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
- 来源:
- 关键词:Activities of Daily LivingAdjuvantAgonistAmputationAnimal Cancer ModelAnimal ModelAntigen-Presenting CellsAntigensBioinformaticsBiologicalBiological AssayBiological MarkersBiological ModelsBloodCCR1 geneCD8-Positive T-LymphocytesCancer ModelCanis familiarisCarboplatinCellsClinical TrialsClone CellsCollaborationsCredentialingCytotoxic T-LymphocytesDataDendritic CellsDendritic cell activationDiseaseEffectivenessElementsEnrollmentEnsureEvolutionExcisionExhibitsFailureFlow CytometryFutureGenerationsGeneticGoalsHumanIL8RA geneImmuneImmune checkpoint inhibitorImmune responseImmunityImmunologic MarkersImmunologicsImmunooncologyImmunotherapyInflammasomeInterleukin-1 betaLinkLosartanLungLymph Node TissueLysophosphatidylcholinesMalignant NeoplasmsMetastatic Neoplasm to the LungMetastatic OsteosarcomaMicroscopicModelingMusNatureNeoplasm MetastasisNucleotidesOralPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPlasmaPopulationPre-Clinical ModelPrimary NeoplasmProcessProductionProgression-Free SurvivalsRandomizedReagentRegimenRelapseResidual stateResistanceResourcesSamplingSeriesSignal TransductionSingle Nucleotide PolymorphismSiteSomatic MutationStimulusT cell responseT memory cellT-Cell ActivationT-LymphocyteTestingTherapeuticTissue SampleTranslationsTumor ImmunityTumor MarkersTumor-DerivedVaccinationVaccinesValidationVariantWhole BloodWorkanti-tumor immune responseantigen-specific T cellsaspiratebiobankcancer genomecell free DNAcheckpoint inhibitionchemotherapyclinical efficacyclinical translationcomparative genomicsconditioningcytokinedesigndraining lymph nodeexome sequencingimmunomodulatory therapiesimprovedin vivoindustry partnerinhibitorkinase inhibitorlymph nodesmigrationmouse modelneoantigensneoplastic cellnovelnovel strategiesnovel therapeutic interventionnovel vaccinesobjective response rateosteosarcomapeptide Iprogrammed cell death protein 1prospectiverandomized, clinical trialsresiquimodresponsestandard of caretooltranscriptomicstranslational medicinetranslational oncologytreatment responsetumortumor microenvironmenttumor-immune system interactionsvaccine platformvaccine response
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
尽管治疗策略有了实质性的改进,但在
体细胞突变负担较低的人类癌症仍然是一个巨大的挑战。最近的数据表明,
在这一过程中起关键作用的是树突状细胞(DC),它不能有效地激发高效和持久的T细胞反应
除非它们已经进入了一种独特的过度激活状态。在此设置中,DC可增强迁移到
局部淋巴结(LN)和IL-1β的持续分泌,这是一种对记忆T细胞形成至关重要的细胞因子。在……里面
小鼠肿瘤模型,接种全瘤裂解物加由TLR7/8激动剂组成的佐剂
R848(Resquimod)联合独特的分离溶血磷脂酰胆碱(22:0 lyso PC)促进DC
抗原特异性CD8+T细胞的过度激活、扩增,以及对肿瘤的强大排斥。虽然这些发现
是令人鼓舞的,并表明识别特定的新抗原并不是启动和扩大
细胞毒性T细胞(CTL)池,这种方法的验证和优化需要使用一个模型
这一系统更接近地概括了人类癌症的免疫状况。因此,目的是
这项建议的目的是利用自发性犬癌,特别是骨肉瘤作为桥梁
动物模型验证DC过度激活作为基础元素在产生
强大的抗肿瘤免疫力。在此应用程序中要检验的中心假设是组合
WTL来源的新抗原对DC的高度激活将扩大肿瘤特异性CTL的多样性群体
能清除犬初次肿瘤切除后残留的显微转移的OS肿瘤细胞
(截肢)。我们进一步预测,将DC过度激活/WTL与新的肿瘤微环境相结合
由toceranib/氯沙坦/拉达利辛组成的(TME)预适应方案将提高客观缓解率
在发生肉眼肺转移的狗身上。为了做到这一点,我们将进行前瞻性随机
OS犬截肢及卡铂化疗配合辅助护理的临床试验
单独或佐剂+WTL。出现肺转移的狗将接受TME调理治疗
方案联合佐剂+西药治疗。将从狗身上收集组织样本和血液的生物库
这些试验包括匹配的原发/转移肿瘤和相关的淋巴结、全血、血浆、
外周血单核细胞、无细胞DNA和从疫苗中排出的淋巴结节样本。这些将用于执行一组
旨在描述免疫微环境和肿瘤基因组的补充性分析
复发/耐药过程,证明一种新的新抗原预测管道,并评估抗原特异性T细胞
细胞反应。一支出色的团队,在临床试验、翻译和
肿瘤学、比较基因组学和免疫肿瘤学已经汇集在一起,以确保所述的里程碑是
已实现。这一点得到了与我们的行业合作伙伴Corner Treateutics的动态合作的支持,后者是
致力于支持这项工作,以促进优化和成功地转化为人类患者。
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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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
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10793931 - 财政年份:2023
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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
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$ 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:
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:
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:
6640368 - 财政年份:2002
- 资助金额:
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