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) 的体细胞突变率非常高，并且已确定致癌驱动因素在大多数患者中，PTEN 是一种调节致癌 PI3K-AKT 信号传导的肿瘤抑制因子。我们之前的研究表明，高达 30% 的肿瘤中表达完全丧失。研究表明，PTEN 的缺失与 III 期黑色素瘤患者的总体生存期缩短有关，并且与基于这些研究，IV 期疾病患者的靶向治疗结果较差。最近我们研究了PTEN缺失对抗肿瘤免疫反应和免疫治疗的影响。初步临床前研究表明，黑色素瘤中 PTEN 的缺失会增加免疫抑制细胞因子，减少关键效应 T 细胞的瘤内浸润，并导致晚期黑色素瘤群体的体外和体内对 T 细胞介导的免疫治疗的耐药性分析。患者表明 PTEN 缺失与 III 期黑色素瘤中 CD8+ T 细胞浸润减少相关患者，并且在 IV 期疾病中对 FDA 批准的抗 PD-1 抗体的反应率显着降低。使用 GSK2636771（一种 PI3Kβ 异构体特异性抑制剂）治疗，可降低 AKT 激活，增加 T 细胞浸润，并提高了体内抗 PD-1 检查点抑制剂治疗的功效 PTEN 缺失、PD-1 耐药的黑色素瘤的免疫活性模型值得注意的是，GSK2636771 不会损害细胞。免疫细胞的活力或功能，与 PTEN 细胞对 PI3Kβ 的选择性依赖一致基于这些研究，我们发现抑制 PI3K-AKT 通路将克服耐药性。对 PTEN 缺失的黑色素瘤进行抗 PD-1 免疫治疗来检验这一假设，并解决未满足的问题。由于PD-1难治性患者需要有效的治疗方法，我们正在进行I/II期临床试验 GSK2636771联合抗PD-1抗体pembrolizumab治疗转移性黑色素瘤患者未能对抗 PD-1 做出反应的 PTEN 缺失的血液和肿瘤样本将在之前和之前收集。在治疗期间和进展过程中，以提高我们对该方案的效果和治疗效果的理解在目标 1 中，我们将确定该治疗对 PI3K-AKT 激活的影响。途径，以及途径抑制、GSK2636771 稳态水平和治疗之间的关系在目标 2 中，我们将通过评估肿瘤和免疫效果来评估联合治疗的免疫效果。血液样本中免疫细胞亚群和免疫调节细胞因子的存在和变化，还将与临床反应性进行比较，在目标 3 中，我们将使用临床前模型来评估间歇性。与其他异构体选择性 PI3K 抑制剂的剂量和组合方法作为进一步的策略提高GSK2636771与抗PD-1的功效这些研究将提高我们对其作用的理解。 PI3K-AKT 通路在抗肿瘤免疫反应和免疫治疗耐药中的作用，并帮助识别未来在这种癌症和其他 PTEN 缺失的癌症中进行测试的其他合理策略。