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。