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: 9295843
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295843
• 关键词: Adjuvant; Agonist; Antibodies; Antigen Presentation; Antigens; BRAF gene; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; 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 response; 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; PDCD1LG1 gene; 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; Tumor Immunity; 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; new combination therapies; novel strategies; phase II trial; prospective; prostate cancer cell; public health relevance; 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（由申请人提供）：实体瘤的癌症免疫疗法即将到来，前列腺癌，黑色素瘤和肾细胞癌中FDA批准的免疫治疗药。白介素-2（IL-2）和CTLA4抗体ipilimumab被批准用于黑色素瘤；两者都诱导持久的临床回归。最近的数据还暗示了对BRAF抑制剂vemurafenib的临床反应中的抗肿瘤免疫力。其他非常有前途的免疫疗法正在发育中，持续的临床回归是由PD-1/PD-L1的阻断和抗原特异性的收养T细胞疗法引起的。这种不断增长的全身免疫治疗药的武器库令人兴奋，其作用主要由T淋巴细胞介导，其作用通常持久。尽管这些疗法有效，但仍有大约70-80％的患者使他们失败，并继续发展为进行性疾病。这是建立在免疫和有针对性疗法的靶向疗法的理想时机，该疗法为晚期黑色素瘤建立新的联合疗法，其目标是高持久的临床益处。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组成部分。在过去的三年中，癌症疫苗已被批准用于前列腺癌，并且一项前瞻性试验显示，将肽疫苗添加到高剂量IL-2中的临床价值。因此，经过数十年的开发和优化，现在有证据表明癌症疫苗可以改善临床结果，特别是与其他活跃疗法结合使用。 我们已经开发了一种疫苗，具有6种中间长度的肽，可诱导CD4+辅助剂T（Th）细胞（6个辅助肽，6MHP），该疫苗在40-80％的患者中具有免疫原性，在晚期黑色素瘤中具有临床活性，具有固定反应的临床活性。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有显着关联。当前的建议是针对三个临床试验的一系列建议，以优化具有AS的6MHP疫苗 15辅助（AIM 1），并获得有关与单独使用任何一种药物相比，与BRAF抑制（AIM 2）或CTLA4封锁（AIM 3）的结合（AIM 2）或CTLA4封锁（AIM 3）的初步数据可能会改善临床结果。应用程序中提出的三项临床试验还将纳入有关血液，皮肤，淋巴结和肿瘤中免疫反应的相关研究，以使对宿主的更完整了解：在这些组合疗法的背景下肿瘤的关系。