A Novel Paradigm for the Development of a Peptide Vaccine to Treat KRAS Mutant Cancers
开发治疗 KRAS 突变癌症的肽疫苗的新范例
基本信息
- 批准号:10438897
- 负责人:
- 金额:$ 18.06万
- 依托单位:
- 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 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAntitumor ResponseAutoimmunityBindingBiological AssayCD8-Positive T-LymphocytesCD8B1 geneCOVID-19 pandemicCOVID-19 vaccineCTL assayCancer VaccinesCellsClinical TrialsCodon NucleotidesColon CarcinomaCoupledDendritic CellsDevelopmentEGFRvIII PeptideEpidermal Growth Factor ReceptorEpitopesGenerationsGlioblastomaGoalsHLA-A2 AntigenHigh PrevalenceHumanImmune checkpoint inhibitorImmunologicsImmunotherapyKRAS2 geneKRASG12DLeadMHC Class I GenesMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMembraneMethodsMindModelingMusMutationNatural Killer CellsNormal tissue morphologyOncologyOutcome StudyPeptide VaccinesPeptidesProcessProteinsRNA SplicingSerumT cell responseT-LymphocyteT-Lymphocyte EpitopesTechnologyTestingToxicologyTranslatingTumor ImmunityTyrosineUp-RegulationUrsidae FamilyVaccinationVaccinesWorkanti-PD1 therapyanti-cancerantitumor effectbasecancer immunotherapycancer vaccinationcheckpoint therapyepidermal growth factor receptor VIIIexperimental studyimprovedinterestmethod developmentmulticatalytic endopeptidase complexmutantneoantigensnovelprotein structuresuccesssynergismtherapeutically effectivetumortumor immunologyvaccine development
项目摘要
Abstract
Ras mutations are highly prevalent in many human tumors but translating this major discovery into
effective therapeutics has been difficult. Immunotherapy has emerged as the most promising approach in the
field of oncology thus far. Anti-cancer vaccines offer the promise of a simple yet directed approach to cancer
immunotherapy. Yet early efforts at anti-Ras vaccines, dating from 30 years ago, were not successful. Clearly,
Ras based vaccines would benefit from the significant amount that has recently been learned about tumor
immunology. We developed an anti-EGFRvIII peptide vaccine that showed some success in clinical trials for
glioblastoma. To improve the sequence, we found enhancing proteasomal processing significantly enhances the
anti-tumor effect and results in greater synergy with anti-PD-1 therapy. Moreover, this enhanced proteasome
catalyzed peptide splicing (PCPS) leading to the creation of numerous antigenic peptides that increases the
efficacy. When the COVID-19 pandemic struck, we applied what we learned towards SARS-CoV-2. We
developed methods to accelerate the identification of these epitopes from large proteins and methods to find the
PCPS fragments from lengthy sequences. Applying this to KRasG12D vs. wt KRAS, we were surprised to find
that while the two proteins had 18 fragments in common, 89 fragments were unique to KRasG12D but wt Ras
only had 13 unique peptides that bound to HLA-A2. This indicates the unexpected finding that there are many
more CD8+ epitopes present in mutant Ras that are outside the vicinity of codon 12 that could be exploited as
the basis for vaccines.
Specific Aim #1. Identifying the MHC Class I binding peptides that arise from the KRasG12D
mutation. In this aim, we will extend our work to identify those peptides that bind to murine MHC H-2Kb.
Proteasome vs. immunoproteasome generation of fragments will be evaluated, as well as whether a tyrosine
substitution at codon 12 further enhances mutant specific fragment generation. We expect many peptides will be
found, so we will further evaluate which peptides are highly positive in a MHC-I membrane stabilization assay.
Further refinement of the peptide set will be done by evaluating which peptides are actively endogenously
presented by GL261 cells which bear KRasG12D. Specific Aim #2. Anti-tumor and CTL activity of mutant
KRAS specific peptides. Selected peptides from Specific Aim #1 will be used in tumor vaccination
experiments using GL261 cells and tumor regression and survival will be assessed. Immunologic studies to
assay serum titers, and the number of CD8+, CD4+, dendritic and NK cells will be determined. We will also
analyze for the upregulation of several checkpoint molecules. If indicated, we will perform vaccination
experiments plus checkpoint inhibitors to see if this potentiates the anti-tumor effect. CTL assays will be
performed to confirm induction of CD8+ T cells. Finally, toxicology studies will be performed to verify that
these peptides do not induce autoimmunity against normal tissues.
摘要
Ras突变在许多人类肿瘤中非常普遍,但将这一重大发现转化为
很难找到有效的治疗方法。免疫疗法已成为治疗中最有前途的方法。
到目前为止,肿瘤学。抗癌疫苗为癌症提供了一种简单而直接的方法
免疫疗法。然而,从30年前开始的抗Ras疫苗的早期努力并不成功。很显然,
基于Ras的疫苗将受益于最近对肿瘤的大量了解,
免疫学我们开发了一种抗EGFRvIII肽疫苗,在临床试验中显示出一些成功,
胶质母细胞瘤为了改善序列,我们发现增强蛋白酶体加工显著增强了
抗肿瘤作用,并与抗PD-1治疗产生更大的协同作用。此外,这种增强的蛋白酶体
催化肽剪接(PCPS)导致产生许多抗原肽,
功效当COVID-19大流行来袭时,我们将所学应用于SARS-CoV-2。我们
开发了加速从大蛋白质中鉴定这些表位的方法,以及找到这些表位的方法。
从长序列中提取PCPS片段。将其应用于KRasG 12 D与wt KRAS,我们惊讶地发现
虽然这两种蛋白质有18个共同的片段,但89个片段是KRasG 12 D独有的,而野生型Ras
只有13种独特的肽与HLA-A2结合。这表明了一个意想不到的发现,
更多的CD 8+表位存在于突变型Ras中,其在密码子12附近之外,这可以被利用作为
疫苗的基础。
具体目标#1。鉴定由KRasG 12 D产生的MHC I类结合肽
突变在这个目标中,我们将扩展我们的工作,以确定这些肽的结合鼠MHC H-2Kb。
将评价蛋白酶体与免疫蛋白酶体产生片段的情况,以及酪氨酸是否
密码子12的取代进一步增强突变体特异性片段的产生。我们预计许多肽将
因此,我们将进一步评估哪些肽在MHC-I膜稳定化测定中是高度阳性的。
通过评估哪些肽是内源性活性肽,
由携带KRasG 12 D的GL 261细胞呈递。具体目标#2突变体的抗肿瘤和CTL活性
KRAS特异性肽。来自特定目标#1的选定肽将用于肿瘤疫苗接种
将评估使用GL 261细胞和肿瘤消退和存活的实验。免疫学研究,
测定血清滴度,并确定CD 8+、CD 4+、树突细胞和NK细胞的数量。我们还将
分析几种检查点分子的上调。如有需要,我们会进行疫苗接种。
实验加上检查点抑制剂,看看这是否增强了抗肿瘤作用。CTL检测将
进行检测以确认CD 8 + T细胞的诱导。最后,将进行毒理学研究,以验证
这些肽不诱导针对正常组织的自身免疫。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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ALBERT J. WONG其他文献
ALBERT J. WONG的其他文献
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{{ truncateString('ALBERT J. WONG', 18)}}的其他基金
A Novel Paradigm for the Development of a Peptide Vaccine to Treat KRAS Mutant Cancers
开发治疗 KRAS 突变癌症的肽疫苗的新范例
- 批准号:
10290826 - 财政年份:2021
- 资助金额:
$ 18.06万 - 项目类别:
Using Insights from EGFRvIII to Improve EGFR Directed Therapy in Human Gliomas
利用 EGFRvIII 的见解改进人类神经胶质瘤的 EGFR 定向治疗
- 批准号:
7184032 - 财政年份:2007
- 资助金额:
$ 18.06万 - 项目类别:
Using Insights from EGFRvIII to Improve EGFR Directed Therapy in Human Gliomas
利用 EGFRvIII 的见解改进人类神经胶质瘤的 EGFR 定向治疗
- 批准号:
7629773 - 财政年份:2007
- 资助金额:
$ 18.06万 - 项目类别:
Using Insights from EGFRvIII to Improve EGFR Directed Therapy in Human Gliomas
利用 EGFRvIII 的见解改进人类神经胶质瘤的 EGFR 定向治疗
- 批准号:
7840438 - 财政年份:2007
- 资助金额:
$ 18.06万 - 项目类别:
Using Insights from EGFRvIII to Improve EGFR Directed Therapy in Human Gliomas
利用 EGFRvIII 的见解改进人类神经胶质瘤的 EGFR 定向治疗
- 批准号:
7456531 - 财政年份:2007
- 资助金额:
$ 18.06万 - 项目类别:
Using Insights from EGFRvIII to Improve EGFR Directed Therapy in Human Gliomas
利用 EGFRvIII 的见解改进人类神经胶质瘤的 EGFR 定向治疗
- 批准号:
8078129 - 财政年份:2007
- 资助金额:
$ 18.06万 - 项目类别:
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