Strategy escalation: an emerging paradigm for safe clinical development of T cell gene therapies

Abstract

Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs) for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications.

Figure 1

Safe pathways for Strategy Escalation. Note that all escalations are permissible except 0 → 4. Dotted paths are proposed as plausibly safe but not advised. See text.

Figure 2

Optimal pathways for Strategy Escalation. All paths to 2^nd generation engrafted ("4") pass through a full prior test of 2^nd generation infused ("3"). See text.