Improving Responses to Immunotherapy in Bladder Cancer

Transcript:

Jonathan Rosenberg, MD: At this time, we do routine next-generation sequencing as part of research protocols. I do think it’s reasonable to consider tumor mutation burden when considering other therapies. At the moment, we only have 1 class of treatments. So, what is your alternative? Your alternative would be chemotherapy, which might not work very well, to begin with. And so, I’m not routinely using it as a decision-making tool today.

In several years, I suspect that we’ll probably have composite biomarkers that relate to RNA expression profiles as well as tumor mutation burden and/or somatic DNA damage repair mutations or even germline DNA damage repair mutations—all of which might lead to improved responses. But I worry that if we’re looking at only 1 particular domain, in terms of a biomarker, we’re going to miss a lot of information. We need to show that they’re clinically useful and that they help us make a decision that leads to better patient outcomes. Currently, none of them have truly shown that. We really don’t have an alternative for patients.

There are many reasons why a tumor may not respond to immunotherapy. It may range from the fact that there are not sufficient antigens to the fact that the antigens are not presented or that the immune cells can’t get into the tumor. Or even if they get into the tumor, the immune microenvironment is preventing them from acting. A big step is getting the immune cells into the tumor. There is a group of tumors, that we call immune-excluded tumors, where the immune system can never really get inside the cancer and be in a position to attack. And so, there are a lot of approaches that are trying to push the tumor immune microenvironment to accept the T cells into that environment. Hopefully, this will lead to improved immune responses.

There are also approaches looking at TGF-beta. There are approaches looking at vaccines. There are approaches looking at changing the microenvironment through antiangiogenic agents, which may have modulator effects beyond allowing immune cells in. This may potentially affect the types of immune cells that get into the tumor, reducing T-regulatory T cells and decreasing MDSCs (myeloid-derived suppressor cells), which would suppress and shift an immune response. In addition, things like IDO inhibitors also probably work through changing the tumor immune microenvironment and the activity of different types of T cells that might be within the immune microenvironment.

And so, there are multiple different ways that this is being targeted. You can imagine that in 5 to 10 years down the road we’ll be using combinations of 3, 4, 5 therapies that all do different things. The issue will be tolerability. Can they be combined safely? This has been a concern for certain agents.

Trancript Edited for Clarity