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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 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。由我们的母体 R01CA252713 项目确定的特定新抗原 (pTSNA) 候选物，题为“Canine MHC- I 基因分型和肿瘤特异性新抗原测定”。这些被定义为突变肽：1) 源自犬类和人类癌症的热点突变；2) 预计与 I 类 MHC (MHC-I) 结合在犬/人类群体和/或亚群体（品种或种族群体）中占主导地位的等位基因。我们将与两位领先的疫苗研发人员 Biao He 和 Dong An 博士合作进行两项研究 1)。我们将串联 pTSNA 候选物克隆到疫苗载体副流感病毒 5 (PIV5) 和 PIV5- He 博士和 An 博士开发的基于自扩增病毒样颗粒 (AVLP) 和 AVLP 是理想的选择。疫苗载体，特别是用于癌症疫苗开发，因为它们能引发更强大的细胞免疫 2）我们将感染外周血单核细胞（PBMC）从携带 rPIV5-pTSNA 和 rAVLP-pTSNA 病毒的所需 MHC-I 等位基因的狗中分离出来，鉴定通过质谱法由 MHC-I 等位基因呈递的 pTSNA，并鉴定免疫原性 pTSNA 通过干扰素-g 测定。这项拟议的补充研究将通过加速显着增强母体 R01 的目标 2c 此外，该研究将产生关键试剂（rPIV5-pTSNA 和 rAVLP-）。 pTSNA 疫苗）以及影响大量人群的未来癌症疫苗开发知识考虑到基于 PIV5 的疫苗已被证明可以对狗和人类产生影响，这项研究尤其重要。对狗来说是安全且具有免疫原性的，基于 PIV5 的疫苗通常通过鼻内注射。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Feng,Yuan;Ho,Kun-Lin;Zhang,Mengyuan;Sundaresha,NikithaBrahmasamudra;Cavanagh,HannahLorelle;Zhao,Shaying
通讯作者：
Zhao,Shaying

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

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