Chimeric antigen receptor (CAR) T cells have hit prime time, with the 2 recent FDA approvals for this class of cell-based therapy. Undoubtedly this option will be a game changer for patients with B-cell malignancies who have only a small number of available treatment options; however, questions regarding the real-world utility of CAR T-cell therapies remain. Several challenges may affect the adoption of CAR T-cell therapy, which range from logistical complexities of therapeutic development to the potentially fatal toxicities of treatment.
It will be several years before the true impact of CAR T cells becomes apparent, but it is increasingly evident that long-term clinical success requires unlocking the potential of CAR T-cell therapy beyond B-cell malignancies, particularly in solid tumors, which account for the vast majority of cancer deaths.
A number of innovations are already entering the scene, including next-generation “armored” CARs and the application of state-of-the-art genome-editing technologies.
Harnessing Antitumor Immune Cells
CAR T-cell therapy falls under the banner of adoptive cellular therapy (ACT), in which the effector cells of the immune system, predominantly the T cells, are transplanted into a patient. The graft-versus-tumor effect observed in patients undergoing allogeneic hematopoietic stem cell transplantation served as the stimulus for pursuing ACT. T cells present in the transplanted material were seemingly capable of mounting an effective antitumor immune response, but this was limited by the development of graft-versus-host disease (GVHD), wherein the transplanted T cells also attacked healthy tissue, causing severe toxicity.
Genetically modifying host T cells to endow them with tumor-killing specificity originated in the 1980s. Seminal studies demonstrated that replacing the region of the T-cell receptor (TCR) responsible for antigen recognition with the singlechain variable fragment (scFv) of an antibody could couple antibody specificity for a tumor-associated antigen (TAA) with the T-cell activating machinery of the TCR.1
This permitted direct activation of T cells by tumor cells that express the target antigen, in a manner that bypasses the need for antigen presentation by the major histocompatibility complex.2
The prototypical CAR was composed of an extracellular portion, consisting of the antibody scFv, joined to a hinge or spacer and then a transmembrane domain that spans into the cell and links to an intracellular signaling region.3
The latter mediates T-cell activation and was most often derived from the CD3ζ chain of the TCR, which harbors 3 immunoreceptor tyrosine-based activation motifs (ITAMs). When the CAR engages its target antigen, the ITAMs become phosphorylated and serve as adaptors for a panel of signaling proteins that coordinate T-cell activation and proliferation.
CAR T cells are generated by collecting host T cells through leukapheresis, where the CAR is introduced to the T cells through a viral vector. Clinical trials of the resulting CAR T cells, which can then be infused back into the patient, were pioneered by investigators at Memorial Sloan Kettering Cancer Center and the University of Pennsylvania.
Several subsequent generations of CARs have been developed to improve on the efficacy of the first generation. The realization that full activation of T cells required 2 signals led to the incorporation of costimulatory domains in secondand third-generation CARs, with enhanced T-cell activity and persistence and greater antitumor efficacy.3-5
Figure. Mechanism of Action of CAR Therapies
The CAR T-Cell Race to the Market
In this rapidly evolving field of immuno-oncolytic therapeutic development, the most clinically advanced CAR T cells are currently those engineered against CD19, a cell surface receptor constitutively expressed on tumors in hematologic malignancies. Several pharmaceutical companies raced to be the first to secure regulatory approval, but ultimately the first-to-market advantage went to Novartis’ tisagenlecleucel (Kymriah).