Tumors deploy multiple parallel mechanisms that synergize – meaning that they work together to get more bang for their buck. In this way, tumors are able to subvert the immune response and protect themselves from being eradicated by the immune system. Thus, we need to similarly deploy multiple parallel synergistic mechanisms to re-program the immune response – to re-hijack it from tumors.
It is very rare that you find a patient with a tumor that has a dominant immune checkpoint – where you can simply reverse that one mechanism and see an effect. To put it frankly, we need to move towards combination approaches in immunotherapy.
In the past, if a drug didn’t have a measurable effect as a monotherapy it would often be dead in the water. I call this ‘monotherapistic fetishism’. We need to put this in the past.
With our ImmunoPulse gene-electro therapy (GET) using IL-12 in melanoma patients, luckily, we have seen an effect. Frankly, we are surprised by how much of a monotherapy effect we are seeing from electroporation of IL-12 in our melanoma patients – but that is a great problem to have.
We are working on trying to understand why it is that IL-12 is driving the immune response strongly enough to push through the PD-1 checkpoint. By that, I mean – you would expect that if IL-12 is driving the generation of tumor-infiltrating lymphocytes (TIL’s), and the TIL’s come into the tumor, you should see an up-regulation of PD-L1. This would then turn off the PD-1 checkpoint on the T-cells and turn off the immune response. In a significant number of patients, we are blowing right through the PD-1 checkpoint and we don’t quite understand how that is happening with IL-12.
But like I said, that is a great problem to have.