Strategies to overcome antigen heterogeneity in glioblastoma, including nontraditional CAR targets and CAR T cells engineered to secrete bispecific T-cell engagers (BiTEs) or cytokines, represent an active line of investigation in this field and may sidestep several of the barriers that have limited the success of immunotherapy in this disease, according to Peter E. Fecci, MD, PhD.
“We’re becoming smarter,” Fecci said of the evolving glioblastoma research paradigm in an interview with OncLive ahead of Glioblastoma Awareness Day, which is observed annually on the third Wednesday in July. “I think of this as a chess match. For many years glioblastoma has been a lot of moves ahead, but we’re learning and catching up, there is hope for the future.”
In the interview, Fecci discussed unmet needs in glioblastoma management, highlighting the lack of FDA-approved immunotherapies and the challenges posed by the tumor’s immunosuppressive nature and heterogeneity. He explained that CAR T-cell therapy shows early promise in this disease, particularly with innovative modifications, but faces challenges due to tumor heterogeneity.
Fecci is a professor and chair of the Department of Neurosurgery at the University of Colorado Anschutz in Aurora.
OncLive: What are some of the most pressing unmet needs for patients with glioblastoma?
Fecci: Glioblastoma and pancreatic cancer are 2 of the cancers that we continue to think of as incurable. There’s an unacceptably high, nearly 100%, mortality rate from both of those, and a lot of the therapies we have aren’t working to the extent that we’d like them to. My work focuses on immunotherapy, and glioblastoma is one of those cancers that still lacks an FDA-approved immunotherapy, that is an unmet need.
A lot of us in cancer now have seen tremendous success in immunotherapies for other solid cancers like lung cancer, breast cancer, and melanoma. Melanoma is the best example of where immunotherapy has worked fantastically, and yet we have not seen that efficacy in glioblastoma. It’s a trickier tumor. Therapies in general don’t have tremendous access to the brain, so working on getting better access to where glioblastoma sits is important.
Also, glioblastoma is tremendously immunosuppressive compared with some other cancers, and despite the fact that it sits in the safe harbors of the brain and doesn’t really leave there, it exerts a tremendous influence on the immune system, to the extent that, in some regards, the T-cell counts of patients with glioblastoma can, at some point, almost look like those of patients with AIDS. Those T cells and other immune cells that are left behind typically don’t function well. [Another facet of glioblastoma is] tumor heterogeneity. If you cut apart a glioblastoma, every cell looks different than the next one. You’re not fighting a single disease. In some ways, you’re fighting a thousand or a million [different diseases]. Those are the biggest challenges we face. There’s not going to be a single smoking gun here, but we have to address all those things with any therapy we start to think about.
In what ways has CAR T-cell therapy shown early promise for glioblastoma, and what limitations are currently still posing hurdles?
Emerging CAR T-Cell Therapeutic Strategies for Glioblastoma
- Building on an interest in addressing glioblastoma heterogeneity in CAR T-cell research, Fecci and colleagues conducted a preclinical study of EGFRvIII-directed CAR T cells armored with a single-chain IL-12 payload, which were tested in glioblastoma mouse models with heterogeneous EGFRvIII expression.1
- This study found that intracranially administering single-chain IL-12–secreting CAR T-cells in the mouse models targeted tumors without the need for lymphodepletion, with survival benefits that correlated with the presence of CD8-positive T cells.
- Previously, a first-in-human phase 1 study of CARv3-TEAM-E T cells in 3 patients with recurrent glioblastoma showed this treatment to be well tolerated and induce rapid radiographic tumor regression, although eventual disease progression was seen in 2 patients.2
CAR T-cell therapies are one of the therapies that we are seeing a signal with in some of the clinical trials out there. It’s early, of course, and there’s a lot that still needs to be done. Some of the early trials didn’t necessarily show much, but some of the more ingenious and clever modifications of those therapies have seen signals.
The jury is still out, but, they are some of the more exciting signals we’ve seen to date with therapies and immunotherapies. I’m on the CAR T-cell train. I’m a little biased because my own group works on these types of therapies as well, but they bypass at least some of the issues we see with immunotherapies in glioblastoma, which is that if patients are missing T cells and the T cells that are there don’t function well, then taking T cells out, modifying them, and improving their function is one way to sidestep that limitation.
T cells do get into the brain, and we can implant them directly into the brain, into the tumor, and the CSF spaces. All that’s really left [of the previously mentioned limitations in glioblastoma management] is tumor heterogeneity, and some of the cleverer modifications that we’re making to these therapies help to sidestep that. That is where our lab focuses, is how to make how to make tumor heterogeneity a problem of the past for immunotherapies and other therapies for glioblastoma.
What future research avenues are being pursued with CAR T-cell therapy in glioblastoma?
Tumor heterogeneity is the key problem that my group wants to address because it’s the major thing limiting the efficacy of CAR T cells. One of the cancers where CAR T cells has worked fantastically are liquid cancers, typically lymphomas. A big part of the reason [CAR T-cell therapies] work so well in lymphoma is that lymphoma cells are clonally expanded. Every cell in a lymphoma pretty much looks exactly like the cell next to it, and there are certain antigens or targets that are expressed by lymphoma that are universally expressed by all cells in the tumor.
We don’t have [those similarities] in glioblastoma, and we don’t have that in a lot of other solid tumors either. If we find a tumor-specific protein or target we can go after, it might only be expressed by 30% of the cells in the tumor, if we’re lucky, and cutting out only one-third of the tumor isn’t going to do anyone any favors. We have to find a way to either target many targets, encompassing 95% or 100% of the tumor cells present, or step further back and completely change the way we think about this.
Maybe the answer is not protein targets, maybe it’s something else about the tumor or the cell membrane. Some of the things we do are look at outside the box of CAR T-cell targeting strategies that allow us to go after targets that are less heterogeneous and may not be traditional targets. Another strategy that is already out there and that we’re adopting too is to engineer CAR T cells to secrete other products, particularly BiTEs.
There are also cytokines and a variety of immunomodalities that CAR T cells can secrete in and around the tumor when they’re there that help add second- and third-line strategies, or backups. There are more clever modalities that people are loading into CAR T cells to sidestep some of the problems with glioblastoma. Our group is doing that, and some of the most promising data we’ve seen so far are out of a group at Harvard that has put together an EGFRvIII-targeting CAR that secretes an EGFR BiTE. That’s where we’re starting to see some signals.
What is the important to keep top of mind regarding the glioblastoma disease landscape and continuing research in this area?
More than ever, we’re seeing larger numbers of people doing research on glioblastoma, and that’s always helpful. The more minds thinking about problems, the better the solutions we often get. That’s something to be hopeful and thankful for all at once.
We’ve started to see some hits in recent years. We haven’t moved the needle much, but we’re starting to see signs of signals, and that’s exciting because it provides us that opportunity to find out or think about why we’re seeing signals in some cases. If you don’t see a signal, you can’t study the difference between patients who have a signal and those who don’t. We’re also learning a lot more about immunotherapy from the successes we’re seeing in other cancers, and we can use some of the clever solutions that people have employed in those other cancers to try to improve the efficacy of the therapies we’re looking at in glioblastoma. We’re seeing a lot more concentration and a lot more industry interest in this area, and the more cooks in the kitchen the better off we’ll be.
References
- Shen S, Mohan AA, Hotchkiss KM, et al. IL-12-secreting CAR-T cells reprogram the tumor microenvironment and improve efficacy against heterogeneous models of glioblastoma. J Immunother Cancer. 2026;14(3):e012532. doi:10.1136/jitc-2025-012532
- Choi BD, Gerstner ER, Frigault MJ, et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N Engl J Med. 2024;390(14):1290-1298. doi:10.1056/NEJMoa2314390
