Regulating innovation in the early development of cell therapies

Abstract

Clinical need for paradigm shifts in efficacy and safety is driving the rapid and wide-ranging innovation in cell therapies for cancer beyond existing regulatory frameworks. Critical issues emerging during clinical trials frequently reflect unresolved elements of the regulation of innovation conundrum from earlier stages of development. We address this challenge using a global regulators’ perspective on the preclinical development of cell therapies, as a navigational aid to intended commercial use which maximises the clinical relevance of developmental data. We examine the implications of tumour targeting based on B cell, natural killer cell, conventional and unconventional T cell receptor domains; multiplex approaches; genetic manipulation strategies; and autologous versus allogeneic cell sources. We propose that detailed characterisation of both the cell source and final product is critical to optimising manufacture of individualised autologous or off the shelf allogeneic cell therapies, enabling product consistency to underpin extrapolation of clinical trial data to the expected commercial use. We highlight preclinical approaches to characterising target antigens including the Human Cell Atlas initiative, multi-dimensional cell culture, and safety testing against activated, proliferating or stressed control cells. Practical solutions are provided for preclinical toxicity studies when cell therapies target uniquely human tumour antigens, including illustrative mitigation measures for potential toxicity likely to support timely approval of first-in-human clinical trials. We recommend addressing the regulation of innovation conundrum through serial engagement between innovators and regulators early in the development of cell therapies for cancer, accelerating patient access while safeguarding against unacceptable toxicities.