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：
Cheryl A London
金额：
$ 65.78万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
https://reporter.nih.gov/project-details/10688274
关键词：
Activities of Daily Living Adjuvant Agonist Amputation Animal Cancer Model Animal Model Antigen-Presenting Cells Antigens Bioinformatics Biological Biological Assay Biological Markers Biological Models Blood CCR1 gene CD8-Positive T-Lymphocytes Cancer Model Canis familiaris Carboplatin Cells Clinical Trials Clone Cells Collaborations Credentialing Cytotoxic T-Lymphocytes Data Dendritic Cells Dendritic cell activation Disease Effectiveness Elements Enrollment Ensure Evolution Excision Exhibits Failure Flow Cytometry Future Generations Genetic Goals Human IL8RA gene Immune Immune checkpoint inhibitor Immune response Immunity Immunologic Markers Immunologics Immunooncology Immunotherapy Inflammasome Interleukin-1 beta Link Losartan Lung Lymph Node Tissue Lysophosphatidylcholines Malignant Neoplasms Metastatic Neoplasm to the Lung Metastatic Osteosarcoma Microscopic Modeling Mus Nature Neoplasm Metastasis Nucleotides Oral Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Population Pre-Clinical Model Primary Neoplasm Process Production Progression-Free Survivals Randomized Reagent Regimen Relapse Residual state Resistance Resources Sampling Series Signal Transduction Single Nucleotide Polymorphism Site Somatic Mutation Stimulus T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Therapeutic Tissue Sample Translations Tumor Immunity Tumor Markers Tumor-Derived Vaccination Vaccines Validation Variant Whole Blood Work anti-tumor immune response antigen-specific T cells aspirate biobank cancer genome cell free DNA checkpoint inhibition chemotherapy clinical efficacy clinical translation comparative genomics conditioning cytokine design draining lymph node exome sequencing immunomodulatory therapies improved in vivo industry partner inhibitor kinase inhibitor lymph nodes migration mouse model neoantigens neoplastic cell novel novel strategies novel therapeutic intervention novel vaccines objective response rate osteosarcoma peptide I programmed cell death protein 1 prospective randomized, clinical trials resiquimod response standard of care tool transcriptomics translational medicine translational oncology treatment response tumor tumor microenvironment tumor-immune system interactions vaccine platform vaccine 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.

项目摘要尽管治疗策略有很大改善，但在较低的体细胞突变烧伤的人类癌症仍然是一个重大挑战。最近的数据表明在此过程中的关键参与者，树突状细胞（DC），无法有效地引起高效且耐用的T细胞响应除非他们进入了独特的过度激活状态。在这种情况下，DC暴露了增强的迁移到局部淋巴结（LNS）和IL-1β的持续分泌，这是记忆T细胞形成至关重要的细胞因子。在小鼠肿瘤模型，全肿瘤裂解物的疫苗接种以及由TLR 7/8激动剂组成的调节 R848（resiquimod）与独特的孤立溶液磷脂酰胆碱（22：0 lyso PC）结合使用，促进了DC 过度活化，抗原特异性CD8+ T细胞的扩张以及肿瘤的稳健排斥。而这些发现令人鼓舞的，并暗示对特定新抗原的识别是不需要的细胞毒性T细胞（CTL）的池，这种方法的验证和优化有必要使用模型相对于免疫景观，更紧密地概括了人类癌症的系统。因此，目的该建议是使用赞助犬类癌，特别是骨肉瘤（OS）作为桥接动物模型以验证直流过度激活的实用性作为生成的基础元素强大的抗肿瘤免疫。在此应用中要测试的中心假设是结合 WTL衍生的新抗原的DC过度激活将扩大潜水员和肿瘤特异性的CTL种群去除原发性肿瘤后，能够消除狗中残留的显微镜转移性OS肿瘤细胞（截肢）。我们进一步预测，将直流过度激活/WTL与新型肿瘤微环境相结合（TME）由Toceranib/Losartan/Ladarixin组成的调理方案将提高客观响应率在发展宏观肺转移的狗中。为此，我们将进行前瞻性随机性与OS结合截肢和护理标准卡铂化学疗法的狗的临床试验单独或调整+WTL。然后将使用TME调节治疗发展肺转移的狗与调节+WTL结合使用方案。将从狗那里收集组织样品和血液的生物库参加了这些试验，包括匹配的原发性/转移性肿瘤和相关的LN，全血，血浆， PBMC，无细胞的DNA和来自疫苗排水LN的样品。这些将用于执行一组完全旨在表征免疫微环境和肿瘤基因组上的阿萨斯救济/抵抗的过程，证书是新型的新抗原预测管道，并评估抗原特异性T 细胞反应。一支杰出的团队，具有临床试验的完善专业知识，翻译已经组装了肿瘤学，比较基因组学和免疫肿瘤学，以确保陈述的里程碑是成就了。与我们的行业合作伙伴Corner Therapeutics进行了动态合作的支持，这是致力于支持这项工作，以支持优化和成功翻译为人类患者。