Department of Pathology, Immunology and Laboratory Medicine, Rutgers University- New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA.
Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, 07101, USA.
Cell Commun Signal. 2020 Aug 25;18(1):134. doi: 10.1186/s12964-020-00617-7.
Chimeric Antigen Receptor (CAR) immunotherapy utilizes genetically-engineered immune cells that express a unique cell surface receptor that combines tumor antigen specificity with immune cell activation. In recent clinical trials, the adoptive transfer of CAR-modified immune cells (including CAR-T and CAR-NK cells) into patients has been remarkably successful in treating multiple refractory blood cancers. To improve safety and efficacy, and expand potential applicability to other cancer types, CARs with different target specificities and sequence modifications are being developed and tested by many laboratories. Despite the overall progress in CAR immunotherapy, conventional tools to design and evaluate the efficacy and safety of CAR immunotherapies can be inaccurate, time-consuming, costly, and labor-intensive. Furthermore, existing tools cannot always determine how responsive individual patients will be to a particular CAR immunotherapy. Recent work in our laboratory suggests that the quality of the immunological synapse (IS) can accurately predict CAR-modified cell efficacy (and toxicity) that can correlate with clinical outcomes. Here we review current efforts to develop a Synapse Predicts Efficacy (SPE) system for easy, rapid and cost-effective evaluation of CAR-modified immune cell immunotherapy. Ultimately, we hypothesize the conceptual basis and clinical application of SPE will serve as an important parameter in evaluating CAR immunotherapy and significantly advance precision cancer immunotherapy. Video abstract Graphic abstract for manuscript CCAS-D-20-00136 by Liu, D., et al., 'The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy". The various branches of evaluating cancer immunotherapy metaphorically represented as a Rubik's cube. The development of a novel approach to predict the effectiveness of Chimeric Antigen Receptor (CAR)-modified cells by quantifying the quality of CAR IS will introduce a new parameter to the rapidly expanding field of cancer immunotherapy. Currently, no single parameter can predict the clinical outcome or efficacy of a specific type of CAR-modified cell. IS quality will serve as a quantifiable measure to evaluate CAR products and can be used in conjunction with other conventional parameters to form a composite clinical predictor. Much like a Rubik's cube has countless configurations, several methods and combinations of clinical metrics have arisen for evaluating the ability of a given immunotherapeutic strategy to treat cancer. The quality of IS depicting cancer immunotherapy is metaphorically expressed as a Rubik's cube. Each face/color represents one aspect of cancer therapy. Each grid in one face indicates one factor within that aspect of cancer therapy. For example, the green color represents the tumor microenvironment, and one out of the nine grids in the green color indicates suppressor cells (suppressors in green). Changes in one factor may completely alter the entire strategy of cancer therapy. However, the quality of IS (illuminated center red grid) makes the effectiveness of CAR immunotherapy predictable.
嵌合抗原受体 (CAR) 免疫疗法利用经过基因工程改造的免疫细胞，这些细胞表达一种独特的细胞表面受体，将肿瘤抗原特异性与免疫细胞激活结合在一起。在最近的临床试验中，将经过 CAR 修饰的免疫细胞（包括 CAR-T 和 CAR-NK 细胞）过继转移到患者体内，在治疗多种难治性血液癌方面取得了显著成功。为了提高安全性和疗效，并将潜在的适用性扩展到其他癌症类型，许多实验室正在开发和测试具有不同靶特异性和序列修饰的 CAR。尽管 CAR 免疫疗法取得了总体进展，但用于设计和评估 CAR 免疫疗法的疗效和安全性的传统工具可能不够准确、耗时、昂贵且劳动强度大。此外，现有的工具并不总是能够确定个体患者对特定 CAR 免疫疗法的反应如何。我们实验室最近的工作表明，免疫突触 (IS) 的质量可以准确预测 CAR 修饰细胞的疗效（和毒性），并且可以与临床结果相关。在这里，我们回顾了目前为开发用于简单、快速和具有成本效益的评估 CAR 修饰免疫细胞免疫疗法的 Synapse Predicts Efficacy (SPE) 系统所做的努力。最终，我们假设 SPE 的概念基础和临床应用将作为评估 CAR 免疫疗法的重要参数，并显著推进精准癌症免疫疗法。
