Chimeric Antigen Receptor-T (CAR-T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective

Figure 1

Key features of T-cells. The T-cell populations can be divided into two broad effector classes with their differing immune and metabolic profiles. T cells are naïve until primed with two signals: (i) antigen presentation and (ii) costimulation. Once primed, the T cells are activated and become effector T cells and express CD40L on their surface. (a) CD4⁺ T-cells are helper T cells which have a variety of functions such as recognition of antigen peptides on dendritic cells via MHC class II and secrete cytokines dependent on the subtype of CD4⁺ T cell, for instance, Th1, Th2, Th7, and T_reg release different cytokines which bring about various responses. (b) CD8⁺ T cells are cytotoxic cells which bind via MHC class I. (c) T cells secrete cytokines in response to activation via their cognate antigen/MHC and coligation with various cell surface molecules, such as CD40/CD40L. (d) CD8⁺ T cells bring about cancer cell death through the secretion of perforin (PFN) and granzyme B (GzmB) and cytokines such as IFN-γ and TNF-α. T cell metabolism differs greatly between the different subtypes; (e) naïve T cells, memory T cells, and stem cell memory T cells depend on (f) oxidative phosphorylation and mitochondrial biogenesis to satiate their energetic demands and effector T cells, whereas effector memory T cells depend on (g) glycolysis and amino acid metabolism for sustenance. These metabolic profiles explain why effector CD8⁺ T cells exhaust and differentiate into terminally differentiated effector phenotypes and experience cell death. Key: MHC = major histocompatibility complex, IL-10 = interleukin 10, TGF-β = transforming growth factor beta, IL-4 = interleukin 4, IL-15 = interleukin 15, IL-9 = interleukin 9, IL-13 = interleukin 13, IL-17 = interleukin 17, IL-22 = interleukin 22, IFNy = interferon Γ, TNF-α = tumour necrosis factor alpha, TCR = T-cell receptor, Th2 = T helper cell 2, Th17 = T helper cell 17, Th1 = T helper cell 1, T_reg = regulatory T cells, PFN = perforin, GzmB = granzyme B,  = naïve T cells, T_scm = stem cell memory T cell, and T_cm = central memory T cell.