Targeted antigen receptor treatment of cancer

描述(申请人提供)：临床免疫治疗计划是一项高度互动的研究工作，具有丰富的历史，通过临床前模型将实验室中发现的靶点带入早期临床试验，目的是选择实验疗法进行后期临床试验。目前的方案延续了这一传统，通过使用抗原受体靶向组织特异性抗原进行癌症治疗。其理论基础是T细胞和B细胞上的抗原受体具有显著的特异性。共同的主题包括靶向分化抗原和肿瘤间质，抗原受体的特异性，基于抗原受体的治疗的有效性的增强，免疫调节，克服肿瘤的异质性，以及成像和定量的复杂方法的应用。探索了两种治疗策略：主动免疫疗法(疫苗)以产生抗体和T细胞反应，以及被动免疫疗法与抗体(单抗)。该方案有四个使用新方法的项目(例如，单链抗体单抗片段、阿尔法发射体、纳米发电机、光学成像、异源DNA 疫苗，用于疫苗接种的T细胞动态平衡)用于：1)通过在非常短的距离内配备具有非凡能量的阿尔法粒子发射器来提高抗体效力。2)利用新型小型化的抗体抗原结合域，克服了以实体瘤为靶向抗体的局限性，从而更有效地穿透肿瘤。3)克服肿瘤对组织特异性自身抗原的耐受性，通过合理设计抗原突变体增强抗原提呈，提高主动免疫的效力。4)在骨髓切除后免疫平衡恢复的过程中，主动免疫后对肿瘤抗原的免疫应答增强和倾斜。管理核心提供生物统计、数据管理、护理和药房支持。生物物理和核医学核心提供最先进的光学和核成像、剂量学、放射化学和先进的分子成像。免疫监测核心测量细胞因子、抗体和T细胞，包括数量、特异性和表型。最终目标是为基于抗原受体的治疗建立新的原则和策略，更具体地说，开发针对不同和重叠的细胞和组织间隔的抗体和T细胞相结合的协同治疗方法。

DESCRIPTION (provided by applicant): The Clinical Immunotherapy Program is a highly interactive research effort that has a rich history of bringing targets discovered in the laboratory through preclinical models into early stage clinical trials with the goal of selecting experimental therapies for late stage clinical testing. The present proposal continues this tradition through targeting tissue-specific antigens for cancer therapy using antigen receptors. The rationale is based on the remarkable specificity of the antigen receptors on T cells and B cells. Shared themes include targeting differentiation antigens and tumor stroma, specificity of antigen receptors, enhancement of potency of antigen receptor-based therapies, modulation of immunity, overcoming heterogeneity in the tumor, and the application of sophisticated methods for imaging and quantitation. Two strategies for therapy are explored active immunotherapy (vaccines) to generate antibody and T-cell responses and passive immunotherapy with antibodies (monoclonal antibodies, mAb). The Program has four projects that use new approaches (e.g., single chain Fv mAb fragments, alpha emitters, nanogenerators, optical imaging, heteroclitic DNA vaccines, T-cell homeostasis for vaccination) for: 1) Increasing antibody potency by arming with alpha particle emitters with extraordinary energy over a very short range. 2) Overcoming limitations of targeting antibodies to solid tumors using novel miniaturized antigen-binding domains of antibodies to penetrate tumors more effectively. 3) Overcoming tolerance against tissue-specific self antigens in cancers for active immunization by increasing potency through rationally designed antigen mutants to enhance antigen presentation. 4) Enhancing and skewing immune responses toward tumor antigens following active immunization during recovery of immune homeostasis after bone marrow ablation. An Administrative Core provides biostatistics, data management, nursing, and pharmacy support. The Biophysics and Nuclear Medicine Core provides state-of-the-art optical and nuclear imaging, dosimetry, radiochemistry, and advanced molecular imaging. The Immune Monitoring Core measures cytokines, antibodies and T-cells, including quantitation, specificities and phenotype. The ultimate goal is to establish new principles and strategies for antigen receptor-based therapies, and more specifically develop synergistic treatments that combine antibodies and T cells directed at different and overlapping cellular and tissue compartments.