Targeting Lung Tissue Resident NK Cells with Inhaled IL-15 and TIGIT Blockade in Osteosarcoma

通过吸入 IL-15 和 TIGIT 阻断治疗骨肉瘤，靶向肺组织驻留 NK 细胞

• 批准号: 10438449
• 负责人: Robert J. Canter
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438449
• 关键词: Adoptive Transfer; Advanced Malignant Neoplasm; Antitumor Response; Back; Blood; CD3 Antigens; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Canis familiaris; Cell Death; Cell Proliferation; Cellular immunotherapy; Clinical; Combination immunotherapy; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Disease; Dose; Drug Kinetics; Exposure to; Female; Foundations; Functional disorder; Goals; Homeostasis; Human; ITIM; Immune; Immunocompetent; Immunoglobulins; Immunosuppression; Immunotherapy; In complete remission; Inbred BALB C Mice; Inbred C3H Mice; Inhalation; Interleukin-15; Interleukin-2; Intravenous; Longevity; Lung; Lung Neoplasms; Lymphokine-Activated Killer Cells; Malignant Neoplasms; Manuscripts; Mediating; Memory; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Monoclonal Antibodies; Mus; Natural Killer Cells; Nebulizer; Neoplasm Metastasis; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Play; Population; Preparation; Regulatory T-Lymphocyte; Resistance; Risk; Role; Sampling; Site; Stable Disease; Structure of parenchyma of lung; Systemic Therapy; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Translations; Treatment Efficacy; Tumor Immunity; Tyrosine; Up-Regulation; antitumor effect; base; cancer therapy; cancer type; cytokine; cytokine release syndrome; cytotoxic; cytotoxicity; effector T cell; exhaustion; human model; immune checkpoint; immune checkpoint blockade; immune function; immunopathology; immunoregulation; improved; innovation; male; melanoma; mouse model; novel; novel strategies; osteosarcoma; partial response; pathogen exposure; phase I trial; primary bone cancer; programmed cell death ligand 1; programmed cell death protein 1; response; sarcoma; success; survival outcome; systemic toxicity; trafficking; tumor; tumor-immune system interactions

PROJECT SUMMARY Cytokine immunotherapies, such as IL-2 and more recently IL-15, have been used to stimulate endogenous cytotoxic natural killer (NK) and T cell responses against advanced cancers and to support adoptively transferred lymphokine-activated killer cells. While responses have been achieved in some patients, the use of IL-2 and IL- 15 has been hampered by modest benefits with the risk of severe systemic toxicity, particularly when given intravenously (IV). Distinct from IV delivery, inhaled IL-15 therapy offers the advantages of concentrated delivery to the lungs, a frequent site of gross metastatic disease, while limiting systemic exposure and potential toxicity. Osteosarcoma (OSA) is an aggressive primary bone cancer with a high propensity for lung metastases, and outcomes for patients with lung metastases have been stagnant for the past 4 decades. In our recently completed (manuscript in preparation) first-in-kind trial of inhaled rhIL-15 in dogs with spontaneous lung metastases from OSA and melanoma, we observed clinical benefit in 37% (1 complete response, 1 partial response, and 5 stable disease at 60 days in 19 dogs). Here, we propose to evaluate the immune mechanisms of response to inhaled IL-15 in mouse and human models of metastatic OSA, hypothesizing that a unique tissue resident NK population in the lungs has heightened cytotoxic and proliferative responses consistent with a memory- like phenotype which enables augmented anti-tumor responses. In Aim 1, we will analyze lung resident NK cells (CD3-NKp46+CD49a+) in K7M2 and LM8 models of OSA, hypothesizing that inhaled IL-15 delivered by nebulizer will stimulate NK-mediated anti-tumor responses against OSA lung metastases. Matched human blood, non-tumor-bearing lung, and tumor samples from patients with OSA undergoing metastasectomy will be used to validate these mouse studies, in particular that human lung NK cells show features of heightened cytotoxicity and effector function which can be harnessed to infiltrate immunosuppressive OSA metastases in the setting on inhaled IL-15. In Aim 2, we will evaluate combination therapy. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) has emerged as a critical marker of NK cell exhaustion which limits anti-tumor responses in multiple cancer types, including sarcomas. Thus, we will combine inhaled IL-15 with TIGIT blockade using anti-TIGIT monoclonal antibodies to assess NK phenotype and function, trafficking to lung tumors, persistence, and tumor regression following treatment in mouse models. Toxicity will also be carefully assessed given the potential for combination immunotherapy to precipitate immunopathology and cytokine storm. Metastatic OSA is a rare and difficult-to-treat cancer. Despite great success in other cancers, immunotherapy targeting PD-1, PD-L1, and CTLA-4 has shown minimal efficacy in OSA, underscoring the need for novel immunotherapies for these aggressive cancers. This proposal will evaluate novel strategies to stimulate tissue-resident NK cells in the lungs using inhaled IL-15 to maximize the therapeutic exposure at the site of action while limiting systemic exposure and toxicity.

项目概要 细胞因子免疫疗法，例如 IL-2 和最近的 IL-15，已被用于刺激内源性 针对晚期癌症的细胞毒性自然杀伤 (NK) 和 T 细胞反应并支持过继转移 淋巴因子激活的杀伤细胞。虽然一些患者已取得缓解，但使用 IL-2 和 IL- 15 受到了适度益处的阻碍，并存在严重全身毒性的风险，特别是在给予时 静脉注射（IV）。与静脉注射不同，吸入IL-15疗法具有集中输送的优点 肺部是肉眼转移性疾病的常见部位，同时限制全身暴露和潜在毒性。 骨肉瘤 (OSA) 是一种侵袭性原发性骨癌，极有可能发生肺转移，并且 过去 4 年来，肺转移患者的治疗结果一直停滞不前。在我们最近完成的 （手稿准备中）在患有自发性肺转移的狗中进行吸入 rhIL-15 的首次同类试验 OSA 和黑色素瘤，我们观察到 37% 的临床获益（1 例完全缓解，1 例部分缓解，5 例稳定） 19 只狗在 60 天时患病）。在这里，我们建议评估吸入的免疫反应机制 IL-15 在小鼠和人类转移性 OSA 模型中的作用，假设一种独特的组织驻留 NK 肺部的细胞群具有增强的细胞毒性和增殖反应，这与记忆一致。 像能够增强抗肿瘤反应的表型。在目标 1 中，我们将分析肺驻留 NK OSA 的 K7M2 和 LM8 模型中的细胞 (CD3-NKp46+CD49a+)，假设吸入 IL-15 雾化器将刺激 NK 介导的针对 OSA 肺转移的抗肿瘤反应。匹配的人类 来自接受转移切除术的 OSA 患者的血液、非肿瘤肺和肿瘤样本将被 用于验证这些小鼠研究，特别是人肺 NK 细胞显示出增强的特征 细胞毒性和效应功能可用于浸润免疫抑制性 OSA 转移 吸入 IL-15 的设置。在目标 2 中，我们将评估联合疗法。 T 细胞免疫受体 免疫球蛋白和免疫受体基于酪氨酸的抑制基序结构域 (TIGIT) 已成为关键的 NK 细胞耗竭的标志物，限制了多种癌症类型（包括肉瘤）的抗肿瘤反应。 因此，我们将使用抗 TIGIT 单克隆抗体将吸入 IL-15 与 TIGIT 阻断相结合来评估 NK 表型和功能、向肺部肿瘤的运输、持续性以及治疗后的肿瘤消退 鼠标模型。鉴于联合免疫疗法的潜力，毒性也将被仔细评估 促进免疫病理学和细胞因子风暴。转移性 OSA 是一种罕见且难以治疗的癌症。尽管 尽管在其他癌症中取得了巨大成功，但针对 PD-1、PD-L1 和 CTLA-4 的免疫疗法却显示出微乎其微的疗效 在 OSA 中，强调了针对这些侵袭性癌症的新型免疫疗法的需求。该提案将 评估使用吸入 IL-15 刺激肺部组织驻留 NK 细胞的新策略，以最大限度地提高 作用部位的治疗暴露，同时限制全身暴露和毒性。