Laser interstitial thermal therapy (LITT) can overcome the blood-brain barrier and the immunosuppressive nature of high-grade astrocytoma, creating a therapeutic synergy with immune checkpoint inhibitors (ICIs) that could prolong patient survival compared with traditional surgery, according to David Dinh Tran, MD, PhD.
“Our paper, and several other works before ours, has shown that if you know the tumor is invisible to the immune system, if you remove it and throw it away, you make it even less visible to the immune system,” Tran said in an interview with OncLive® during Brain Tumor Awareness Month, which is observed annually in May. “Among immunotherapists, there are discussions that perhaps we should do more of this [LITT] approach rather than surgical resections. [However], to make that recommendation, we will need a larger trial to answer that question.”
In the interview, Tran discussed findings from a phase 1/2b study (NCT02311582) published in Nature Communications that evaluated the use of LITT followed by pembrolizumab (Keytruda) vs non-LITT surgery followed by pembrolizumab in patients with recurrent high-grade astrocytoma.1
Tran is a medical oncologist and brain tumor specialist at Keck Medicine of the University of Southern California (USC) in Los Angeles.
What was the rationale for investigating LITT plus adjuvant ICI in patients with recurrent high-grade astrocytoma?
Tran: ICIs, or immunotherapy, have been a sea change for a lot of different solid tumors, including lung cancer, melanoma, and more recently breast cancer. However, it has not been shown to be very efficacious for brain cancer [for] many reasons. One is the blood-brain barrier. Brain cancer develops behind the blood-brain barrier, which makes it difficult for immune cells to access the tumor. This also prevents a lot of the drugs we have—antibodies and chemotherapy—from accessing the tumor. This makes it extremely difficult to manage brain cancer.
Secondly, brain cancers are notoriously immunosuppressed tumors, meaning the tumors grow in a way that protecting themselves from being detected by the immune system. Few immune cells can be found in these tumors. There are few dendritic cells. Not a lot of T cells can traffic into the tumor. The tumor grows more or less invisible to the immune system.
The third reason, which is important, [is that brain tumors] grow in the brain, which is probably the most critical organ in the human body. This affects a lot of different functions, [such as] cognitive abilities, motor abilities, speech, etc. If patients are not already debilitated because of the cancer, then a lot of [treatments]—radiation, chemotherapy, etc.—can also affect normal brain [tissue] and sometimes be debilitating.
For a long time, ICIs have not fared well in brain cancer, but brain cancer expresses high levels of immune checkpoints, so in theory, if a drug targets [certain] genes, and those genes are expressed highly in the tumor, that should work. However, all the reasons I mentioned make it difficult for these drugs to work.
Approximately 10 years ago, we had several ideas of how to break this log jam to allow the tumors to be visible to the immune system and to allow drugs like checkpoint inhibitors to have access to the tumors. One of these approaches is LITT. [At USC, we were] the first group to show that if you can use these lasers to heat the tumor and kill it by cooking it. The temperature inside the tumor can reach approximately 260 degrees Fahrenheit, hot enough to cook an egg. We have no problem cooking the tumors, but we’ve shown that as the heat dissipates into the surrounding normal brain, where the tumor is sitting, the temperature drops precipitously to the range of 100 to 104 degrees Fahrenheit. It’s like a high fever type of temperature and is not hot enough to instantly kill normal cells, but is hot enough to disrupt the blood-brain barrier.2
We’ve shown that by injecting dye into patients and seeing the dye leak out into normal brain structures surrounding the tumor. You would ask: Why do we care about the peritumoral regions? This is because approximately 90% of recurrent tumors in this disease occur within approximately 1 inch of the regional tumor, so these regions of normal brain around the tumor are critical because this tumor is known to be infiltrating. There are a lot of infiltrating tumor cells that collect themselves into the normal brain structure.
LITT Followed by ICI in Astrocytoma: Highlights
- LITT facilitates effective brain cancer management by disrupting the blood-brain barrier for at least 6 weeks and releasing tumor proteins that alert the immune system to attack infiltrating cancer cells.
- Clinical trials have demonstrated that combining LITT with the ICI pembrolizumab prolonged patient survival compared with traditional surgical removal followed by the same immunotherapy.
- To overcome treatment resistance and further improve outcomes, researchers are exploring the addition of secondary checkpoint inhibitors, like those targeting IDO-1, to the LITT/pembrolizumab regimen in future phase 3 trials.
Based on MRI or histology, it looks more or less normal, but if you look hard enough, you can see microscopic tumor cells there. If we can disrupt the barrier to get the immune cells or chemotherapy in there, the hope is that [those treatments can] target the infiltrating tumor cells. If we can eliminate [the infiltrating tumor cells], in addition to eliminating the core tumor mass, the hope is that it will result in better tumor control and longer survival.
The key thing is, this disruption lasts for at least 6 weeks. Six weeks is a long time, and some other later papers showed that it may even last even longer than that. Why that is the case, we still don’t understand, but that’s what we documented. It’s long enough for a lot of [treatments] we can do for patients.
We had a subsequent trial where we gave patients chemotherapy that normally would not get into the brain and showed that [these treatments] can improve survival for these patients. The key here is that because of the disrupted blood-brain barrier and heating the tumor, the heated tumor that is left there creates inflammatory reactions that recruit immune cells into the tumor and the surrounding regions, and [this] also allows heated kill-tumor proteins or antigens to leak into the circulation, alerting the immune system that something bad is happening there that they need to generate immune reactions to and attack. We created 2-way traffic. We allowed the tumor to become visible to the immune system. Now that the immune system could see the tumor, it could see all the abnormal proteins and genes that were expressed in the tumor, develop reactions, and allow T cells that are specific to the tumor to track into the tumor and eliminate the tumor cells. The next stage was to develop this clinical trial that resulted in publication in Nature Communications asking the question: If we use LITT to heat this tumor, kill it, disrupt the barrier, and activate the immune system, can we then create a therapeutic synergy with the immune checkpoint to allow it to work when it didn’t work before?1
What were the key findings from the phase 1/2b study of LITT followed by pembrolizumab in recurrent high-grade astrocytoma?
The trial showed that the combination works well and prolongs survival compared with only giving patients an ICI without LITT. The comparator arm [comprised] patients who underwent conventional surgery, either biopsy or surgical removal of the tumor, followed by an immune checkpoint inhibitor, the same drug [used in the investigational arm]: pembrolizumab. We showed that if you heat the tumor and kill it, and then give the pembrolizumab, it’s much more effective than removing the tumor, then treating with pembrolizumab. Heating creates inflammatory reactions that the surgical resection could not generate, and that’s how this all works.
What are the next steps for evaluating LITT plus ICI in astrocytoma?
We have evidence that the combination of LITT with an ICI, in this case, pembrolizumab, is effective as activating the immune system in these patients and prolonging survival, but it’s not a cure. There are patients who did not respond to it, or patients who responded to it well, but then developed resistance over time. The next stage of the research would be [determining] how to help the patients who didn’t respond, and then how to help the patients who responded, but then developed resistance.
We conducted a lot of analyses to find out exactly what’s so special about the patients who responded and lived a long time. We found that there’s another immune checkpoint system that appeared to be important in the patients who didn’t respond to the therapy or who responded but then developed resistance: IDO-1. The next phase of research would [ask]: Would we make more patients respond to the therapy, or would we make the patients who responded respond a lot longer if we combine the pembrolizumab with a second checkpoint inhibitor, like an IDO-1[–directed agent], to prevent the tumor from developing resistant mechanisms LITT plus pembrolizumab?
Right now, LITT is an FDA-cleared procedure, so it’s already used widely around the US to manage brain tumor, especially tumors that are not candidates for surgical resections. ICIs like pembrolizumab are approved by the FDA to manage a variety of solid cancers. [Pembrolizumab] is not approved for glioblastoma, but it is available from the from the drug manufacturer for compassionate-use cases, so this combination is being used right now in clinical practice. However, to advance the field further, the next step would be a larger phase 3 trial, where we would compare LITT plus pembrolizumab vs LITT plus pembrolizumab with another agent, for example, an IDO-1 inhibitor, to make this approach even more effective.
In what ways does LITT differ from conventional surgery that may contribute to its increased use in brain cancer management over time?
The reason this study is attractive is because LITT is considered a minimally invasive surgery. It achieves similar outcomes as open surgery, but instead of removing the tumor, you leave the tumor there for these inflammatory reactions to occur. When you do an open surgery for a brain tumor, there’s always higher risks to the patients, just from a surgical standpoint, compared with a minimally invasive approach like LITT.
LITT is attractive in the sense that there are cases where the tumor cannot be removed because it’s located in an eloquent part of the brain, where doing surgery would cause too much damage to the brain. Having a small probe inserted into the tumor and heated up is much safer to do. In those cases, LITT has become such a go-to approach that there are now discussions among experts in the field that perhaps even in tumors that are resectable, LITT might still be considered a favored approach.
References
- Campian JL, Le SB, Ghiaseddin A, et al. Laser interstitial thermal therapy and adjuvant pembrolizumab in recurrent high-grade astrocytoma: a phase 1/randomized phase 2b trial. Nat Commun. 2026;17(1):1763. doi:10.1038/s41467-026-69522-w
- Leuthardt EC, Duan C, Kim MJ, et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier. PLoS One. 2016;11(2):e0148613. doi:10.1371/journal.pone.0148613
