CAR-based therapies: opportunities for immuno-medicine beyond cancer

Abstract

One of the most exciting new therapies for cancer involves the use of autologous T cells that are engineered to recognize and destroy cancerous cells. Patients with previously untreatable B cell leukaemias and lymphomas have been cured, and efforts are underway to extend this success to other tumours. Here, we discuss recent studies and emerging research aimed to extend this approach beyond oncology in areas such as cardiometabolic disorders, autoimmunity, fibrosis and senescence. We also summarize new technologies that may help to reduce the cost and increase access to related forms of immunotherapy.

Figure 1 –. Chimeric antigen receptor (CAR) and chimeric autoantigen receptor (CAAR) T cell therapies to treat diseases beyond cancer.

Second generation CARs consist of a single-chain variable fragment (scFv) fused to a costimulatory domain (CS, e.g. CD28 or 4-1BB) and a CD3ζ signaling domain, while CAARs substitute a recombinant autoantigen in place of the scFv. Pictured are examples of therapy for fibrotic diseases (anti-fibroblast activation protein – FAP – CAR), autoimmune diseases (anti-CD19 CAR and autoantigen CAAR), and diseases arising from cell senescence (anti-uPAR CAR). TM – transmembrane.

Figure 2 –. Preclinical strategies using CAR T cells for the treatment of diabetes.

(a) CAR T cells can be used to ablate insulin autoantigen presenting cells (APCs) by targeting the insulin peptide:MHC class II complex, and pathogenic CD4⁺ T cells responsible for beta cell destruction by using a biomimetic five-module chimeric antigen receptor (^5MCAR). (b) CAR Tregs can be targeted to the pancreas to locally suppress the immune system and prevent type 1 diabetes. (c) Anti-beta cell CAR T cells can potentially be used to deplete insulin producing cells in congenital hyperinsulinemism.

Figure 3. Tarteted lipid nanoparticle (tLNP) reprogramming of T cells in vivo.

tLNPs loaded with modified mRNAs encoding a CAR are decorated with antibodies targeted to T cells and when bound will be endocytosed and release their cargo. mRNA is subsequently directly translated in the cytoplasm and CAR proteins are localized to the cell membrane, thus producing a CAR T cell in the body.