CAR T-cell structure
CARs are typically composed of four regions: (1) an extracellular antigen-binding domain; (2) a hinge or spacer peptide; (3) a transmembrane domain that anchors the CAR to the cell membrane; and (4) one or more intracellular signalling domains that leads to T-cell activation.5-7The extracellular antigen-binding domain is derived from a single-chain variable fragment (scFv) constructed through fusion of the antigen-binding regions of both heavy (VH) and light (VL) chains of a monoclonal antibody.6,8The intracellular signalling domain is most commonly derived from lymphocyte signal-initiating molecules including the CD3 zeta-chain (CD3z) of the T-cell receptor (TCR)/CD3 complex.9Incorporation of additional co-stimulatory signalling proteins, such as the CD28 family or the tumour necrosis factor receptor (TNFR) family of genes, can augment the ability of CARs to stimulate cytokine secretion, potentiate T-cell persistence and enhance anti-tumour efficacy.7,10
In chimeric antigen receptor (CAR) T-cell immunotherapy, autologous effector T-cells are harvested from the peripheral blood of patients with cancer through leukapheresis and genetically engineered ex vivousing a lentiviral or gammaretroviral vector to express synthetic proteins known as CAR receptors.1-4These receptors are directed against pre-determined cell-surface antigens expressed on tumor cells.1-4Lymphodepleting chemotherapy is given to the patient and then the re-programmed CAR T-cells are infused back into the patient, where they induce a selective immune response against tumor cells expressing the corresponding antigen.3,4
Approved CAR T-cell therapies
CAR T-cell immunotherapy has shown promising results in clinical trials with high rates of durable responses achieved in patients with pre-treated and chemotherapy-resistant chronic and acute B-cell precursor lymphoblastic leukaemia (B-ALL) and B-cell lymphoma.11-15Consequently, in August 2017, the FDA approved tisagenlecleucel, a CD19-directed CAR T-cell therapy for the treatment of relapsed or refractory B-cell ALL in patients under 25 years old.16Shortly thereafter, in October 2017, axicabtagene ciloleucel, another CD-19-directed T-cell therapy was approved for use in adult patients with relapsed or refractory large B-cell lymphoma.17More recently, in May 2018, tisagenlecleucel gained additional approval for the treatment of relapsed or refractory large B-cell lymphoma in adults.18
Key target of CAR T-cell therapy in multiple myeloma
Currently, CAR T-cell therapy is being investigated for the treatment of relapsed or refractory multiple myeloma (MM).14,19-22The principal target of CAR T-cell therapies for multiple myeloma is the B-cell maturation antigen (BCMA).22-24This is a transmembrane glycoprotein expressed exclusively by B-lineage-derived cells, particularly in the interfollicular region of the germinal centers, and on plasmablasts and differentiated plasma cells (PCs).24-27BCMA is selectively induced during PC differentiation, supporting humoral immunity by mediating survival of normal bone marrow PCs and plasmoblasts.23-25,28As BCMA expression is virtually absent on naïve and most memory B-cells, it is not critical for overall B-cell homeostasis but is required for optimal survival of long-lived PCs.26-30In patients with MM, BCMA is widely expressed on malignant PCs at significantly higher levels.22-24Indeed, BCMA expression increases as MM progresses, from normal to monoclonal gammopathy of undetermined significance to smouldering to active MM.22Due to the lineage-restricted expression profile of BCMA and its survival function in plasma cells, it is a potentially viable target for CAR T-cell therapy in patients with MM.22-25Given the poor outcome of patients with relapsed or refractory multiple myeloma, there is a high unmet need for effective treatments. It is hoped that novel treatment options such as CAR T-cell immunotherapy may offer hope for heavily pre-treated patients.
References
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