Targeted antigen receptor treatment of cancer

描述（由申请人提供）：临床免疫治疗项目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，目标是为后期临床试验选择实验疗法。目前的建议通过使用抗原受体靶向组织特异性抗原进行癌症治疗来延续这一传统。其基本原理是基于抗原受体对T细胞和B细胞的显著特异性。共同的主题包括靶向分化抗原和肿瘤基质，抗原受体的特异性，增强抗原受体治疗的效力，调节免疫，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）产生抗体和t细胞反应，被动免疫疗法与抗体（单克隆抗体，mAb）。该计划有四个使用新方法的项目（例如，单链Fv单抗片段、α发射器、纳米发生器、光学成像、异晶DNA）

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.