Media Thread, page-13881

I agree, Harry; there is A LOT to like about OnCARlytics...and also Azer-Cel.

As Leslie mentions in the recent newsletter, it is a "one-two punch" with multiple distinct but powerful anti-tumour mechanisms: immune activation/tagging, oncolysis and then CAR-T. So, in effect, it is more like a jab, straight right followed by a lead hook.

1. Synergistic Effects Enhanced Tumor Visibility: By converting solid tumours to express CD19, CF33 essentially "tags" these normally resistant tumour cells for destruction by Azer-cel, making the tumour more visible and vulnerable to the immune system.

2. Modification of Tumor Microenvironment: Oncolytic viruses can alter the tumour microenvironment, reducing its immunosuppressive characteristics and making it more permissive for immune cell infiltration and activity, turning 'cold' tumours 'hot'. This alteration can potentially enhance the efficacy of Azer-cel within the tumour site.

3. Broadened Immune Response: The combination of direct lysis by CF33 and the targeted attack by Azer-cel may lead to a broader immune response, with the initial viral attack stirring up the immune system and the CAR-T cells providing a second, highly targeted wave of anti-tumour activity.

One thing that is also of note and likely a key reason why Saul Priceman et al. combined CF33 with CD19 of all the possible (BCMA, CD22 of note) targets, is that cancer is extremely tricky, and tumours often develop resistance to therapies through various mechanisms, including loss of target antigens. Targeting CD19 might overcome some traditional resistance mechanisms by 'artificially' inducing antigen expression (CD19 via CF33) and then targeting it (Azer-cel, Blincyto, etc.).

Also, growing evidence shows that even if resistance to CD19-targeted therapies and CD19 negative relapses occur, CD19 remains a viable target. In infrequent cases where CD19 antigen loss happens, it typically involves alternative splicing of the CD19 gene or mutations in the CD19 isoform (different structure) rather than complete antigen loss. Meaning a different type of resistance mechanism that may still leave room for therapeutic intervention. I don't know enough about how CD19 is expressed and whether CD19 mutations can even occur, considering OnCARlytics artificially adds CD19 to the tumours. It will likely come out much later (if at all) in the OASIS trial. By all means if anyone knows, please fill us in.

One thing is also likely to occur with the OnCARlytics trial that IMU is not as used to, that is much more significant and more serious side effects. Namely t-Cell exhaustion, cytokine release syndrome and neurotoxicity, being the main ones (but there are others). It will be interesting to see which of these and possibly others become apparent in the OASIS trial. Also, keep in mind even with Blincyto's sides, it's still considered a 'wonder drug' in certain indications.

But, as far as CAR-Ts go, I believe IMU has done exceptionally well in acquiring Azel-Cel...

Firstly, by using healthy doner T-Cells, the strength and durability of response has the potential to be even better than already stellar auto CAR-T. The genius of Azer-Cel and what allows it to be 'off the shelf' though is the ARCUS platform, which knocked out the T-cell receptor (TCR) gene, which reduces the risk of graft-versus-host disease (GVHD), allowing the modified T cells to be used across different patients. Now, coupled with the Beta2 microglobulin gene being knocked out to prevent immune rejection by the patient's body and to improve the persistence of the CAR-T cells, it has the potential to be a perfect match for OnCARlytics. The possibility of being a completely off-the-shelf, low friction, relatively low-cost therapy for treating many (potentially) solid tumours (even cold ones!).

As far as I'm aware, combo patients haven't been dosed yet, so it's still a few months until we have data on them. What I'll be keeping an eye out for, though, is data on CF33 causing CD19 expression on tumours through both IT and IV; once that is confirmed, it's 'game on'.

Cheers.