Project 1 Targeting the PI3K Pathway to Overcome Resistance to Immunotherapy in Melanomas with Loss of PTEN

项目 1 靶向 PI3K 通路克服 PTEN 缺失黑色素瘤的免疫治疗耐药性

基本信息

批准号：
10415938
负责人：
Michael Davies
金额：
$ 41.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415938
关键词：
AKT Signaling Pathway Address BRAF gene Blood Blood specimen CD8-Positive T-Lymphocytes Cell Survival Cell physiology Cells Clinic Clinical Clinical Trials Cohort Analysis Combination immunotherapy Combined Modality Therapy Cutaneous Melanoma Dependence Disease Dose Drug Kinetics FDA approved Future Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunosuppression Immunotherapy In Vitro Inferior Infiltration Malignant Neoplasms Mediating Melanoma Cell Metastatic Melanoma Modeling Molecular Mus Oncogenic Outcome PTEN gene Pathway interactions Patients Pharmacodynamics Phase Phase I/II Clinical Trial Pre-Clinical Model Prognosis Protein Isoforms Proto-Oncogene Proteins c-akt Refractory Regimen Resistance Role Safety Sampling Schedule Signal Pathway Somatic Mutation T-Lymphocyte TCR Activation Testing Toxic effect Translations Treatment outcome Tumor Suppressor Proteins Tumor Tissue Tumor-infiltrating immune cells University of Texas M D Anderson Cancer Center Vascular Endothelial Growth Factors anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response base biomarker development cancer immunotherapy cancer type checkpoint therapy clinical application cohort combinatorial cytokine effective therapy effector T cell experience immune activation immune function immunoregulation improved in vivo inhibitor loss of function melanoma mutant neoplastic cell novel pembrolizumab preclinical study programmed cell death protein 1 resistance mechanism response targeted treatment trafficking treatment effect tumor tumor growth

项目摘要

Project 1: Project Summary/Abstract Cutaneous melanomas (CM) have a very high rate of somatic mutations, and oncogenic drivers are identified in the majority of patients. PTEN, a tumor suppressor that regulates the oncogenic PI3K-AKT signaling pathway, demonstrates complete loss of expression in up to 30% of these tumors. Our previous studies showed that loss of PTEN is associated with shorter overall survival in stage III melanoma patients, and with inferior outcomes with targeted therapies in patients with stage IV disease. Building upon these studies, recently we investigated the impact of PTEN loss on the anti-tumor immune response and immunotherapy. Initial preclinical studies demonstrated that loss of PTEN in melanomas increases the expression of immunosuppressive cytokines, decreases the intratumoral infiltration of critical effector T cells, and causes resistance to T-cell mediated immunotherapy in vitro and in vivo. Analyses of cohorts of advanced melanoma patients showed that loss of PTEN was associated with decreased CD8+ T cell infiltration in stage III melanoma patients, and significantly decreased response rates to FDA approved anti-PD-1 antibodies in stage IV disease. Treatment with GSK2636771, an isoform-specific inhibitor of PI3Kβ, decreased AKT activation, increased T cell infiltration, and increased the efficacy of anti-PD-1 checkpoint inhibitor therapy in vivo in an immunocompetent model of PTEN-null, PD-1-resistant melanoma. Notably, GSK2636771 did not harm the viability or function of immune cells, consistent with the selective dependence on PI3Kβ in cells with PTEN loss. Based on these studies, we hypothesize that inhibition of the PI3K-AKT pathway will overcome resistance to anti-PD-1 immunotherapy in melanomas with loss of PTEN. To test this hypothesis, and address the unmet need for effective therapies for PD-1-refractory patients, we are conducting a phase I/II clinical trial of GSK2636771 in combination with the anti-PD-1 antibody pembrolizumab in metastatic melanoma patients with PTEN loss that failed to respond to anti-PD-1. Blood and tumor samples will be collected prior to and during treatment as well as at progression to improve our understanding of the effects of this regimen and the results of the trial. In Aim 1 we will determine the effects of this treatment on the activation of the PI3K-AKT pathway, and the relationship between pathway inhibition, GSK2636771 steady-state levels, and treatment outcomes. In Aim 2 we will evaluate the immune effects of the combination treatment by evaluating tumor and blood samples for the presence and changes in immune cell subsets and immunoregulatory cytokines, which will also be compared to clinical responsiveness. In Aim 3 we will use preclinical models to evaluate intermittent dosing and combinatorial approaches with additional isoform-selective PI3K inhibitors as strategies to further improve the efficacy of GSK2636771 with anti-PD-1. These studies will improve our understanding of the role of the PI3K-AKT pathway in the anti-tumor immune response and immunotherapy resistance, and help identify additional rational strategies for future testing in this and other cancers with PTEN loss.

项目1：项目摘要/摘要皮肤黑色素瘤（CM）具有很高的体细胞突变，并且鉴定出致癌驱动器在大多数患者中。途径表明我们先前的研究中多达30％的表达受压表明PTEN的丧失与III期黑色素瘤患者的总体生存率较短有关在研究期间患有靶向疗法的靶向疗法的下方面的结局。最近，我们研究了PTEN损失对抗肿瘤免疫反应和免疫疗法的影响。最初的临床前研究表明，黑色素瘤中PTEN的损失增加了免疫性的细胞因子，减少临界的肿瘤内浸润，并导致在体外和体内对T细胞介导的免疫疗法的抗性。患者表明，PTEN的丧失与CD8+ T细胞III黑色素瘤降低有关患者，并在IV期疾病中显着降低了对FDA批准的抗PD-1抗体的反应率。用PI3Kβ的同工型特异性抑制剂GSK2636771治疗，降低了Akt激活，T增加了T 细胞浸润，并提高抗PD-1检查点抑制剂在体内的疗效 PTEN-NULL，PD-1抗性黑色素瘤的免疫能力模型。免疫细胞的生存力或功能，与PTEN细胞中对PI3Kβ的选择性依赖性一致损失基于研究，我们假设吸入PI3K-AKT途径在黑色素瘤中进行抗PD-1免疫疗法，以检验这种假设，并解决未满足的需要对PD-1-饮食患者进行有效疗法，我们正在进行一项I/II期临床试验 GSK2636771与转移性黑色素瘤患者的抗PD-1抗体Pembrolizumab结合使用随着PTEN的损失，未能对抗PD-1做出反应。在治疗期间和进步期间，以提高我们对该方案的影响的理解 AIM 1中的试验结果我们将确定治疗对PI3K-AKT的影响途径以及Inhiber途径之间的关系，GSK2636771稳态级别和信任结果。血液样本以阳ot的存在和变化，即兴结合细胞因子，这还将与AIM 3中的临床反应性进行比较。用其他同工型选择PI3K抑制剂作为进一步的策略的剂量和组合方法通过抗PD-1提高GSK2636771的功效。抗肿瘤免疫反应和免疫疗法抗性的PI3K-AKT途径，并有助于识别在此和PTEN损失的癌症中进行未来测试的广泛合理策略。