OncoSec Medical Inc (ONCSQ)

[hschlauch]

So why would someone want to electroporate DNA-encoded checkpoint inhibitors intratumorally?

1. Safety - systemic applications of combined CTLA-4, PD-1/PD-L1 and any other checkpoint inhibitor combinations thereof leads to high toxicities, i.e. grade 3/4 in the majority of treated patients. Combinations lead to greater efficacies versus any checkpoint inhibitor used alone; however these combinations lead to very high toxicities.

2. Efficacy - the checkpoints that you really want to eliminate are found in tumor microenvironments (TME), NOT THROUGHOUT THE BODY! Once intratumoral EP DNA-encoded IL-12 or any other cytokine ramps up the interferon gamma in the TME, you get up-regulation of antibodies, especially PD-1/PD-L1, CTLA-4 and TIM3, on tumor cells and immune cells specifically in the TME. That is, when you elevate the TME interferon gamma signature, you see more tumor infiltrating lymphocytes and tumor cells with up-regulated antibodies. This not only increases the total number of tumor fighting immune cells (antigen-specific TIL), but it also increases the number of checkpoints, SPECIFICALLY IN THE TME. Electroporating DNA-encoded checkpoint inhibitors intratumorally allows local tumor cells to express the checkpoint inhibitors (e.g., anti-PD-1/PD-L1, anti-CTLA-4, etc.) right where they are needed most - in the TME. Moreover, these checkpoint inhibitors would be expressed over an extended period of time in the TME. Durable expression should also lead to quicker response times and quicker release of tumor-specific antigens, thus speeding up immune activation and improving abscopal effects.

3. Efficiency - DNA-encoded checkpoint inhibitor plasmids delivered intratumorally is a far more efficient means of delivery than a systemic approach. DNA-encoded plasmids allow cells to do the work that would be accomplished ex-vivo, in labs.