Combinational Immunotherapy Targeting the Melanoma-Associated Vasculature

针对黑色素瘤相关脉管系统的组合免疫疗法

基本信息

批准号：
8548313
负责人：
Walter J. Storkus
金额：
$ 39.46万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8548313
关键词：
Animal Model Animals Antibodies Antigens Attention Autophagocytosis BAY 54-9085 BRAF gene Blood Vessel Tissue Blood Vessels Bypass CD8B1 gene CXCL9 gene CXCR3 gene Cell Line Cells Clinical Clinical Trials Combined Modality Therapy Combined Vaccines Complementary DNA Dasatinib Diagnosis Disease Disease regression Drug resistance Effectiveness Effector Cell EphA2 Receptor Epitopes Exhibits Flow Cytometry Frequencies Genetic Heterogeneity Growth HLA-A2 Antigen Human Hydroxychloroquine Immune Immune Targeting Immunity Immunofluorescence Microscopy Immunotherapy Incidence Individual Integrin alpha4beta1 Integrins Label Lesion Ligands Luciferases Malignant Neoplasms Melanoma Cell Modeling Molecular Monitor Mus Nature Neoplasms in Vascular Tissue Normal tissue morphology Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Pre-Clinical Model Prevalence Prevention Progression-Free Survivals Progressive Disease Protocols documentation Randomized Recruitment Activity Recurrence Refractory Refractory Disease Regulation Regulatory T-Lymphocyte Research Residual Neoplasm Residual state Serum Site Solid Solid Neoplasm Staging Stem cells Stromal Cells T cell response T-Lymphocyte Testing Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Tyrosine Kinase Inhibitor Vaccination Vaccine Therapy Vaccines Visual anergy arm attributable mortality base bevacizumab bioluminescence imaging cancer therapy chemokine comparative effective therapy human disease immunogenicity improved in vivo inhibitor/antagonist innovation kinase inhibitor melanoma neoplastic cell novel novel therapeutics peptide based vaccine peripheral blood pre-clinical public health relevance response self-renewal src-Family Kinases stem success therapeutic vaccine therapy development tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The incidence of melanoma continues to rise at an alarming pace, with estimates of the 70,000 patients diagnosed and 8,700 deaths attributable to this disease in 2011. Despite recent successes for BRAF inhibitors and ipilumimab (anti-CTLA-4 mAb) in providing objective clinical responses in melanoma patients, such benefits are typically of short duration, with durable responses observed in only 5-15% of treated individuals. A major reason for disease recurrence and the development of treatment-refractory disease reflects the genetic heterogeneity of tumor cells in a given lesion and the ability of subsets of tumor cells to select for compensatory growth and survival pathways that circumvent specific therapeutic blockade. As an attempt to bypass such tumor-intrinsic limitations, we have recently developed vaccines that promote CD8+ T cell targeting of tumor-, but not normal tissue-, associated blood vessel cells. In melanoma models applied to HLA-A2 transgenic (Tg) mice, these vaccines can promote tumor regression and durable disease-free status. We have also determined that therapeutic vaccines may become increasingly efficacious based on the co-administration of tyrosine kinase inhibitors, such as dasatinib (DAS), based on the "off target" abilities of this drg to diminish immune regulatory cells, to increase vaccine-induced T effector cells in the tumor-bearing host, and to alter chemokine and integrin expression in the tumor microenvironment to facilitate the recruitment of protective CD8+ T cells. Based on these preliminary findings, we hypothesize that combination therapies consisting of tumor blood vessel antigen-based vaccines and dasatinib will prove safe and of increased effectiveness in the setting of HLA-A2+ patients with advanced stage melanoma (Aim 1). Given our findings of dormant, occult melanomas in a subset of HLA-A2 Tg mice that have been effectively treated with anti-vascular vaccines, we will also test the hypothesis that the rate of complete "molecular cures" in these animals may be improved by combination therapies that allow for enhanced CD8+ T cell recognition and regulation of melanoma initiating cells (aka melanoma stem cells or self-renewing melanoma cells) or that block the tumor (pro-survival) autophagy pathway in vivo (Aim 2). Based on our pre-clinical modeling, we believe that the successful completion of these studies will define a novel therapeutic paradigm for the effective treatment of a broad range of solid (vascularized) cancers.

描述（由申请人提供）：黑色素瘤的发病率继续以惊人的速度上升，估计 2011 年有 70,000 名患者被诊断出患有这种疾病，并有 8,700 人死亡。尽管最近 BRAF 抑制剂和 ipilumimab（抗 CTLA-4）取得了成功mAb）在为黑色素瘤患者提供客观的临床反应时，这种益处通常持续时间较短，只有 5-15% 的治疗患者观察到持久反应个人。疾病复发和难治性疾病发展的一个主要原因反映了给定病变中肿瘤细胞的遗传异质性以及肿瘤细胞亚群的能力选择规避特定治疗封锁的补偿性生长和生存途径。作为绕过这种肿瘤固有限制的尝试，我们最近开发了促进 CD8+ T 细胞靶向肿瘤相关血管细胞而非正常组织相关血管细胞的疫苗。在应用于 HLA-A2 转基因 (Tg) 小鼠的黑色素瘤模型中，这些疫苗可以促进肿瘤消退和持久的无病状态。我们还确定，基于酪氨酸激酶抑制剂（例如达沙替尼（DAS））的共同施用，治疗性疫苗可能会变得越来越有效，因为该药物具有“脱靶”能力，可以减少免疫调节细胞，从而增加疫苗的效果。在荷瘤宿主中诱导 T 效应细胞，并改变肿瘤微环境中的趋化因子和整合素表达，以促进保护性 CD8+ T 细胞的募集。基于这些初步研究结果，我们假设由基于肿瘤血管抗原的疫苗和达沙替尼组成的联合疗法将被证明是安全的，并且在 HLA-A2+ 晚期黑色素瘤患者的治疗中具有更高的有效性（目标 1）。鉴于我们在已接受抗血管疫苗有效治疗的 HLA-A2 Tg 小鼠子集中发现了休眠、隐匿性黑色素瘤，我们还将检验以下假设：这些动物的完全“分子治愈”率可能会通过以下方法得到改善：联合疗法可增强 CD8+ T 细胞对黑色素瘤起始细胞（又称黑色素瘤干细胞或自我更新黑色素瘤细胞）的识别和调节，或阻断肿瘤（促进生存）体内自噬途径（目标 2）。基于我们的临床前模型，我们相信这些研究的成功完成将为有效治疗多种实体（血管化）癌症定义一种新的治疗范式。