Combination immunotherapies for the treatment of melanoma

用于治疗黑色素瘤的联合免疫疗法

• 批准号: 8453586
• 负责人: MICHAEL W FANGER
• 金额: $ 28.83万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453586
• 关键词: Antibodies; CTLA4 gene; Cancerous; Caring; Cell Proliferation; Cells; Cessation of life; Clinical Trials; Combined Modality Therapy; Data; Diagnosis; Disease; Endothelial Cells; Endothelium; Genetic; Genetic Models; Glioblastoma; Growth; Growth Factor; Human; Hypoxia; Immune system; Immunotherapy; In Vitro; In complete remission; Incidence; Individual; Life; Malignant Neoplasms; Marketing; Metastatic Melanoma; Modeling; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Normal tissue morphology; Pathologic Neovascularization; Patients; Pharmaceutical Preparations; Phase; Physiologic Neovascularization; Progression-Free Survivals; Proteins; Relapse; Role; Site; Small Interfering RNA; Solid Neoplasm; Staging; Therapeutic; Toxic effect; Tumor Immunity; Vascular Endothelial Growth Factors; Work; angiogenesis; base; cancer cell; cancer therapy; chemotherapy; falls; hazard; human disease; in vivo; inhibitor/antagonist; killings; knockout gene; lifetime risk; meetings; melanoma; migration; neoplastic cell; novel therapeutic intervention; panacea; partial response; plasmalemmal vesicle; pre-clinical; prevent; public health relevance; response; small molecule; therapeutic target; tumor; tumor growth; vasculogenesis

DESCRIPTION (provided by applicant): Melanoma is the most common form of cancer in young adults1, and its incidence is rising at a rate higher than any of the seven most common cancers2, increasing 45% between 1992 and 20043. Plexxikon and Roche are codeveloping a BrafV600E inhibitor (i.e. PLX4032 (Vemurafenib)) and BMS/Medarex recently attained FDA approval for their anti-CTLA4 antibody (i.e. ipilimumab (Yervoy)). PLX4032 is a small molecule inhibitor of BrafV600E that induces rapid melanoma regression in the subset of patients that harbor this mutation4. BrafV600E inhibition provides promising early responses, but a combination therapy will undoubtedly be required for durable melanoma control. Immunotherapy is another approach that has recently demonstrated significant efficacy in patients with metastatic melanoma.6, 7 Ipilimumab has shown clear efficacy in clinical trials for metastatic melanoma however, only 11% of patients show partial or complete response, while posing significant challenges to clinicians due to associated toxicities. We have focused on targeting Plasmalemmal Vesicle Associated Protein-1 (Plvap/PV1), an endothelial specific protein with roles in angiogenesis8-10 and diapedesis of leukocytes11. PV1 is expressed on a subset of endothelia in normal tissues12-16. Importantly, PV1 is upregulated on the endothelium of most, if not all, human solid tumors, melanoma included8, 10, 17-19. In human glioblastomas, PV1 is among the top four most upregulated endothelial genes17, regulated by hypoxia8 and growth factors such as VEGF and HGF 8, 10, 19. Although PV1 is actively involved in pathological angiogenesis associated with tumor growth8-10, our preliminary data using PV1 gene knockouts show that PV1 in not required for normal tissue vasculogenesis or physiological angiogenesis, which is a particularly appealing feature of an anti-PV1 cancer therapy. Based on its association with tumor growth, we have investigated PV1 for its potential as a target for the therapy of cancer, especially melanoma. Data presented herein demonstrate that PV1 is expressed at high levels on endothelial cells associated with melanoma, and that anti-PV1 monoclonal antibodies delivered systemically effectively inhibit tumor growth in a genetic model of melanoma (Braf/Pten). PV1 an intriguing therapeutic target for solid tumors, especially in combination therapies that (1) directly target tumor cell proliferation and (2) stimulate anti-tumor immunity. To date, we have shown that systemic administration of anti-PV1 mAb confers a clear inhibition of melanoma growth in a murine melanoma model, on par with the efficacy of PLX4032. We plan to define the therapeutic window for anti-PV1 mAb when used in combination with state of the art therapies for melanoma and demonstrate synergistic efficacy of anti-PV1 combination therapies in a genetic murine melanoma model that closely mimics human disease.

描述(申请人提供)：黑色素瘤是年轻人最常见的癌症1，其发病率的上升速度高于7种最常见的癌症2中的任何一种，1992年至20043年间增加了45%。 Plexxikon和罗氏正在共同开发一种BRAFV600E抑制剂(即PLX4032(Vemurafenib))，BMS/Medarex最近获得了FDA对其抗CTLA4抗体(即ipilimumab(Yerway))的批准。PLX4032是BRAFV600E的一种小分子抑制剂，可以在携带这种突变的患者亚群中诱导黑色素瘤快速消退4。抑制BRAFV600E提供了有希望的早期反应，但毫无疑问，为了持久控制黑色素瘤，联合治疗将是必要的。免疫疗法是最近证明对转移性黑色素瘤患者有显著疗效的另一种方法。6，7伊匹单抗在转移性黑色素瘤的临床试验中显示出明显的疗效，然而，只有11%的患者表现出部分或完全反应，同时由于相关的毒副作用给临床医生带来了巨大的挑战。我们专注于针对质膜囊泡相关蛋白-1(Plvap/PV1)，这是一种内皮特异性蛋白，在血管生成8-10和白细胞裂解中发挥作用11。PV1在正常组织的内皮细胞亚群12-16上表达。重要的是，PV1在大多数(如果不是全部)人实体肿瘤的内皮细胞上表达，包括黑色素瘤8、10、17-19。在人类胶质母细胞瘤中，PV1是四个最上调的内皮基因17之一，受低氧8和生长因子如VEGF和HGF 8、10、19的调节。尽管PV1积极参与与肿瘤生长相关的病理性血管生成8-10，但我们使用PV1基因敲除的初步数据表明，PV1不是正常组织血管生成或生理性血管生成所必需的，这是抗PV1癌症治疗的一个特别吸引人的特征。 基于PV1与肿瘤生长的关系，我们研究了PV1作为治疗癌症，特别是黑色素瘤的靶点的潜力。本文提供的数据表明，PV1在与黑色素瘤相关的内皮细胞上高水平表达，并且在黑色素瘤遗传模型(BRAF/PTEN)中，抗PV1单抗系统地有效地抑制了肿瘤的生长。PV1是一个耐人寻味的实体肿瘤治疗靶点，特别是在(1)直接靶向肿瘤细胞增殖和(2)刺激抗肿瘤免疫的联合治疗中。到目前为止，我们已经证明，在小鼠黑色素瘤模型中，系统性给予抗PV1单抗可以明显抑制黑色素瘤的生长，与PLX4032的疗效相当。我们计划确定抗PV1单抗与最先进的黑色素瘤治疗方法结合使用时的治疗窗口，并在接近模拟人类疾病的遗传小鼠黑色素瘤模型中展示抗PV1联合治疗的协同效果。