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

描述（由申请人提供）：针对实体肿瘤的癌症免疫疗法正在成熟，fda批准了针对前列腺癌、黑色素瘤和肾细胞癌的免疫疗法。白介素-2 （IL-2）和CTLA4抗体ipilimumab被批准用于黑色素瘤；两者都会引起持久的临床衰退。最近的数据也表明抗肿瘤免疫与BRAF抑制剂vemurafenib的临床反应有关。其他非常有前景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。令人兴奋的是，这种不断增长的全身免疫疗法的作用主要是由T淋巴细胞介导的，其作用通常是持久的。尽管这些治疗方法有效，但仍有大约70-80%的患者未能成功，并继续发展为进行性疾病。这是一个理想的时机，可以在免疫和靶向治疗的基础上，为晚期黑色素瘤建立新的联合治疗方法，目标是获得高持久的临床效益。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治疗的一个组成部分。在过去的3年里，一种癌症疫苗被批准用于前列腺癌，一项随机前瞻性试验表明，在高剂量IL-2的基础上添加肽疫苗具有临床价值。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种诱导CD4+辅助性T （TH）细胞的中长度肽的疫苗（6辅助性肽，6MHP），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，recist定义的缓解率和疾病控制率分别为8%和30%。重要的是，对6MHP的免疫反应与存活之间也存在显著关联。目前的建议是进行一系列的三个临床试验，以优化含有AS的6MHP疫苗

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.