FGL2-Directed Immunotherapy Under Exploration in Glioblastoma

FGL2-Directed Immunotherapy Under Exploration in Glioblastoma

Amy Heimberger, MD

Novel immunotherapy strategies are beginning to emerge for patients with brain tumors, despite years of setbacks related to the heterogeneity and relative obscurity of the inner workings of the disease. While checkpoint inhibitors have shown early promise, additional approaches are still needed. To this end, researchers at the MD Anderson Cancer Center have pinpointed a potential role for the immunosuppressive protein FGL2 in glioblastoma.

Preclinical research conducted on tumor samples and mouse models showed that FGL2 is secreted by glioblastoma, which causes the upregulation of immune suppression mechanisms. Additionally, in these early studies, an anti—FGL2 antibody demonstrated therapeutic potential. The next step for translating these findings into practice is currently ongoing, Amy Heimberger, MD, professor in the Department of Neurosurgery, University of Texas MD Anderson Cancer Center, toldTargeted Oncologyin an interview.

TARGETED ONCOLOGY:Can you give us an overview of FGL2 in the context of glioblastoma?

HEIMBERGER:There is a great deal of excitement in immunotherapeutics. In the context of glioblastoma, the mechanisms that the tumor uses for immunosuppression are very different and very heterogeneous, meaning there are multiple redundant mechanisms.

Right now there is a great deal of enthusiasm on things like immune checkpoints, but we think there are only going to be a subset of patients who respond to that. Therefore, we are going after key targets and key hubs of tumor-mediated immune suppression. These are particular pathways or mechanisms that deal with more than one mechanism of immune suppression.

In the case of FGL2, this is a secreted protein that glioblastoma makes. What it does is it exploits multiple mechanisms of immune suppression to stay behind the detection of the immune system. It specifically increases T regulatory cells, which are known to inhibit immune responses. It also induces M2, or the tumor-supported macrophage, as well as recruits a myeloid-derived suppressor cell.

FGL2 is not just working on immune checkpoints. It’s also working on other cells that are also contributing to the tumor-mediated immune suppression. We think this is going to impact more patients because it hits more than one mechanism and we think it will have a more profound impact, because what we found is that if we hit one immune-suppressive target, then other immune-suppressive mechanisms become upregulated.

We think getting at these hubs is going to be important for getting at the heterogeneous tumors that don’t exploit one particular mechanism all the time.

TARGETED ONCOLOGY:Can you discuss the early phase studies into FGL2?

HEIMBERGER:This is work that was done with Shulin Li, PhD, at MD Anderson Cancer Center. It’s preclinical work where we looked at data from patients with glioblastoma, so we know that this is an operational mechanism that is important for these patients. We then built model systems in mice, to understand the biology system I just described.

We’ve taken glioma cell lines and we’ve overexpressed this protein, and then we studied the immunobiology. When you upregulate FGL2 in mice, what you see is a much greater degree of immunosuppression, the tumors grow quicker, and the animals die faster. If you do the exact same experiment where you’ve taken away the immune system and you’ve overexpressed FGL2, you do not see any therapeutic effect.

So what you’re seeing really is that the way FGL2 works is by really controlling that immunosuppression, which allows the tumors to grow, propagate, and kill the mice.

We have gone so far as to create an antibody that targets the FGL2 and it actually showed a therapeutic effect in animals with intracranial tumors. Now we are going through the process of “humanizing” the antibody so that we could potentially move it into clinical trials. That is several years away, though — we have to go through several steps to get there.

TARGETED ONCOLOGY:What should community oncologists know now about FGL2?

HEIMBERGER:There needs to be an appreciation of the fact that immune suppression is complex and simply hitting a single mechanism is not going to be a home run. We have to look at the complexity of the biology that we’re dealing with and realize that it’s not just about immune checkpoints and it’s not just about T regulatory cells. It’s about the whole picture of how the tumor exploits the immune system to stay behind detection.

I think as we move forward into the next generation of immunotherapeutics, we need to think about the approaches that get at more than one thing. We need to be going after the complex, comprehensive immune suppression that exists.