Treating Solid Organ Diseases with Innovative Chimeric-Antigen Receptor T-cells: Current indications, progress, limitations and potential strategies

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About this Research Topic

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Background

The success of chimeric antigen receptor (CAR)-T cell therapy for select B cell leukemias or lymphomas is clear and remarkable. In contrast, a demonstration of similar levels of efficacy for CAR-T treatment of diseases of solid organs, including cancer and autoimmunity (using chimeric autoantigen receptor T cells [CAAR-T]) has been lacking. Indeed, a paucity of active clinical trials testing CART therapy in solid organs is found in clinicaltrials.gov. Multiple, significant differences exist between solid organ and "liquid" indications (i.e. leukemias) that may limit effective CAR-T cell therapy, including a failure to gain entry into solid organs, poor CAR-T retention and/or survival within the tumor microenvironment, serious toxicities and lack of specificity of the target antigen selected.



The challenges that CAR-T/CAAR-T therapy for solid organ disease faces can be categorized into four major groups: unique toxicities; target cell recognition; trafficking; and persistence. Although the development of CAAR-T therapy for autoimmune diseases is quite new in its development, compared to oncology indications, many of the challenges for a CAAR-T are similar to those identified for CAR-T therapies directed against solid organ tumors. One primary difference, however, lies in target antigen heterogeneity, in that there are only a few autoimmune diseases where a predominant single autoantigen is driving disease. The goal of this research topic is to provide a state-of-the-art overview of the field's understanding of these four challenges, for malignancies and autoimmune disorders, and of advances made in potential strategies to overcome them, for both CAR-T and CAAR-T constructs.

The scope of the Research Topic is to provide a significantly-detailed review of each of the 4 challenges outlined above, with articles focused on individual challenges. Background information, pre-clinical model translatability, clinical trial data, and strategies for improvement should be discussed for the specific challenge in each article. For example, a review on CAR-T trafficking challenges would provide: 1) background information on the adhesion-related repertoires that control the entry of healthy T cell phenotypes into solid organs under constitutive and inflamed conditions; 2) the pre-infusion adhesion repertoire found on solid organ-directed CAR-Ts; 3) pre-clinical data (and clinical data, if available) on CAR-T numbers, localization and persistence, post-infusion, in the target organ and peripheral circulation; and 4) strategies to enhance trafficking into the target solid organ of choice. A single review article discussing CAAR-Ts may be sufficient to cover all four challenges and advances, given the limited knowledge of CAAR-Ts to date.

Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.

Keywords: CAR-T, CAAR-T, solid organ malignancies, anti-tumor activity, persistence, therapeutic efficacy, adhesion, tumor infiltration, autoimmune

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