Chimeric Antigen Receptor Immunotherapy for Solid Tumors: Choosing the Right Ingredients for the Perfect Recipe

Simple Summary Despite the success in hematology, chimeric antigen receptor T cell therapies have shown, to date, unsatisfactory results in other clinical settings. A remarkable number of different CAR-based approaches have been developed, varying not only the specific antigen to be targeted, but also the type of cell to be modified, the costimulatory domain, and the additional signals incorporated to overcome solid-tumor-specific challenges. This variety of options has created a broad diversification of CAR approaches that, on one hand, may accelerate the identification of successful strategies, but on the other hand, may hamper the interpretation of clinical results and the overall advancement of the field. In this review, we present the most promising approaches under development and discuss their specific advantages and challenges to facilitate the identification of winning strategies. Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development.