MELANOMA VACCINE FOR HELPER T CELLS COMBINED WITH TARGETED OR IMMUNE THERAPIES

辅助性 T 细胞黑色素瘤疫苗与靶向或免疫疗法相结合

基本信息

批准号：
8692713
负责人：
Craig Lee Slingluff
金额：
$ 38.94万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692713
关键词：
6 Helper Peptide Adjuvant Agonist Antibodies Antigen Presentation Antigens BRAF gene Blood CD4 Positive T Lymphocytes CD8B1 gene CTLA4 gene Cancer Vaccines Cells Clinical Clinical Trials Combined Modality Therapy Correlative Study Cyclophosphamide Data Dendritic Cells Deposition Development Dose Eastern Cooperative Oncology Group Effectiveness Evaluation FDA approved Goals Helper-Inducer T-Lymphocyte Immune Immune Targeting Immune response Immunity Immunologics Immunotherapeutic agent Immunotherapy Infiltration Interleukin-2 Investigation Length Leukocyte L1 Antigen Complex Malignant neoplasm of prostate Mediating Melanoma Cell Melanoma Vaccine Mutation Myelogenous Neoplasm Metastasis New Agents Outcome Pathway interactions Patients Peptide Vaccines Peptides Phase II Clinical Trials Progression-Free Survivals Progressive Disease QS21 Randomized Renal Cell Carcinoma Safety Series Signal Transduction Skin Solid Neoplasm T cell response T cell therapy T-Lymphocyte TLR4 gene Testing Time Vaccination Vaccine Adjuvant Vaccines Work arm base cancer immunotherapy disorder control immunogenic immunogenicity improved incomplete Freund&apos s adjuvant inhibitor/antagonist lymph nodes melanoma neoplastic cell novel strategies prospective prostate cancer cell public health relevance randomized trial response tumor vaccine development vaccine effectiveness

项目摘要

DESCRIPTION (provided by applicant): Cancer immunotherapy for solid tumors is coming of age, with FDA-approved immunotherapeutics in prostate cancer, melanoma, and renal cell cancer. Interleukin-2 (IL-2) and the CTLA4 antibody ipilimumab are approved for melanoma; both induce durable clinical regressions. Recent data also implicate antitumor immunity in clinical response to the BRAF inhibitor vemurafenib. Other very promising immune therapies are in development, with durable clinical regressions induced by blockade of PD-1/PD-L1 and by antigen-specific adoptive T cell therapy. There is excitement about this growing armamentarium of systemic immunotherapeutics, whose effects are mediated predominantly by T lymphocytes and whose effects are typically durable. Despite the effectiveness of those therapies, still about 70-80% of patients fail them, and go on to develop progressive disease. This is an ideal time to build on the armamentarium of immune and targeted therapies to build new combination therapies for advanced melanoma, with a goal of high rates of durable clinical benefit. Cancer vaccines inducing antigen-specific T cell responses are emerging as a component of combination immunotherapy. In the past 3 years, a cancer vaccine has been approved for prostate cancer, and a randomized prospective trial showed clinical value of adding a peptide vaccine to high-dose IL-2. Thus, after several decades of development and optimization, there is now evidence that cancer vaccines may improve clinical outcomes, in particular in combination with other active therapies. We have developed a vaccine with 6 intermediate-length peptides that induce CD4+ helper T (TH) cells (6 helper peptides, 6MHP), which is immunogenic in 40-80% of patients, has clinical activity in advanced melanoma with RECIST-defined response rates and disease control rates of 8% and 30%, respectively. Importantly, there also is a significant association between immune response to the 6MHP and survival. The current proposal is for a series of three clinical trials, to optimize the 6MHP vaccine with the AS 15 adjuvant (Aim 1), and to obtain preliminary data on whether combination with BRAF inhibition (Aim 2) or CTLA4 blockade (Aim 3) may improve clinical outcomes compared to either agent alone. The three clinical trials proposed in the application also will incorporate correlative studies of immune responses in blood, skin, lymph nodes, and tumor to obtain a more complete understanding of the host:tumor relationship in the context of these combination therapies.

描述（由申请人提供）：针对实体瘤的癌症免疫疗法已经成熟，FDA 已批准针对前列腺癌、黑色素瘤和肾细胞癌的免疫疗法。白细胞介素-2 (IL-2) 和 CTLA4 抗体伊匹单抗 (ipilimumab) 被批准用于治疗黑色素瘤；两者都会引起持久的临床退化。最近的数据还表明抗肿瘤免疫与 BRAF 抑制剂维莫非尼的临床反应有关。其他非常有前途的免疫疗法正在开发中，通过阻断 PD-1/PD-L1 和抗原特异性过继 T 细胞疗法诱导持久的临床消退。这种不断增长的全身免疫治疗药物令人兴奋，其作用主要由 T 淋巴细胞介导，并且其作用通常是持久的。尽管这些疗法有效，但仍有约 70-80% 的患者失败，并继续发展为进行性疾病。现在是在免疫和靶向治疗武器库的基础上构建针对晚期黑色素瘤的新联合疗法的理想时机，其目标是获得高比例的持久临床获益。诱导抗原特异性 T 细胞反应的癌症疫苗正在成为联合免疫疗法的一个组成部分。过去3年，一种癌症疫苗已被批准用于前列腺癌，一项随机前瞻性试验显示了在高剂量IL-2中添加肽疫苗的临床价值。因此，经过几十年的开发和优化，现在有证据表明癌症疫苗可以改善临床结果，特别是与其他积极疗法相结合。我们开发了一种含有 6 种中等长度肽的疫苗，可诱导 CD4+ 辅助性 T (TH) 细胞（6 种辅助肽，6MHP），该疫苗对 40-80% 的患者具有免疫原性，对晚期黑色素瘤具有临床活性，并具有 RECIST 定义的反应发病率和疾病控制率分别为8%和30%。重要的是，对 6MHP 的免疫反应与生存之间也存在显着关联。目前的提案是进行一系列三项临床试验，以优化 6MHP 疫苗与 AS 15 佐剂（目标 1），并获得关于与单独使用任一药物相比，与 BRAF 抑制（目标 2）或 CTLA4 阻断（目标 3）联合使用是否可以改善临床结果的初步数据。该申请中提出的三项临床试验还将纳入血液、皮肤、淋巴结和肿瘤中免疫反应的相关研究，以便在这些联合疗法的背景下更全面地了解宿主与肿瘤的关系。