OncoSec Medical Inc (ONCSQ)

[hschlauch]

The FIRST multigene construct data not only show successful expression of multiple encoded genes in a single product, but the selected genes highlight a rational approach to increasing intratumoral CTLs. The flt3l-encoded gene fused with an antigen is going to accomplish more than just drive a single tumor antigen-specific immune response.

Flt3l fused with an antigen will lead to endogenous expansion of dendritic cells and maturation of those cells (through activation with the fused antigen). The maturation of dendritic cells through activation with an antigen increases the costimulatory molecules CD80 and CD86. So, not only does the fusion of Flt3l and an antigen lead to dendritic cell expansion and activation, but it vastly increases CD80 and CD86 intratumorally.

And what do we know about CTLA-4 on T regs? They outcompete CD28 binding on T cells for CD80 and CD86 on mature dendritic cells. By significantly increasing the number of CD80 and CD86 costimulatory molecules on dendritic cells, you're shifting the balance of power in favor of T cell activation. You end up with more mature dendritic cells per T reg, thus altering ratios that would otherwise suppress T cell activation and proliferation.

Bottom line: the combination will lead to more intratumoral CTLs. It will accomplish this by improving neoantigen presentation, increasing mature antigen presenting cells intratumorally, and mitigating the overall effect T regs have on immune suppression.