Generation of tumor specific immunity in canine osteosarcoma through dendritic cell hyperactivation

通过树突状细胞过度激活在犬骨肉瘤中产生肿瘤特异性免疫

基本信息

  • 批准号:
    10688274
  • 负责人:
  • 金额:
    $ 65.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Despite substantial improvements in therapeutic strategies, generating robust anti-tumor immune responses in human cancers with a lower somatic mutation burden remains a substantial challenge. Recent data indicate that a critical player in this process, dendritic cells (DCs), fail to effectively elicit efficient and durable T cell responses unless they have entered a unique state of hyperactivation. In this setting, DCs exhibit enhanced migration to local lymph nodes (LNs) and sustained secretion of IL-1β, a cytokine critical for memory T cell formation. In mouse tumor models, vaccination with whole tumor lysate plus an adjuvant consisting of the TLR 7/8 agonist R848 (resiquimod) in combination with a unique isolated lysophosphatidylcholine (22:0 Lyso PC) promotes DC hyperactivation, expansion of antigen specific CD8+ T cells, and robust rejection of tumors. While these findings are encouraging and suggest that identification of specific neoantigens is not necessary to prime and expand a pool of cytotoxic T cells (CTLs), validation and optimization of this approach necessitates the use of a model system that more closely recapitulates human cancers with respect to immune landscape. As such, the purpose of this proposal is to use spontaneous canine cancer, specifically osteosarcoma (OS), as a bridging animal model to validate the utility of DC hyperactivation as a foundational element for generation of robust anti-tumor immunity. The central hypothesis to be tested in this application is that combining hyperactivation of DCs with WTL derived neoantigen will expand a diverse and tumor-specific population of CTLs capable of eliminating residual microscopic metastatic OS tumor cells in dogs following primary tumor removal (amputation). We further predict, that combining DC hyperactivation/WTL with a novel tumor microenvironment (TME) conditioning regimen consisting of toceranib/losartan/ladarixin will enhance the objective response rate in dogs that develop macroscopic lung metastasis. To accomplish this, we will conduct a prospective randomized clinical trial in dogs with OS combining amputation and standard of care carboplatin chemotherapy with adjuvant alone or adjuvant+WTL. Dogs that develop lung metastasis will then be treated with the TME conditioning regimen in combination with adjuvant+WTL. A biobank of tissue samples and blood will be collected from dogs enrolled in these trials including matched primary/metastatic tumors and associated LNs, whole blood, plasma, PBMCs, cell-free DNA, and samples from the vaccine draining LNs. These will be used to perform a set of complementary assays designed to characterize the immune microenvironment and tumor genome over the course of relapse/resistance, credential a novel neoantigen prediction pipeline, and evaluate antigen specific T cell responses. An outstanding team with complementary sets of expertise across clinical trials, translational oncology, comparative genomics, and immuno-oncology has been assembled to ensure stated milestones are achieved. This is bolstered by a dynamic collaboration with our industry partner, Corner Therapeutics, which is committed to supporting this work to facilitate optimization and successful translation into human patients.
项目总结

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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Cheryl A London其他文献

Tissue factor-targeted immunotherapy of melanoma and triple negative breast cancer using a second generation ICON
  • DOI:
    10.1186/2051-1426-3-s2-p304
  • 发表时间:
    2015-11-04
  • 期刊:
  • 影响因子:
    10.600
  • 作者:
    Zhiwei Hu;Elizabeth McMichael;Amanda Campbell;Cheryl A London;William E Carson
  • 通讯作者:
    William E Carson

Cheryl A London的其他文献

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{{ truncateString('Cheryl A London', 18)}}的其他基金

Optimizing integration of veterinary clinical research findings with human health systems to improve strategies for early detection and intervention
优化兽医临床研究结果与人类健康系统的整合,以改进早期检测和干预策略
  • 批准号:
    10764456
  • 财政年份:
    2023
  • 资助金额:
    $ 65.78万
  • 项目类别:
Resources and workforce development for the New England Regional Biosafety Laboratory
新英格兰地区生物安全实验室的资源和劳动力发展
  • 批准号:
    10793931
  • 财政年份:
    2023
  • 资助金额:
    $ 65.78万
  • 项目类别:
Cross-Disciplinary Research Training for Veterinary Students
兽医学生跨学科研究培训
  • 批准号:
    10666627
  • 财政年份:
    2022
  • 资助金额:
    $ 65.78万
  • 项目类别:
Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches
使用合理的组合方法提高DLBCL免疫治疗的疗效
  • 批准号:
    10247897
  • 财政年份:
    2017
  • 资助金额:
    $ 65.78万
  • 项目类别:
Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches
使用合理的组合方法提高DLBCL免疫治疗的疗效
  • 批准号:
    10256800
  • 财政年份:
    2017
  • 资助金额:
    $ 65.78万
  • 项目类别:
COMPARTIVE ANIMAL CORE
比较动物核心
  • 批准号:
    8516645
  • 财政年份:
    2013
  • 资助金额:
    $ 65.78万
  • 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
  • 批准号:
    6785866
  • 财政年份:
    2002
  • 资助金额:
    $ 65.78万
  • 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
  • 批准号:
    7219356
  • 财政年份:
    2002
  • 资助金额:
    $ 65.78万
  • 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
  • 批准号:
    6546067
  • 财政年份:
    2002
  • 资助金额:
    $ 65.78万
  • 项目类别:
c-Kit Mutations and Their Role in Tumor Biology
c-Kit 突变及其在肿瘤生物学中的作用
  • 批准号:
    6640368
  • 财政年份:
    2002
  • 资助金额:
    $ 65.78万
  • 项目类别:

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