Lymphocyte and inflammatory cytokine markers of response in the first-in-human combination of anti-PD-1 mAb and IL-15/IL-15Ra complexes and investigation of mediators of anti-tumor immune responses

抗 PD-1 mAb 和 IL-15/IL-15Ra 复合物的首次人体组合反应中的淋巴细胞和炎症细胞因子标记物以及抗肿瘤免疫反应介质的研究

• 批准号: 9902376
• 负责人: MARK P RUBINSTEIN
• 金额: $ 39.78万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902376
• 关键词: Affect; Agonist; Antibodies; Applications Grants; Biological; Biological Markers; Biological Sciences; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Caring; Cell Compartmentation; Clinic; Clinical; Clinical Trials; Complex; Critical Pathways; Cytometry; Data; Development; Diagnosis; Disease; Dose; Dose-Limiting; Funding; Future; Goals; Human; Immune; Immunotherapy; In complete remission; Inflammatory; Interferon Type II; Interferons; Interleukin-15; Interleukin-2; Interleukin-6; Investigation; Lewis Lung Carcinoma; Life; Lung; Lung Neoplasms; Lymphocyte; Lymphocyte Depletion; Lymphocyte Subset; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Natural Killer Cells; Nivolumab; Non-Small-Cell Lung Carcinoma; Oncology; PD-1 blockade; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase Ib/II Trial; Population; Production; Publications; Publishing; Regimen; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Request for Applications; Research Personnel; Safety; Sampling; Schedule; Serum; Specimen; T cell clonality; T-Lymphocyte; Testing; Time; Toxic effect; Translating; Treatment Failure; Treatment outcome; United States; anti-CTLA4; anti-PD-1; anti-PD-L1 antibodies; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; checkpoint therapy; chemokine; clinical predictors; combinatorial; cytokine; experience; first-in-human; high dimensionality; immune checkpoint; improved; interleukin-15 receptor; longitudinal analysis; melanoma; molecular marker; mouse model; novel; novel drug class; optimal treatments; partial response; pre-clinical; preclinical evaluation; preclinical study; predicting response; programmed cell death protein 1; response; response biomarker; standard of care; targeted treatment; tumor

Because PD-1 therapies only benefit approximately 1 in 5 patients with NSCLC, there is a great need to improve immunotherapy for this disease. A distinct form of immunotherapy, IL-2, can yield complete responses in melanoma and renal cell carcinoma. Use of IL-2 is limited due to common life-threatening toxicity. An alternative to IL-2 is IL-15/IL-15Rα complexes. ALT-803 is a clinical grade IL-15/IL-15Rα complex and powerful super-agonist for IL-15 responsive CD8+ lymphocytes and natural killer (NK) cells with dramatically improved safety compared with IL-2. Preclinical studies combining ALT-803 with anti-PD-1 mAb demonstrate remarkable anti-tumor efficacy associated with expansion of both CD8+ T cells and NK cells, and the production of inflammatory cytokines such as IL-6 and IFNγ. We have moved this therapy into the clinic with an investigator- initiated, first-in-human, phase Ib/II trial testing the clinical hypothesis that adding IL-15/IL-15Rα complexes (ALT- 803) to anti-PD1 mAb (nivolumab) is safe and efficacious in NSCLC (NCT02523469). To date 11 patients have been treated with three highly active dose levels (6, 10, 15 mcg/kg SC, 15 being the highest planned dose) with zero observed dose limiting toxicities (DLTs) and excellent activation of CD8+ T cells and NK cells and increases in serum IL-6 and IFNγ. The goal of this application is to determine the mechanistic basis and predictors of response for this promising combinatorial approach using our unique bank of trial-derived samples and a powerful preclinical lung tumor model. We hypothesize that the addition of IL-15/IL-15Rα complexes to anti-PD- 1 mAb augments anti-tumor efficacy through enhanced expansion and functional activation of tumor-reactive CD8+ lymphocytes and NK cells and that the induction of inflammatory cytokines such as IL-6 and IFNγ will be associated with anti-tumor efficacy. We further hypothesize enhanced anti-tumor efficacy will depend on effector lymphocytes (CD8+ and NK but not CD4+) and correlate with cytokines (IL-6 and IFNγ). Specific Aim 1: Using state-of-art mass cytometry we will perform the high-dimension characterization of both NK and CD8+ T cell compartments from longitudinal PBMC samples of up to 116 patients. We will perform TCR sequencing on expanded T cells to determine if they originate from tumor. We will also perform 65-plex serum cytokine/chemokine analysis of longitudinally acquired samples to identify novel serum biomarkers. We will associate changes in lymphocyte and serum cytokines/chemokines parameters with clinical response. Specific Aim 2: We will use our Lewis lung carcinoma (LLC) mouse model to inform our future clinical efforts with the combination of anti-PD-1 mAb and IL-15/sIL-15Rα complexes. First, we will identify cellular and molecular markers that correlate with treatment outcome using longitudinal analysis of responding and non-responding mice. Second we will validate critical pathways using antibody-mediated depletion of lymphocyte subsets or cytokines. Finally, we will evaluate the effects of alternate dosing and schedule on key effector populations, and also integrate anti-CTLA-4 mAb therapy into our treatment.

由于 PD-1 疗法仅使大约五分之一的 NSCLC 患者受益，因此存在很大的局限性。 需要改进这种疾病的免疫治疗。 IL-2 是一种独特的免疫疗法，可以产生完全的免疫治疗效果。 黑色素瘤和肾细胞癌的反应。由于常见的危及生命的毒性，IL-2 的使用受到限制。 IL-2 的替代品是 IL-15/IL-15Rα 复合物。 ALT-803 是一种临床级 IL-15/IL-15Rα 复合物， IL-15 反应性 CD8+ 淋巴细胞和自然杀伤 (NK) 细胞的强效超级激动剂 与 IL-2 相比，安全性更高。 ALT-803 与抗 PD-1 mAb 结合的临床前研究表明 与 CD8+ T 细胞和 NK 细胞的扩增以及生产相关的显着抗肿瘤功效 炎症细胞因子，例如 IL-6 和 IFNγ。我们已经与一名研究人员一起将这种疗法转移到诊所- 启动的首次人体 Ib/II 期试验测试了添加 IL-15/IL-15Rα 复合物（ALT- 803) 与抗 PD1 单克隆抗体 (nivolumab) 在 NSCLC 中安全有效 (NCT02523469)。迄今为止已有11名患者 接受三种高活性剂量水平（6、10、15 mcg/kg SC，15 是最高计划剂量）治疗 零观察到的剂量限制毒性 (DLT) 以及 CD8+ T 细胞和 NK 细胞的出色激活并增加 血清中IL-6和IFNγ。该应用程序的目标是确定机械基础和预测因素 使用我们独特的试验衍生样本库和一个 强大的临床前肺肿瘤模型。我们假设将 IL-15/IL-15Rα 复合物添加到抗 PD- 1 mAb 通过增强肿瘤反应性的扩增和功能激活来增强抗肿瘤功效 CD8+ 淋巴细胞和 NK 细胞，以及 IL-6 和 IFNγ 等炎症细胞因子的诱导 与抗肿瘤功效有关。我们进一步假设增强的抗肿瘤功效将取决于效应器 淋巴细胞（CD8+ 和 NK，但不是 CD4+）并与细胞因子（IL-6 和 IFNγ）相关。具体目标 1：使用 我们将采用最先进的质谱流式细胞仪对 NK 和 CD8+ T 细胞进行高维表征 来自多达 116 名患者的纵向 PBMC 样本的隔室。我们将进行 TCR 测序 扩增 T 细胞以确定它们是否源自肿瘤。我们还将进行 65 重血清 对纵向采集的样品进行细胞因子/趋化因子分析，以鉴定新的血清生物标志物。我们将 将淋巴细胞和血清细胞因子/趋化因子参数的变化与临床反应相关联。具体的 目标 2：我们将使用 Lewis 肺癌 (LLC) 小鼠模型为我们未来的临床工作提供信息 抗 PD-1 mAb 和 IL-15/sIL-15Rα 复合物的组合。首先，我们将识别细胞和分子 使用有反应和无反应的纵向分析与治疗结果相关的标记 老鼠。其次，我们将使用抗体介导的淋巴细胞亚群耗竭来验证关键途径或 细胞因子。最后，我们将评估交替给药和时间表对关键效应人群的影响，以及 还将抗 CTLA-4 mAb 疗法纳入我们的治疗中。