Novel Strategies for Precision T-cell Therapies

 描述（由申请人提供）：免疫疗法，包括生物制剂和基于细胞的疗法，正在成为治疗癌症的非常有前途和有效的策略。伴随着这些方法的巨大潜力的是持续的挑战，包括1）与生物制剂相关的非靶向全局免疫调节，导致严重的副作用; 2）基于细胞的疗法的可扩展性的挑战（例如，目前的问题包括：（1）缺乏特异性（过继性/CAR-T疗法）和双特异性，（2）缺乏分化，因为大多数努力都集中在相对较少的治疗靶点和机制上;（3）缺乏灵活的平台来快速有效地靶向新的适应症和机制。为了应对这些挑战，我们描述了一类用于治疗癌症的新型可溶性精密生物制剂。我们的方法操纵抗原特异性（即，克隆）淋巴细胞群体，通过共价连接单链肽-MHC（sc-pMHC）和共刺激分子，以重现免疫突触处经历的接近、定向和整体组织的方式。sc-pMHC单元用于选择性地靶向不同的T细胞克隆，用于递送可以代表任何潜在共刺激功能的调节结构域。这些构建体作为Fc融合蛋白（即，IgG）用于增强的亲合力和稳定性。这种组合的靶向：调节构建体被称为synTac（用于T细胞活化的人工免疫突触）。使用这种策略，我们已经证明了体外克隆特异性T细胞增殖和活化，以及体内克隆T细胞扩增。与这些试剂相关的极端特异性消除了与当前使用的免疫治疗药物相关的广泛副作用，并且高度模块化的设计分别通过取代疾病相关肽表位和协同调节模块来支持广泛的适应症和治疗机制。拟议的工作重点是继续开发synTac平台，用于特异性靶向恶性肿瘤的CTL的选择性体内扩增。我们的具体目标是：目标1：继续开发synTac融合蛋白平台，包括探索具有改变的化学计量和新的共调节结构域的新呈现平台。目标2：对synTac功效的亲和力和整体分子组织的评估，以实现对细胞表面受体信号传导的新见解和控制synTac治疗的新策略 活动目标3：synTac在特定疾病回归模型中的应用，以研究synTac在黑色素瘤和胰腺癌中的功能，使用疾病和肿瘤回归模型，包括HLA-A2转基因。该项目的持续成功有望为快速开发、评估和实施新型生物制剂家族提供一个独特且高度灵活的平台，以通过多种不同的机制治疗一系列适应症，并使我们能够启动胰腺导管腺癌的临床试验。

 DESCRIPTION (provided by applicant): Immunotherapies, including biologics and cell-based therapies, are emerging as highly promising and effective strategies for the treatment of cancer. Accompanying the great potential of these approaches are continuing challenges, including 1) untargeted global immune modulation associated with biologics, resulting in serious side effects; 2) challenges in scalability of cell-based therapies (e.g., adoptive/CAR-T therapies) and bispecifics, 3) lack of differentiation, as most efforts are focused on relatively few therapeutic targets and mechanisms; and 4) the lack of flexible platforms to rapidly and efficiently target new indications and mechanisms. To address these challenges, we describe a novel class of soluble precision biologics for the treatment of cancer. Our approach manipulates antigen-specific (i.e., clonal) lymphocyte populations by covalently linking single chain peptide-MHC (sc-pMHC) and costimulatory molecules in a manner that recapitulates the proximity, orientation and overall organization experienced at the immunological synapse. The sc-pMHC unit serves to selectively target distinct T cell clones for the delivery of a modulatory domain that can represent any potential costimulatory function. These constructs are generated as Fc-fusion proteins (i.e., IgG) for enhanced avidity and stability. This combined targeting:modulation construct is referred to as synTac (artificial immunological Synapse for T-cell Activation). Using this strategy we have already demonstrated clonal-specific T cell proliferation and activation in vitro, and clonal T cell expansion in vivo. The extreme specificity associated with these reagents eliminates the extensive side effects associated with currently used immunotherapeutics and the highly modular design supports a wide range of indications and therapeutic mechanisms via substitution of the disease relevant peptide epitope and comodulatory modules, respectively. The proposed work focuses on the continued development of the synTac platform for the selective in vivo expansion of CTLs that specifically target malignancies. Our Specific Aims are: AIM 1: Continued development of the synTac fusion protein platform, including the exploration of new presentation platforms with altered stoichiometries and new comodualory domains. AIM 2: Assessment of affinity and overall molecular organization on synTac efficacy to realize new insights into cell surface receptor signaling and new strategies for controlling synTac therapeutic activity. AIM 3: Application of synTacs to specific disease regression models to investigate synTac function in melanoma and pancreatic cancer, using disease and tumor regression models, including HLA-A2 transgenics. The continued success of this program promises to deliver a unique and highly flexible platform for the rapid development, evaluation and implementation of a novel family of biologics to treat a range of indications via a number of distinct mechanisms, and position us to initiate clinical trials for pancreatic ductal adenocarcinoma.