From CARs to TRUCKs and Beyond: Safely en Route to Adoptive T-cell Therapy for Cancer

This year’s American Society of Hematology (ASH) Annual Meeting (December 2016, San Diego, USA) had an emphasis on leukemia and adoptive therapy, as did previous ASH meetings. But this year, ASH also had a dedicated session on “Adoptive Immunotherapy: CAR-T Toxicity and Clinical Trials”, and experience with chimeric antigen receptor (CAR) T-cell therapy in various clinical trials to date was presented in hundreds of talks and posters throughout the conference. There are numerous exciting developments in this relatively young field of cancer immunotherapy. Following the success of immune checkpoint inhibitors–a topic touched upon in the November 2016 EBioMedicine editorial–all eyes are now on CAR T cells, which are being tested in more than 100 ongoing clinical trials in various cancers. CAR T cells are genetically engineered in vitro so that their chimeric receptors contain an extracellular antigen-recognition domain of amonoclonal antibody and an intracellular T-cell activation domain (such as CD3ζ or FcRγ). Newer-generation CAR T cells also incorporate intracellular costimulatory domains (such as CD28, ICOS, OX-40 and 4-1BB). As such, CAR T cells can recognize antigens and become activated independently of MHC-I restriction, thus bypassing two principal mechanisms that tumors use to evade the immune system (MHC-I downregulation and proteasomal antigen processing). Among several antigen candidates, CD19 is arguably an ideal model antigen to demonstrate the efficacy of CAR T-cell therapy in hematological malignancies. CD19 is expressed exclusively on B lymphocytes and their progenitors, and anti-CD19 CAR T cells have been tested in various clinical trials in acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, multiple myeloma and lymphoma–in fact nearly half of all clinical trials using CAR T cells involve CD19 as a target. Given that these patients had advanced stage, lethal diseases that were refractory to standard treatments at trial enrollment, it is impressive that CAR T-cell infusion can induce remission in many patients, some of whom have not had disease recurrence since the therapy. Because CD19 is also expressed on healthy B cells, there is a potential risk of B-cell aplasia following the therapy, but this can be mitigated by IgG replacement therapy. In practice, most of these patients already had chemoradiotherapy-induced lymphocytopenia so the on-target/off-tumor effect of CAR T cells on healthy B cells is virtually absent. A serious safety concern with CAR T-cell therapy is cytokine release syndrome (CRS), whereby activation of CAR T cells can lead to production of several proinflammatory cytokines such as IL-6, TNFα and IFNγ, which canmanifest as high fever, hypotension, tissue edema, hypoxia and organ failure. Studies have shown that CRS can be controlled using cytokine-blocking agents such as tocilizumab or corticosteroids. Neurotoxicity has also been reported in a few cases following CAR T-