A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
基本信息
- 批准号:10320831
- 负责人:
- 金额:$ 37.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvantAlgorithmsAntibody ResponseAntigen-Presenting CellsAntigensAntitumor ResponseBindingBiochemicalBiologicalBiological AssayCD44 geneCD8-Positive T-LymphocytesCD8B1 geneCancer VaccinesCancer cell lineCellsChemicalsClinicalCobaltCyclophosphamideDataDendritic CellsDevelopmentDoseEnvironmentEpitopesFrequenciesGenerationsGoalsHistocompatibilityImmuneImmune TargetingImmunizationImmunizeImmunosuppressionImmunotherapyInbred BALB C MiceLaboratoriesLengthLiposomesMalignant NeoplasmsMediatingMemoryMetastatic Neoplasm to the LungModelingMolecularMouse StrainsMurine leukemia virusMusNanotechnologyNatureNeoplasm MetastasisOncogenesPeptide VaccinesPeptidesPhagosomesPhospholipidsPorphyrinsPrimary NeoplasmQS21SELL geneSafetyScreening procedureSerumSystemT cell responseT-LymphocyteT-Lymphocyte EpitopesTechniquesTestingTherapeuticTimeToll-like receptorsToxic effectTumor AntigensTumor Cell BiologyTumor ImmunityTumor-infiltrating immune cellsVaccinatedVaccinationVaccine AdjuvantVaccine Clinical TrialViral Antigensanti-cancerantigen-specific T cellsbasecancer cellcancer therapycell killingcostcytokinedensitydesigndraining lymph nodehigh throughput screeningimmune checkpoint blockadeimmunogenicimprovedin vivoinsightnanoliposomeneoantigensnext generation sequencingparticlepeptide Ipeptide vaccinationprophylacticrecruitresponsescreeningself assemblystemsynthetic peptidetherapeutic immunizationtherapeutic vaccinetumortumor microenvironmentvaccine efficacy
项目摘要
PROJECT SUMMARY
MHC class I (MHC-I) -restricted peptide cancer vaccines hold the minimal amount of biochemical information
required for generating antigen-specific T cells to elicit anti-tumor responses. On their own, immunization with
minimal peptide epitopes does not provide a satisfactory response, so typically long peptides or conjugated
delivery systems are necessitated. However, such approaches defeat the directness of short synthetic peptide
vaccines. A new peptide vaccine immunization paradigm will be introduced, based on combining (via simple
mixing) MHC-I peptide epitopes with a vaccine adjuvant that induces spontaneous nanoliposome-antigen
particleization (SNAP). Liposomes that contain small amounts of cobalt porphyrin-phospholipid (CoPoP) rapidly
bind short his-tagged peptides (8-9mers) via spontaneous insertion of the his-tag into the bilayer. This gives rise
to particleization that is stable in biological media. His-tagged peptides are simply mixed with CoPoP liposomes
at the time of vaccination (without further purification) to convert these well-characterized peptides into a 100 nm
particle. This approach is potently effective in generating antigen-specific CD8+ T cells. AH1 is a MHC-I H-2Ld
model CD8+ epitope derived from the gp70 murine leukemia virus antigen. An AH1-derived peptide can be used
with SNAP immunization to generate high numbers of antigen specific CD8+ T cells. SNAP immunization with
low nanogram doses peptides completely protects mice from subsequent tumor challenge, and eradicates 100%
of lung metastases in a therapeutic vaccine model. Varying components of SNAP immunization will be assessed,
including the his-tag length, the density and dose of co-incorporated (MPLA and QS-21; both part of GSK’s
vaccine adjuvant AS01) to determine their impact the Ag-specific CD8+ response. Generation of Ag-specific
CD44+ CD62L+ cells will be assessed to determine whether such central memory cells are more effective in
eradicating tumors. Vaccine efficacy will be tested in multiple prophylactic and therapeutic local and metastasis
tumor models. Therapeutic treatment of large tumors will be assessed with the impact of cyclophosphamide and
checkpoint blockade. Mechanistic insights will be probed by assessing how the delivered peptide reaches MHC-
I. It is hypothesized that his-tag peptides bind to CoPoP liposomes, and undergo serum-stable transit to draining
lymph nodes. There, they are phagocytosed by dendritic cells where the reductive environment of phagosomes
is also suspected to induce the release of the peptide from the CoPoP liposomes. Toll-like receptor in the bilayer
are hypothesized to upregulate the expression of MHC-I within the phagosome. Further studies will assess the
viability of SNAP immunization and antigen multiplexing as an in vivo screening tool for peptide microlibraries
using established tumor-associated antigens and neoantigens that will be identified with next-generation
sequencing. Finally, the safety and cobalt response of the system will be assessed. These studies will provide
substantial advancement for short, MHC-I-restricted peptide-based cancer vaccines for cancer therapy and
immunogenic epitope screening.
项目总结
MHC-I类(MHC-I)限制性多肽癌症疫苗含有最少量的生化信息
产生抗原特异性T细胞以引发抗肿瘤反应所必需的。就他们自己而言,通过免疫接种
最小的多肽表位不能提供令人满意的反应,因此通常是长肽或结合多肽
交付系统是必要的。然而,这种方法破坏了短合成肽的直接性。
疫苗。将引入一种新的多肽疫苗免疫范例,基于组合(通过SIMPLE
将MHC-I多肽表位与疫苗佐剂混合,可诱导自发的纳米脂质体抗原
粒子化(SNAP)。快速含有少量钴卟啉-磷脂(CoPoP)的脂质体
通过自发地将组氨酸标签插入到双层中,结合短的组氨酸标记肽(8-9mer)。这就产生了
到在生物介质中稳定的颗粒化。His标记的多肽与CoPoP脂质体简单混合
在接种疫苗时(不需要进一步纯化)将这些特征良好的多肽转化为100 nm
粒子。这种方法在产生抗原特异性CD8+T细胞方面非常有效。AH1是MHC-I H-2LD
模型CD8+表位来源于gp70小鼠白血病病毒抗原。可以使用AH1衍生的多肽
用SNAP免疫产生大量的抗原特异性CD8+T细胞。Snap免疫接种
低纳克剂量的多肽完全保护小鼠免受随后的肿瘤攻击,并100%根除
在治疗性疫苗模型中发现肺转移。将评估SNAP免疫的不同组成部分,
包括His-Tag的长度、共掺的密度和剂量(Mpla和QS-21;都是GSK的一部分
疫苗佐剂AS01),以确定它们对抗原特异性CD8+反应的影响。银离子专一性的产生
将对CD44+CD62L+细胞进行评估,以确定这种中央记忆细胞在
根除肿瘤。疫苗的有效性将在多种预防和治疗局部和转移中进行测试
肿瘤模型。大型肿瘤的治疗将根据环磷酰胺和
检查站封锁。将通过评估递送的多肽如何到达MHC来探索机械洞察-
一、假设His-Tag多肽与CoPoP脂质体结合,并经历血清稳定的转运到排出
淋巴结。在那里,它们被树突状细胞吞噬,吞噬小体的还原环境
也被怀疑能诱导CoPoP脂质体释放多肽。双层膜上的Toll样受体
被认为是为了上调吞噬小体中MHC-I的表达。进一步的研究将评估
SNAP免疫和抗原复合作为多肽微库体内筛选工具的可行性
使用已建立的肿瘤相关抗原和将被下一代识别的新抗原
测序。最后,将对该系统的安全性和钴响应进行评估。这些研究将提供
用于癌症治疗和治疗的MHC-I限制性短肽癌症疫苗的实质性进展
免疫原性表位筛选。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Scott I. Abrams其他文献
Differences in Immune Cell Populations between Individuals with or without MGUS
- DOI:
10.1182/blood-2024-206171 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Sawyer Bawek;Janine M. Joseph;Alan Hutson;Sarah Parker;Joseph D. Tario Jr;Hamza Hassan;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Influence of interferon γ on modulation of Fas expression by human colon carcinoma cells and their subsequent sensitivity to antigen-specific CD8+ cytotoxic T lymphocyte attack
- DOI:
10.1007/s002620000105 - 发表时间:
2000-06-01 - 期刊:
- 影响因子:5.100
- 作者:
Elke S. Bergmann-Leitner;Scott I. Abrams - 通讯作者:
Scott I. Abrams
Immune response to a carcinoembryonic antigen polynucleotide vaccine.
对癌胚抗原多核苷酸疫苗的免疫反应。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
R. Conry;A. Lobuglio;Judy Kantor;Jeffrey Schlom;F. Loechel;S. Moore;L. Sumerel;D. L. Barlow;Scott I. Abrams;David T. Curici - 通讯作者:
David T. Curici
Immune Markers of Multiple Myeloma Patients Demonstrate Significant Change after Participation in Six-Month Physical Activity Intervention
- DOI:
10.1182/blood-2022-167655 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Janine M. Joseph;Michaela Hillengass;Hillary Jacobson;Joseph D. Tario;Kristopher Attwood;Adrienne Groman;Rikki Cannioto;Bryan Wittmeyer;Kirsten Moysich;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Induction of antitumor immunity by recombinant vaccinia viruses expressing B7-1 or B7-2 costimulatory molecules.
通过表达 B7-1 或 B7-2 共刺激分子的重组痘苗病毒诱导抗肿瘤免疫。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
J. Hodge;Scott I. Abrams;J. Schlom;Judy Kantor - 通讯作者:
Judy Kantor
Scott I. Abrams的其他文献
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{{ truncateString('Scott I. Abrams', 18)}}的其他基金
Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
- 批准号:
10322156 - 财政年份:2021
- 资助金额:
$ 37.09万 - 项目类别:
Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
- 批准号:
10463811 - 财政年份:2021
- 资助金额:
$ 37.09万 - 项目类别:
Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
- 批准号:
10287834 - 财政年份:2021
- 资助金额:
$ 37.09万 - 项目类别:
Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
- 批准号:
10543820 - 财政年份:2021
- 资助金额:
$ 37.09万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10653186 - 财政年份:2020
- 资助金额:
$ 37.09万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10171569 - 财政年份:2020
- 资助金额:
$ 37.09万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10404988 - 财政年份:2020
- 资助金额:
$ 37.09万 - 项目类别:
A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
- 批准号:
10557071 - 财政年份:2020
- 资助金额:
$ 37.09万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10248383 - 财政年份:2019
- 资助金额:
$ 37.09万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10472619 - 财政年份:2019
- 资助金额:
$ 37.09万 - 项目类别:
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