Hi @Zior and everyone. Happy Sunday! I hope y'all are out there...

Hi @Zior and everyone.

Happy Sunday! I hope y'all are out there having fun, and not reading this

.... but here we go.

I think I covered CRS issues pretty well in my 25 Jan post ( https://hotcopper.com.au/threads/why-imu-is-a-multi-multi-bagger.5431324/page-20977?post_id=72072148 ) - along with the advantages of Allogeneic CAR-T. I also mentioned that Graft vs Host did not come up as a side effect for Azer-Cel.

But the additional reference I wanted to find again (not included in my 25 Jan post) was this very useful journal paper from late last year: https://www.sciencedirect.com/science/article/pii/S0753332223016864

It gives a deeply interesting overview of all current approaches to the development of "off the shelf" Allogeneic CAR-T. It's also my source for saying that the ARCUS gene editing tool was the key to their success.

The whole paper is worth a detailed read for anyone who is a science wonk, but of Azer-cel (PBCAR0191) it says:

“Precision BioSciences” has developed its proprietary versatile genome-editing platform named ARCUS to generate genome-edited allogeneic CAR-T cells. ARCUS is based on a naturally occurring meganuclease called “I-Crel”. The ARCUS platform has many distinct advantages: ARCUS is a single protein with two parts for DNA binding and DNA cutting; therefore, there is no need to deliver multiple genes. ARCUS has precise on-target activity, so that it can distinguish only one base pair mismatch. ARCUS is only one-fifth the size of CRISPR/Cas9, which makes it compatible with different delivery methods. ARCUS is capable of introducing multiple edits, including deletion, insertion, or repair[68],[69]. PBCAR0191 (NCT03666000) for Non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL), PBCAR20A (NCT04030195) for NHL andchronic lymphocytic leukemia/small lymphocytic lymphoma, and PBCAR269A (NCT04171843) for MM are three allogeneic CAR-T cell products of this company, which are based on the insertion of CAR into theTRAClocus by means of ARCUS. All these products are under investigation in phase I-II clinical trials. The preliminary results of PBCAR0191 showed that it has a safe profile with no incidence of GvHD[70]

Their source for that final statement is in this paper published by the Precision Bioscience researchers: https://ashpublications.org/blood/article/138/Supplement%201/302/479563/Allogeneic-CAR-T-PBCAR0191-with-Intensified

That paper states:

"Most adverse events were mild. Grade 3 or greater neutropenia occurred in 2 NHL and 2 BALL subjects, and 1 Grade 3 self-limited ICANS with no evidence of Graft versus Host Disease (GvHD). There was 1 non-disease progression, infectious death at day 54 that was deemed possibly related to PBCAR0191 by the investigator.. "

Yes - they do mention:

• Grade 3 neutropenia (low white blood cell count)
• A Grade 3 ICANS (a type of neurotoxicity relatively common with autologous CAR-T's)
• Also someone died of an infection that was not their cancer but the investigator thought it was "possibly" related to their treatment.

However before anyone panics about these, you need to understand that this was in the initial Ph1 trial. In the later and much larger Ph 2a trial Precision modified the formulation of Azer-Cel and the results included wonderful safety:

"No Grade 3 or greater cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infection or graft versus host disease was observed in the most recent cohort." Source: https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-provides-update-allogeneic-car-t-0

And:

"Azer-Cel Safety Profile was Significantly Improved Compared to Prior Cohorts in Patients Dosed Using Optimized Product at Lower Intensity Lymphodepletion; No Grade 3 or Greater Allogeneic CAR T Related Adverse Events Were Observed. " Source:https://investor.precisionbiosciences.com/node/9926/pdf

So as far as I can see - Azer-cel is not only much safer than autologous CAR-T's, it is also extremely safe full stop.

Which is deeply impressive - given the well known - and now increasing - concerns over autologous CAR-T safety.

Cheers

Dave