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治疗仅使约1/5的NSCLC患者受益，因此存在很大的风险。 需要改进这种疾病的免疫疗法。一种独特的免疫疗法IL-2可以产生完全的 在黑色素瘤和肾细胞癌中的反应。由于常见的危及生命的毒性，IL-2的使用受到限制。 IL-2的替代物是IL-15/IL-15 R α复合物。ALT-803是一种临床级IL-15/IL-15 R α复合物， 对IL-15应答性CD 8+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。联合ALT-803与抗PD-1 mAb的临床前研究表明， 显著的抗肿瘤功效与CD 8 + T细胞和NK细胞的扩增相关， 炎性细胞因子如IL-6和IFNγ。我们已经把这个疗法带到了诊所，有一个调查员- 启动的首次人体试验，Ib/II期试验，测试了加入IL-15/IL-15 R α复合物（ALT- 803)抗PD 1 mAb（nivolumab）在NSCLC中安全有效（NCT 02523469）。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为最高计划剂量）治疗， 零观察到的剂量限制性毒性（DLT）和优异的CD 8 + T细胞和NK细胞活化， 血清IL-6和IFNγ。该应用程序的目标是确定的机制基础和预测 响应这种有前途的组合方法，使用我们独特的银行的试验衍生样品和 强大的临床前肺肿瘤模型。我们假设，在抗PD-1抗体中加入IL-15/IL-15 R α复合物， 1 mAb通过增强肿瘤反应性细胞因子的扩增和功能活化来增强抗肿瘤功效 CD 8+淋巴细胞和NK细胞，并且炎性细胞因子如IL-6和IFNγ的诱导将被抑制。 与抗肿瘤功效相关。我们进一步假设增强的抗肿瘤功效将取决于效应子 淋巴细胞（CD 8+和NK，而不是CD 4+），并与细胞因子（IL-6和IFNγ）相关。具体目标1：使用 我们将使用最先进的质谱细胞仪对NK和CD 8 + T细胞进行高维表征。 来自多达116名患者的纵向PBMC样品的区室。我们将进行TCR测序， 扩增的T细胞，以确定它们是否来自肿瘤。我们还将进行65重血清 细胞因子/趋化因子分析纵向获得的样品，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 目的2：我们将使用我们的刘易斯肺癌（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-15 R α复合物的组合。首先，我们将识别细胞和分子 使用响应和非响应的纵向分析与治疗结果相关的标志物 小鼠其次，我们将使用抗体介导的淋巴细胞亚群耗竭或 细胞因子最后，我们将评估交替给药和给药方案对关键效应群体的影响， 我们还将抗CTLA-4 mAb疗法整合到我们的治疗中。