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疗法仅使大约五分之一的非小细胞肺癌患者受益，因此有很大的 需要改进对这种疾病的免疫治疗。一种独特的免疫疗法，IL-2，可以产生完全 黑色素瘤和肾癌的反应。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复合体。ALT-803是一种临床级IL-15/IL-15Rα复合体， 强大的IL-15应答CD8+淋巴细胞和自然杀伤(NK)细胞的超级激动剂 与IL-2相比，安全性更高。联合ALT-803和抗PD-1单抗的临床前研究表明 显著的抗肿瘤作用与CD8+T细胞和NK细胞的扩增和产生 炎性细胞因子如IL-6和干扰素γ的表达。我们已经和一位研究人员将这种疗法转移到了诊所- 启动了人类首个Ib/II期试验，测试了临床假说：添加IL-15/IL-15Rα复合体(ALT- 803)抗PD1单抗(Nivolumab)治疗非小细胞肺癌(NCT02523469)安全有效。到目前为止，有11名患者 用三个高活性剂量水平(6、10、15微克/公斤SC，15为最高计划剂量)治疗 零观察剂量限制毒性(DLT)和CD8+T细胞和NK细胞的良好激活并增加 血清IL-6和干扰素γ。此应用程序的目标是确定机械基础和预测因素 对这一有希望的组合方法的响应使用我们独特的试验衍生样本库和 强大的临床前肺肿瘤模型。我们推测，IL-15/IL-15Rα复合体与抗PD- 1单抗通过增强肿瘤反应的扩增和功能激活而增强抗肿瘤效果 CD8+淋巴细胞和NK细胞，并诱导炎性细胞因子如IL-6和干扰素γ 与抗肿瘤疗效有关。我们进一步假设增强抗肿瘤疗效将取决于效应器 淋巴细胞(CD8+和NK，而不是CD4+)，并与细胞因子(IL-6和干扰素γ)相关。具体目标1：使用 我们将进行NK和CD8+T细胞的高维表征 最多116名患者的纵向PBMC样本的隔室。我们将对其进行TCR测序 扩增T细胞以确定它们是否来自肿瘤。我们还将进行65-plex血清 对纵向获取的样本进行细胞因子/趋化因子分析，以确定新的血清生物标志物。我们会 淋巴细胞和血清细胞因子/趋化因子参数的变化与临床疗效的关系。特定的 目的2：我们将使用我们的Lewis肺癌(LLC)小鼠模型来为我们未来的临床工作提供信息 抗PD-1单抗与IL-15/sIL-15Rα复合物的结合首先，我们将鉴定细胞和分子 通过对有效和无效的纵向分析确定与治疗结果相关的标记物 老鼠。其次，我们将使用抗体介导的淋巴细胞亚群耗尽或 细胞因子。最后，我们将评估交替给药和计划对关键效应者种群的影响，以及 同时将抗CTLA-4单抗治疗与我们的治疗相结合。