Chimeric antigen receptor therapy for cancer

Abstract

Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor-based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer.

Figure 1

Antibodies can bind to surface antigens expressed on tumor cells. Chimeric antigen receptors (CARs) have a single-chain antibody fragment (scFv), expressed in tandem with signaling elements derived from the T cell receptor (TCR) and costimulatory domains such as 4-1BB and CD28.

Figure 2

Chimeric antigen receptor (CAR) therapy is similar to an autologous bone marrow transplantation procedure. T cells are collected from the patient by apheresis, and the T cells are expanded and genetically modified using several approaches before they are returned to the patient. Abbreviation: APCs, antigen-presenting cells.