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: 10374802
• 负责人: MARK P RUBINSTEIN
• 金额: $ 38.99万
• 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/10374802
• 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 cell receptor repertoire sequencing; 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疗法仅受益于5例NSCLC患者中的1个，因此有很棒的 需要改善该疾病的免疫疗法。免疫疗法的一种独特的形式IL-2可以完整产生 黑色素瘤和肾细胞癌的反应。由于常见的威胁生命的毒性，IL-2的使用受到限制。 IL-2的替代方法是IL-15/IL-15Rα复合物。 Alt-803是IL-15/IL-15Rα复合物的临床级和 IL-15响应CD8+淋巴细胞和天然杀手（NK）细胞的强大超级激动剂具有急剧 与IL-2相比，安全性提高了。将ALT-803与抗PD-1 MAB结合的临床前研究证明了 与CD8+ T细胞和NK细胞的扩展以及生产相关的显着抗肿瘤效率 炎性细胞因子，例如IL-6和IFNγ。我们已经通过研究人员将这种疗法转移到诊所中 - 启动了人类第一期IB/II期试验，该试验检验了临床假设，即增加IL-15/IL-15Rα复合物（Alt- 803）到抗PD1 mAb（Nivolumab）在NSCLC中是安全有效的（NCT02523469）。迄今有11名患者有 用三个高度活性剂量水平（6、10、15 mcg/kg SC，15是计划中的剂量最高） 零观察到剂量限制毒性（DLT）和CD8+ T细胞和NK细胞的极佳激活，并增加 在血清IL-6和IFNγ中。此应用的目的是确定机械基础和预测指标 使用我们独特的试用样品库和A 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膨胀和功能激活来增强抗肿瘤效率 CD8+淋巴细胞和NK细胞，以及炎性细胞因子（例如IL-6和IFNγ）的诱导将是 与抗肿瘤效率相关。我们进一步假设增强的抗肿瘤效率将取决于效应器 淋巴细胞（CD8+和NK，而不是CD4+），并与细胞因子（IL-6和IFNγ）相关。特定目标1：使用 最先进的质量细胞仪我们将执行NK和CD8+ T细胞的高维度表征 纵向PBMC样品的隔室最多116名患者。我们将在 扩展的T细胞确定它们是否起源于肿瘤。我们还将执行65个PLEX系列 纵向获得样品的细胞因子/趋化因子分析，以鉴定新型血清生物标志物。我们将 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。具体的 AIM 2：我们将使用我们的Lewis肺癌（LLC）鼠标模型来告知我们未来的临床工作 抗PD-1 MAB和IL-15/SIL-15Rα复合物的组合。首先，我们将鉴定细胞和分子 通过对响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的部署验证关键途径 细胞因子。最后，我们将评估替代剂量和时间表对关键效应人群的影响，以及 还将抗CTLA-4 MAB疗法整合到我们的治疗中。