CAR T therapy beyond cancer: the evolution of a living drug

Abstract

Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.

Fig. 1 |. CAR T cells are poised to target a wide variety of diseases and pathological substrates.

CAR T cells may find widespread use in a multiplicity of contexts beyond cancer.

Fig. 2 |. CAR T cells are engineered to be precise and powerful killers.

The components of a CAR, including the variable light (V_L) and variable heavy (V_H) chains that comprise the single-chain variable fragment (scFv), which is fused to a co-stimulatory domain and CD3ζ. This synthetic receptor confers antigen-specific cytotoxicity.

Fig. 3 |. Advantages of CAR T therapy in other diseases in comparison to cancer.

a, Cancer presents several substantial barriers to CAR T cell efficacy including a large target burden, nearly total clearance of malignant cells, a high mutational load and a hostile TME. b, By contrast, other diseases generally have a much smaller target burden, partial clearance of diseased cells can be therapeutic, a lower mutational load, and are generally not localized in such an inhospitable environment.

Fig. 4 |. A comparison of ex vivo and in vivo platforms being explored for CAR T therapy.

a, At present, autologous CAR T cell manufacturing requires extensive infrastructure, time and lymphodepletion of the patient. Allogeneic CAR T cell manufacturing can potentially reduce the associated costs and time required, but still requires lymphodepletion of the patient. b, In vivo platforms, such as targeted viral delivery and tLNP delivery, are much less mature, but have tremendous potential to disrupt this industry by potentially obviating the need for manufacturing facilities and lymphodepletion. tLNP delivery has the additional feature of only transiently expressing the CAR.