Hot Topics: Harnessing Dendritic Cell Recruitment and the Organization of GBM

So the trial combines two complementary strategies, HSVTK-mediated tumor cell killing and FLT3 ligand-mediated immune activation.

Can you explain why both components are necessary and what this combination is designed to accomplish that previous gene therapy approaches could not?

The reasoning behind our strategy was that there's a paucity of dendritic cells in the human brain tumors, in the human gliomas.

Yeah.

So we wanted to attract dendritic cells, which are the cells that kickstart the immune response, to the brain tumors.

And then we had to tell the dendritic cells which antigens they should react to.

But as opposed to other strategies that directly tell the dendritic cells what antigens to react to, in our strategy, the availability of antigens given by the killing of the tumor cells anatomically close to where the dendritic cells are allows the dendritic cells to sample the antigens and the dendritic cells decide which are the best antigens to react to.

So the dendritic cells come into the brain.

They get recruited and differentiated by the FLT3 ligand.

Right.

And they get exposed to antigens released from the dying cells from the HSV1 decay plus valacyclovir.

In the natural environment of the tumor as well.

In the

natural environment.

And in addition to that, we discovered that the HSV1 One decay plus phallocyclovir-induced tumor cell killing also induces TLR2 agonists, which stimulate the dendritic cells, make them mature, and go and migrate to the lymph nodes.

That's great.

Real one-two punch.

I mean, you had seen, I assume, gene therapies targeting the tumors themselves before and vaccination efforts targeting the immune system independently.

But was there some moment where you realized putting the two of them together would be very synergistic?

That's what we postulated.

That's what we hypothesized.

And the hypothesis was based on the fact that As I said before, there are very few dendritic cells in the tumors.

Right.

So we wanted to increase that, but we wanted to expose them to tumor antigens that may be relevant, and we wanted the dendritic cells to choose those antigens.

Sure.