Targeted antigen receptor treatment of cancer

临床免疫治疗计划是一项高度互动的研究工作，具有将实验室中通过临床前模型发现的靶点带入早期临床试验的丰富历史，其目标是为后期临床试验选择实验性疗法。本发明通过使用抗原受体靶向用于癌症治疗的组织特异性抗原来延续这一传统。基本原理是基于T细胞和B细胞上抗原受体的显著特异性。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，增强基于抗原受体的治疗的效力，免疫调节，克服肿瘤的异质性，以及复杂的成像和定量方法的应用。两种治疗策略是主动免疫治疗（疫苗），以产生抗体和T细胞反应和被动免疫治疗抗体（单克隆抗体，mAb）。该方案有四个项目采用新的方法（例如，单链抗体片段，α发射体，纳米发生器，光学成像，异向DNA 疫苗，用于疫苗接种的T细胞内稳态）用于：1）通过在非常短的范围内装备具有非凡能量的α粒子发射体来增加抗体效力。2)使用抗体的新型小型化抗原结合结构域克服将抗体靶向实体瘤的限制以更有效地穿透肿瘤。3)通过合理设计的抗原突变体增强抗原呈递，提高效力，克服癌症中对组织特异性自身抗原的耐受性，用于主动免疫。4)骨髓消融后免疫稳态恢复期间主动免疫后对肿瘤抗原的免疫应答增强和偏斜。行政核心提供生物统计，数据管理，护理和药房支持。生物物理学和核医学核心提供最先进的光学和核成像，剂量测定，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，包括定量，特异性和表型。最终目标是为基于抗原受体的疗法建立新的原则和策略，更具体地说，开发协同治疗，将联合收割机抗体和针对不同和重叠的细胞和组织区室的T细胞相结合。

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.