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

• 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
• 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

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.

项目概要 尽管治疗策略有了实质性改进，但仍产生强大的抗肿瘤免疫反应 最近的数据表明，体细胞突变负担较低的人类癌症仍然是一个巨大的挑战。 树突状细胞 (DC) 是这一过程中的关键参与者，但无法有效引发有效的诱导和持久的 T 细胞反应 除非它们进入了一种独特的过度激活状态，否则 DC 会表现出增强的迁移能力。 局部淋巴结 (LN) 和持续分泌 IL-1β，这是一种对记忆 T 细胞形成至关重要的细胞因子。 小鼠肿瘤模型，用全肿瘤裂解物和由 TLR 7/8 激动剂组成的佐剂进行疫苗接种 R848（瑞喹莫特）与独特的分离溶血磷脂酰胆碱 (22:0 Lyso PC) 结合可促进 DC 这些发现包括过度激活、抗原特异性 CD8+ T 细胞的扩增以及对肿瘤的强烈排斥。 令人鼓舞，并表明特定新抗原的鉴定对于启动和扩大 细胞毒性 T 细胞 (CTL) 库，该方法的验证和优化需要使用模型 该系统更接近地概括了人类癌症的免疫状况。 该提案的目的是使用自发性犬癌，特别是骨肉瘤（OS）作为桥接剂 动物模型验证 DC 过度激活作为产生 本申请要测试的中心假设是结合。 使用 WTL 衍生的新抗原对 DC 进行过度激活将扩大 CTL 的多样性和肿瘤特异性群体 能够消除原发性肿瘤切除后犬体内残留的微观转移性操作系统肿瘤细胞 （截肢）我们进一步预测，DC 过度激活/WTL 与新型肿瘤微环境相结合。 (TME) 由托西尼布/洛沙坦/拉达辛组成的预处理方案将提高客观缓解率 为了实现这一目标，我们将进行一项前瞻性随机试验。 在患有 OS 的狗中进行的临床试验，结合截肢和卡铂化疗与辅助标准护理 出现肺转移的狗将接受 TME 调理治疗。 结合佐剂+WTL的方案将从狗身上收集组织样本和血液的生物库。 参加这些试验的包括匹配的原发性/转移性肿瘤和相关的淋巴结、全血、血浆、 PBMC、游离 DNA 和来自疫苗引流 LN 的样本将用于执行一组操作。 旨在表征免疫微环境和肿瘤基因组的互补测定 复发/耐药的过程，证明新的新抗原预测管道，并评估抗原特异性 T 一个杰出的团队，在临床试验、转化方面具有互补的专业知识。 肿瘤学、比较基因组学和免疫肿瘤学已汇集在一起​​，以确保实现既定的里程碑 这是通过与我们的行业合作伙伴 Corner Therapeutics 的动态合作实现的。 致力于支持这项工作，以促进优化并成功转化为人类患者。