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

• 批准号: 8915646
• 负责人: Craig Lee Slingluff
• 金额: $ 39.48万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915646
• 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; Health; Helper-Inducer T-Lymphocyte; Immune; 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; 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' s adjuvant; inhibitor/antagonist; lymph nodes; melanoma; neoplastic cell; novel strategies; phase II trial; prospective; prostate cancer cell; randomized trial; response; targeted treatment; tumor; vaccine development; vaccine effectiveness

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(申请人提供)：实体肿瘤的癌症免疫疗法正在走向成熟，FDA批准的免疫疗法用于前列腺癌、黑色素瘤和肾癌。白介素2(IL-2)和CTLA4抗体ipilimumab被批准用于黑色素瘤；两者都会导致持久的临床退化。最近的数据还表明，抗肿瘤免疫与BRAF抑制剂维莫拉非尼的临床反应有关。其他非常有希望的免疫疗法也在开发中，通过阻断PD-1/PD-L1和抗原特异性过继T细胞疗法而导致持久的临床回归。人们对这种日益增长的系统免疫疗法感到兴奋，它的作用主要由T淋巴细胞介导，其作用通常是持久的。尽管这些疗法有效，但仍有约70%-80%的患者未能通过治疗，并继续发展为进展性疾病。这是一个理想的时机，建立在免疫和靶向疗法的基础上，为晚期黑色素瘤建立新的联合疗法，目标是获得高比率的持久临床受益率。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治疗的一个组成部分。在过去的三年里，一种癌症疫苗已经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的基础上添加多肽疫苗的临床价值。因此，经过几十年的发展和优化，现在有证据表明，癌症疫苗可能会改善临床结果，特别是与其他有效疗法相结合。我们已经开发出一种含有6个诱导CD4+辅助T(TH)细胞的中长肽(6个辅助肽，6MHP)的疫苗，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，RECIST定义的应答率和疾病控制率分别为8%和30%。重要的是，对6MHP的免疫反应与存活率之间也有显著的关联。目前的建议是进行一系列的三项临床试验，以优化具有AS的6 MHP疫苗 15佐剂(AIM 1)，并获得初步数据，说明与BRAF抑制(AIM 2)或CTLA4阻断(AIM 3)联合使用是否比单独使用这两种药物都能改善临床结果。申请中提出的三项临床试验还将纳入对血液、皮肤、淋巴结和肿瘤免疫反应的相关研究，以更全面地了解宿主：这些联合治疗背景下的肿瘤关系。