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治疗仅使约五分之一的非小细胞肺癌患者受益，因此有很大的