Immunization Against Melanoma Differentiation Antigens

 描述（由申请人提供）：黑素体分化抗原是在黑素细胞和黑色素瘤细胞上独特表达的蛋白质家族。因此，它们代表了合理和方便的替代标志物，以测量动物模型系统和人类患者对黑素瘤的免疫应答，用于创新免疫策略的临床试验。它们也是非常有吸引力的免疫治疗靶点，因为它们在正常细胞上的表达受到限制。鉴于上一个资助期取得的进展，我们提出了三个具体目标。首先是继续我们的重点是GITR（糖皮质激素诱导的TNF受体家族相关蛋白）作为激动剂免疫策略的新靶点。我们定义了GITR诱导的免疫调节的新机制，其中调节性T细胞（Treg）失去谱系定型和Treg：T效应细胞比率的有利变化。这将应用于我们目前正在领导的GITR激动剂单克隆抗体的首次人体临床试验以及默克抗GITR抗体的I期试验。我们将通过探索肿瘤细胞上免疫调节分子的表达来进一步研究这些生物标志物。我们还计划使用这些生物标志物随时间推移的评估，进一步研究后期时间点（难治性肿瘤与缓解性肿瘤）次优缓解的基础。在目标2中，我们将继续努力，通过研究在可移植和自发的黑色素瘤小鼠模型中，使用对黑素体抗原的免疫力作为结果测量，用针对TNFR超家族受体OX40和GITR的激动剂抗体进行双重共刺激的效果，来鉴定最有效和最相关的免疫调节剂组合。这直接适用于临床试验，因为我们正在与行业合作伙伴合作，以提供临床级试剂用于进一步试验。在目标3中，我们将有一个独特的机会直接比较两种基于细胞的免疫策略，嵌合抗原受体T细胞（CAR+）和携带CAR+细胞识别的相同抗原（TRP1，黑素体抗原）的转基因T细胞受体的T细胞。我们将比较不同的宿主细胞以及抗原受体，以确定一种最佳的细胞疗法，联合收割机与 在先前的目的中定义的抗体组合。我们的总体目标是利用对黑素体抗原的免疫力来确定可以进入临床试验的最有效的黑色素瘤免疫策略。

 DESCRIPTION (provided by applicant): Melanosomal differentiation antigens are a family of proteins uniquely expressed on melanocytes and melanoma cells. As such, they represent rational and convenient surrogate markers to measure immune responses to melanoma in both animal model systems and human patients on clinical trials of innovative immunotherapeutic strategies. They also are very attractive targets for immunotherapies given their restricted expression on normal cells. Given the progress made during the prior funding period, we have proposed three specific aims. The first is to continue our focus on GITR (glucocorticoid-induced TNF-receptor family related protein) as a novel target of agonist immunotherapeutic strategies. We defined a novel mechanism underlying GITR-induced immune modulation with regulatory T cells (Treg) losing lineage commitment and a favorable change in the Treg:T effector cell ratio. This will be applied to a first-in-human clinical trial of an agonist monoclonal antibody to GITR, which we are currently leading as well as a Phase I trial of the Merck anti-GITR antibody. We will further these biomarker investigations by exploring the expression of immune regulatory molecules on tumor cells. We also plan to further investigate the basis for sub-optimal response at later timepoints (refractory vs. responding tumors) using assessment of these biomarkers over time. In Aim 2, we will continue our efforts to identify the most impactful and relevant combinations of immune modulators by studying the effects of dual costimulation with agonist antibodies against the TNFR superfamily receptors OX40 and GITR in transplantable and spontaneous mouse models of melanoma, using immunity to melanosomal antigens as an outcome measure. This is directly applicable to clinical trials as we have ongoing collaborations with industry partners to make clinical grade reagents available for further trials. In Aim 3, we will have a unique opportunity to directly compare two cell-based immunotherapeutic strategies, chimeric antigen receptor T cells (CAR+) and T cells bearing a transgenic T cell receptor for the same antigen that the CAR+ cells recognize (TRP1, a melanosomal antigen). We will compare different host cells as well as antigen receptors to define an optimal cell therapy to combine with the antibody combination defined in prior Aims. Our overall goal is to use immunity to melanosomal antigens to identify the most potent immunotherapeutic strategies for melanoma that can be brought into clinical trials.