Canis familiaris; Cell Separation; Collaborations; Data; Ethnic Population; Future; Genotype; Human; Immune response; Interferons; Knowledge; MHC Class I Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Mutation; Parents; Peptides; Peripheral Blood Mononuclear Cell; Population; Reagent; Research; Resources; Software Tools; Translational Research; Vaccines; Viral Antigens; Virus-like particle; cancer immunotherapy; candidate identification; canine model; immunogenic; immunogenicity; interest; mutant; neoantigen vaccine; neoantigens; parainfluenza virus; response; tumor; vaccine development; vector vaccine

Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. The proposed supplement project aims to validate the immunogenicity of a total 10 public tumor- specific neoantigen (pTSNA) candidates identified by our parent R01CA252713 project, entitled “Canine MHC- I genotyping and tumor specific neoantigen determination”. These are defined as mutant peptides that are: 1) derived from hotspot mutations in canine and human cancers; and 2) predicted to bind MHC class I (MHC-I) alleles dominant in canine/human populations and/or subpopulations (breeds or ethnic groups). We will collaborate with Drs. Biao He and Dong An, two leading vaccine developers to perform two studies. 1) We will clone the pTSNA candidates in tandem into vaccine vectors parainfluenza virus 5 (PIV5) and PIV5- based self-amplifying virus-like particle (AVLP). PIV5 and AVLP, developed by Drs He and An, are ideal vaccine vectors especially for cancer vaccine development, as they elicit more robust cellular immune responses, compared to other strategies. 2) We will infecting peripheral blood mononuclear cells (PBMCs) isolated from dogs harboring the required MHC-I alleles with rPIV5-pTSNA and rAVLP-pTSNA viruses, identify pTSNAs that are presented by the MHC-I alleles via mass-spectrometry, and identify immunogenic pTSNAs via interferon-g assays. This proposed supplement study will significantly enhance Aim 2c of the parent R01, by accelerating immunogenic pTSNA discovery. Furthermore, the study will yield critical reagents (rPIV5-pTSNA amd rAVLP- pTSNA vaccines) and knowledge for future cancer vaccine development that impacts a large population of both dogs and humans. The study is especially significant, considering that PIV5-based vaccines are shown to be safe and immunogenic for dogs, and PIV5-based vaccines are often administrated intranasally.

抽象的 该申请是为了响应特殊利益通知（NOSI）而提交 23-045。拟议的补充项目旨在验证总共10种公共肿瘤的免疫原性 - 由我们的父母R01CA252713项目确定的特定新抗原（PTSNA）候选者，标题为“犬MHC-- 我的基因分型和肿瘤特异性新抗原的测定”。这些定义为突变肽，即：1） 源自犬和人类癌症中的热点突变； 2）预计将结合MHC I类（MHC-I） 等位基因在犬/人类和/或亚群（品种或种族群体）中占主导地位。 我们将与Drs合作。 Biao He和Dong An，两位领先的疫苗开发人员进行了两项研究。 1） 我们将串联的PTSNA候选者克隆到疫苗载体parainfluenza病毒5（PIV5）和PIV5-- 基于自我扩增的病毒样粒子（AVLP）。由He和An开发的PIV5和AVLP是理想的 疫苗向量，尤其是用于癌症疫苗发育的疫苗，因为它们引起了更健壮的细胞免疫 与其他策略相比，回应。 2）我们将感染外周血单核细胞（PBMC） 从带有RPIV5-PTSNA和RAVLP-PTSNA病毒的MHC-I等位基因的狗中分离出来，识别 MHC-I等位基因通过质谱法提出的PTSNA，并识别免疫原性PTSNA 通过干扰素G分析。 这项拟议的补充研究将通过加速来大大提高母体R01的AIM 2C。 免疫原性PTSNA发现。此外，该研究将产生关键试剂（RPIV5-PTSNA AMD RAVLP- PTSNA疫苗）和未来癌症疫苗开发的知识，会影响大量人群 狗和人类。考虑到基于PIV5的疫苗显示为 对于狗来说是安全和免疫原性的，基于PIV5的疫苗通常是鼻内给药的。

项目成果

A Kmer-based paired-end read de novo assembler and genotyper for canine MHC class I genotyping.

• DOI: 10.1016/j.isci.2023.105996
• 发表时间: 2023-02-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Feng, Yuan;Hess, Paul R.;Tompkins, Stephen M.;Hildebrand, William H.;Zhao, Shaying
• 通讯作者: Zhao, Shaying

Canine major histocompatibility complex class I (MHC-I) diversity landscape.

犬主要组织相容性复合体 I 类 (MHC-I) 多样性景观。

• DOI: 10.1101/2024.02.14.580220
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Feng,Yuan;Ho,Kun-Lin;Zhang,Mengyuan;Sundaresha,NikithaBrahmasamudra;Cavanagh,HannahLorelle;Zhao,Shaying
• 通讯作者: Zhao,Shaying

Canine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds.

• DOI: 10.1038/s41467-021-24836-9
• 发表时间: 2021-08-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Alsaihati BA;Ho KL;Watson J;Feng Y;Wang T;Dobbin KK;Zhao S
• 通讯作者: Zhao S

Shared hotspot mutations in oncogenes position dogs as an unparalleled comparative model for precision therapeutics.

• DOI: 10.1038/s41598-023-37505-2
• 发表时间: 2023-07-06
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Rodrigues, Lucas;Watson, Joshua;Feng, Yuan;Lewis, Benjamin;Harvey, Garrett;Post, Gerald;Megquier, Kate;White, Michelle E.;Lambert, Lindsay;Miller, Aubrey;Lopes, Christina;Zhao, Shaying
• 通讯作者: Zhao, Shaying