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：
9111875
负责人：
Walter J. Storkus
金额：
$ 42.32万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111875
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 Cytotoxic T-Lymphocyte-Associated Protein 4 Dasatinib Diagnosis Disease Disease regression Drug resistance Effectiveness Effector Cell EphA2 Receptor Epitopes Exhibits Flow Cytometry Frequencies Genetic Heterogeneity Growth HLA-A2 Antigen Health 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 objective response rate peptide based vaccine peripheral blood pre-clinical 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令人震惊的速度升高，估计有70,000名被诊断出的患者和2011年可归因于这种疾病的8,700例死亡。尽管最近取得了BRAF抑制剂和ipilumimimab（抗CTCTLA-44）的成功。 mab）在提供黑色素瘤患者的客观临床反应时，这种益处通常持续时间很短，只有5-15％的治疗个体观察到持久的反应。疾病复发的主要原因和治疗难治性疾病的发展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补偿性生长和生存途径，以规避特定的治疗阻滞。为了绕过这种肿瘤内在的局限性，我们最近开发了促进CD8+ T细胞靶向肿瘤 - 但不是正常组织的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耐用的无病状态。我们还确定，基于酪氨酸激酶抑制剂（例如dasatinib（DAS））的共同给药，治疗性疫苗可能越来越有效，基于该DRG的“ OFF靶标”能力，以减少免疫调节细胞，以增加疫苗 - 疫苗 - 增加疫苗 - 诱导肿瘤宿主中的T效应细胞，并改变肿瘤微环境中的趋化因子和整联蛋白的表达，以促进保护性CD8+ T细胞的募集。基于这些初步发现，我们假设由肿瘤血管基抗原疫苗和达沙替尼组成的联合疗法将证明是安全的，并且在患有晚期阶段黑色素瘤的HLA-A2+患者的情况下有效性提高（AIM 1）。鉴于我们在休眠的发现，在HLA-A2 TG小鼠的一部分中具有神秘性黑色素瘤，这些小鼠已通过抗血管疫苗有效治疗，我们还将检验以下假设：这些动物中完整的“分子疗法”的速率可以通过这些动物的改善。结合疗法可以增强CD8+ T细胞识别并调节黑色素瘤引发细胞（又称黑色素瘤干细胞或自我更新的黑色素瘤细胞）或在体内阻止肿瘤（亲寿命）自噬途径的结合疗法（AIM 2）。基于我们的临床前建模，我们认为这些研究的成功完成将定义一种新型的治疗范式，以有效治疗广泛的固体（血管化）癌症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment.

DOI：
10.1136/jitc-2020-001906
发表时间：
2021-03
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
Chelvanambi M;Fecek RJ;Taylor JL;Storkus WJ
通讯作者：
Storkus WJ

Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer.

DOI：
10.1007/s00262-018-2259-0
发表时间：
2019-01
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
0
作者：
Weinstein AM;Giraldo NA;Petitprez F;Julie C;Lacroix L;Peschaud F;Emile JF;Marisa L;Fridman WH;Storkus WJ;Sautès-Fridman C
通讯作者：
Sautès-Fridman C