Ann: AGM Presentation, page-150

Well I would think [the FDA] would like to see a treatment that is safer, possibly more effective and certainly one that operates in a precise manner. We all know that 'random' doesn't always sit well in a science that requires precision @Outlander2

The announcement by the FDA of an investigation into the serious risk of T-cell malignancy following autologous CAR-T immunotherapies, appeared to come out of the blue whereas in fact, its probably been years in the making. I've previously used the term insertional mutagenesis but its of more interest that I borrowed the term from the paper by MacLeod et. al and their seminal paper previously linked in Post #: 71208773. Lets dig a little deeper and try to understand how the FDA case may have been building in the background.

According to the article Cancer gene discovery: exploiting insertional mutagenesis by Ranzani et. al. published in October 2013, insertional mutagenesis occurs when an exogenous DNA sequence integrates within the genome of a host organism. It appears that the insertion of a CAR into the T cell genome fits the bill. So what could possibly go wrong!

According to the authors, this exogenous event can result in a deregulation of genes in the neighbourhood of the insertion site and potentially cause a perturbation of cellular phenotype. Remember in the case of autologous CAR-T immunotherapies, the use of lentiviral or retroviral vectors - the exogenous event - results in random insertions that may occur multiple times. The perturbation of cellular phenotype could manifest for instance, in the case of autologous CAR-T immunotherapies, as T-cell malignancy.

So, the investigation, in all likelihood, has not occurred out of the blue. Neither has the development of azer-cel. As you say, "Enter Precision and their amazing ARCUS system, which was used to create Azercabtagene zapreleucel (azer-cel), an anti-CD19 allogeneic CAR T candidate, now owned by IMU."

So, why is the FDA only now investigating the serious risk of T-cell malignancy when the mechanism of action has most likely been understood for a decade? I think the answer is tied up in the fact that CAR-T has promised and delivered enormous benefits and in the absence of alternative approaches why scare the horses. Maybe, just maybe, your explanation of the hope for a safer, more effective and precise CAR-T is the best answer.