New Targets Explored to Boost Immunotherapy in Melanoma

Michael A. Postow, MD

While PD-1, PD-L1, and CTLA-4 checkpoint inhibitors have proven to be effective in treating patients with melanoma, not all patients respond to immunotherapy. To help nonresponders, additional targets and immunotherapy strategies are being investigated in clinical trials to boost the immune system’s response, according to Michael A. Postow, MD. These agents are being incorporated into experimental regimens that improve the efficacy of the immunotherapy agents they are combined with, such as the existing checkpoint inhibitors.

Postow, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, highlighted a number of promising approaches in development in a presentation during the 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® hosted by Physicians' Education Resource. Specifically, Postow addressed targeting the activating receptors OX40, GITR, and CD137 to further stimulate the T cells to fight the tumor cells.

In an interview withTargeted Therapies in Oncology^TM(TTO) following his presentation, Postow discussed the mechanism of action of these 3 targets that make them promising approaches in combination immunotherapy regimens.

TTO:Could you please provide an overview of your presentation?

Postow: Immunotherapy is a big treatment for metastatic melanoma as we know from our prior studies of CTLA-4 blockade. But really this is just the tip of the iceberg. There are a number of additional targets out there that are being tested in clinical trials, either alone or in combination with different strategies, to use the immune system in new ways beyond PD-1/PD-L1, beyond CTLA-4, to see if that can help patients with cancer as well.

My talk focused on 2 main strategies: other costimulatory molecules that you can enhance the T-cell activity with, and ways of reducing immunosuppression within the tumor microenvironment. It’s not just about boosting the T cells, it might be also about reducing negative immunosuppressive cells in the tumor microenvironment. There are a lot of different strategies to block inhibitory cells or inhibitory molecules in tumors to try to help the T cells ght the tumor cells more strongly.

TTO:What other costimulatory molecules are being investigated currently?

My talk focused on 3 types of costimulatory molecules: OX40, CD137, and GITR. Some data have been presented on these 3 targets already, not only for patient outcomes but on the immunologic effects of some of these treatments.

OX40, for example, there’s published data of a mouse antibody that has been given to patients in early-phase clinical studies. For CD137 there’s also published data of antibodies that agonize T cells through CD137, and there are a number of combination studies going on with that area. Then for GITR, there have been presented data and some preliminary data that suggest that there are some immunologic changes that happen with pretty much all of these types of costimulatory molecules.

I think that even if we don’t see a lot of activity as single agents with these drugs, it’s important to really study them thoroughly so that we can be certain if they could have a role in combination settings. I think all of us believe that the role for these agents will mostly be in combination settings, so we don’t have to worry that there might not be huge responses to the single agent. Maybe it’s just going to enhance other immune therapies’ efficacies.

TTO:Have any of these agents shown promising data that suggest they would do well in a combination treatment?

Among all the combinations out there already, I think the one that’s furthest along is an IDO inhibitor called epacadostat in combination with a PD-1 drug pembrolizumab (Keytruda), which is now in a phase III clinical study in a randomized setting (NCT02752074). This IDO inhibitor has the mechanism of action of eliminating immunosuppression within the tumor microenvironment. I think that is a very promising combination approach right now and I think it’s a real testament to a drug where we didn’t see a lot of activity as a single agent, yet in combination with PD-1, although preliminary, we see impressive early efficacy.

That’s 1 example but there are a number of other strategies that are being employed, including a lot of strategies we’re excited about that inhibit myeloid-derived suppressor cells—these are immunosuppressive myeloid cells that are in tumors, and in blood—and blocking them through different mechanisms are also interesting ways of testing whether we can enhance T cells’ ability to kill tumors.