Dude, where's my CAR construct?

Over the past episodes of Reprogrammed, we’ve followed the rapid evolution of CAR T cell therapy—from early experiments demonstrating that antibody-based chimeric receptors could trigger T cell activation and IL-2 production, to the incorporation of co-stimulatory domains like CD28 and 4-1BB that dramatically improved T cell survival and cytotoxic efficacy.In episode 5, we saw how CD28 co-stimulation, when engineered into CARs, could prevent Activation-Induced Cell Death (AICD) and promote proliferation. Then, in episode 6, we contrasted this with 4-1BB-based signaling, which provided a more durable survival signal and fostered memory-like cell states. Most recently, we saw how cytokines like IL-15 could be used to extend the persistence and antitumor activity of engineered T cells in vivo.What all these strategies shared was a focus on enhancing T cell function and persistence by manipulating the CAR’s intracellular signaling domains or the cell’s surrounding environment.But Eyquem et al. (2017) raised a new question entirely, i.e., does transfecting these T Cells pose an unaccounted for risk of causing unwanted effects as a result of where in the T Cell genome the CAR construct was integrated?