Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies

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

Technical note: The calculated real world BNT162b2 vaccine efficacy was 88% when accounting for asymptomatic cases

COVID-19 trials have relied on symptomatic subjects for judging the effectiveness of vaccine candidates, whereas asy–mptomatic subjects have been suspected as the main driver of the pandemic. An assumption of the same impact on symptomatic and asymptomatic breakthrough infections is shown to be flawed, resulting in an overestimate of the vaccines’ true effectiveness. Recent available data provide the first large-scale unbiased data on asymptomatic versus symptomatic infections postvaccination, providing a unique opportunity to reassess the true infection rates after vaccination. By this, the breakthrough of the BNT162b2 vaccine is seen to be 12% rather than 5% for a corrected overall efficiency (symptomatic + asymptomatic) of 88% with the original virus strain in a real-world setting