Challenges With Immunotherapy in Glioblastoma

Transcript:

Andrew S. Chi, MD: There’s a relatively long history of immunotherapy in glioblastoma. There are people who have been developing tumor vaccines for glioblastoma. There also have been people doing oncolytic virus therapy for glioblastoma for decades. So, there is a history of immunotherapy development for glioblastoma. It’s just changed, more recently, given the explosion of new information that has been derived from mechanisms to newer therapies for immunotherapy in oncology, in general.

Currently, immunotherapy in glioblastoma remains incredibly promising. There are many things that we are starting to understand about the tumor microenvironment, in how the glioblastoma tumors interact with the immune system. However, in regard to the current iteration of the immunotherapies that are available in oncology with those immunotherapy agents, there hasn’t been much success in glioblastoma currently. The immune checkpoint inhibitors—many of them are FDA approved, and many of them are in early and late stage clinical trials for other cancers. To date, there has generally been a very small percentage of patients with glioblastoma that benefit from these drugs.

One of the main reasons that we think this is the case is due to the concept of the immune microenvironment and how immunogenic the immune microenvironment is around cancer. In recent literature, in the development of immuno-oncology, we see the concept of hot and cold tumors with regard to the immune system. So, immune hot or immune cold.

Glioblastomas are among the coldest tumors with regard to the immunogenicity in all cancers. Glioblastoma tumors have very few T-cell infiltrates in the infector arms of the immune system. The T cells that are in the tumor are scattered and sparse. The ones that are there tend to be Tregs (regulatory T cells), or the immunosuppressive T cells. Another thing that has been associated with response to immunotherapy, in other cancers, has been tumor mutation burden, which has gotten a large recent focus. Glioblastomas are on the lower end of the tumor mutation burden, if you look at a spectrum of all cancers. Therefore, the predicted neo-androgen burden, or the predicted neo-antigen load, is actually on the lower end compared with other cancers.

Some of the other factors that we think might predict immunotherapy response in other cancers are things like PD-1 and PD-L1 expression within the tumor. In general, if you take a look at all of the glioblastomas, as a group, a very small percentage of glioblastomas have high PD-L1 and PD-1 expression in the tumor. So, those are some of the factors of the tumor immune microenvironment that affect how, in general, we think cancers will respond to current immunotherapies. Glioblastomas, among all of the cancers, are some of the most immunosuppressive and immune cold cancers that we have studied.

We’re also learning more about glioblastoma recurrence after primary therapy. First-line therapy consists of radiation and chemotherapy, with a drug called temozolomide (Temodar). When these tumors recur, there’s more recent evidence that demonstrates that they actually become even more immunosuppressive. That immunosuppressive microenvironment is not just immunosuppressive T cells. These are myeloid-derived immunosuppressive cells, neutrophils, and macrophages, and they create an even more immunosuppressive environment. When we test these immunotherapies in the recurrent setting, after standard therapy, we may actually be stacking the cards against the immunotherapy—trying to test these drugs in the recurrent setting.

With regard to resistance after initial response to immunotherapy, we have very few patients who did respond to immunotherapy. So, in terms of the escape mechanisms from immunotherapy, we really know very little in glioblastoma.

Transcript Edited for Clarity