One of the most aggressive and poorly prognostic tumors of the nervous system is midline diffuse glioma. This type of cancer, mainly affecting children, adolescents, and young adults, cannot be surgically removed or effectively treated with radiation or chemotherapy, making it currently considered incurable.
However, this reality could change based on the preliminary results of a study published this week in the journal Nature.
According to the data, CAR-T therapy, an approach that modifies the patient's lymphocytes to target and attack tumor cells, shows promising results against this type of glioma. The authors of the study, researchers from Stanford University (USA), tested its efficacy in a phase I trial with 11 patients. In nine of them, the treatment led to improvements in their functional status. Four saw their tumor shrink by half, and in one case, a "complete response" was achieved. The tumor completely disappeared from the patient's brain.
The typical prognosis for these tumors is a survival rate of less than a year post-detection. However, Drew, the American boy who benefited greatly from the therapy, is healthy and starting his first year at university four years after diagnosis, as reported by Stanford University.
Michelle Monje, the lead researcher from the American center who conducted the trial, mentioned that it is still too early to talk about a cure. "This is still uncharted territory. We do not know what the future holds, but at the moment, there is no evidence of cancer in the imaging tests. It seems to have disappeared. I definitely hope he is cured," Monje stated via email. The researcher recently visited CNIO and spoke with this newspaper about the progress of her research.
"I am very hopeful," he emphasized after the publication of these new results. "Clearly, we still have a lot of work to do to achieve complete and lasting responses for each patient, but now I believe that someday this cancer that has long seemed untreatable will be a curable disease."
Monje's laboratory discovered in 2018 that there was a specific marker, called GD2, present only on the surface of cells in midline diffuse gliomas, not in healthy cells. Along with immunologist Crystal Mackall, who had just joined Stanford and is also a co-author of the study, they successfully developed a CAR-T therapy targeting GD2, which was then tested in mouse models before moving on to human clinical trials.
Up to now, CAR-T therapies have shown success mainly against hematologic tumors, for which they are already used in clinical practice. However, developing these cellular therapies for solid tumors remains a challenge, although significant progress is being made.
The trial whose results are now published was conducted with 11 patients with midline diffuse gliomas with the H3K27M mutation, with an average age of 15 years. Most of them suffered from an intrinsic diffuse midline glioma, a subtype of the mentioned cancer. All patients received chemotherapy before the CAR-T cell infusion.
The main goal of the phase I trial was to assess the therapy's safety, identify the safest doses, and study the treatment's side effects, initially administered intravenously and later directly into the cerebrospinal fluid.
Of the 11 patients, nine experienced significant benefits, such as a significant tumor reduction or improvement in their neurological functions. These types of tumors often cause severe impairment in patients, with many losing their ability to walk, speak, or swallow, in addition to experiencing incontinence or neuropathic pain, among other disorders.
After the intravenous administration of the cells, most patients experienced a common side effect, known as cytokine release syndrome. However, in the trial, scientists found that a lower dose of the therapy and its direct administration to the central nervous system resulted in fewer side effects.
Most patients improved their symptoms and, with tumor reduction, were able to regain some lost abilities, such as walking. However, except for Drew's case, no other patient was able to overcome the disease. According to Stanford University, the median survival was 20.6 months post-diagnosis, with two patients living more than 30 months, and one of them, Drew, still in remission today.
"I hope they learn from my case to help other kids," stated Drew, now 20 years old, in the statement released by the American university.
Diagnosed in November 2020 while in high school, he visited the doctor after experiencing headaches, strange movements in his left eye, and eventually partial paralysis on the left side of his face.
As the tumor grew, the consequences worsened until he had to rely on a wheelchair to move around.
In June 2021, he entered the trial and received his first CAR-T cell infusion. However, it was not a fairy tale beginning, he recalls. After the administration, he vomited, experienced tremors, and a temporary worsening of his neurological symptoms. However, tests showed that the therapy was working, so he remained hopeful.
His mother described the experience as akin to cleaning out the garage: at some point, before things start falling into place, it seems like you are only making things worse.
Today, Drew, who graduated with his class and is in university, continues to receive therapy infusions periodically. He still experiences some facial paralysis but has regained his ability to walk, run, and has seen improvements in his hearing and sense of taste, as reported by Stanford University.
With Drew's case always in mind, Monje's team continues to work on optimizing the therapy and understanding how to improve its outcomes.
"We are currently studying solely intracranial administration, bypassing the initial intravenous administration, and analyzing whether prior chemotherapy is necessary or not," the researcher explained. Additionally, they aim to understand why some patients respond much better than others to the treatment. "By studying what correlates with therapeutic response and resistance, we hope to establish hypotheses that we can test in the laboratory," added the scientist, who believes that this approach could also be very useful for other types of nervous system cancers.
"Some of the lessons we have learned from this trial will help us optimize CAR-T therapy for brain tumors in general," she noted.
According to Marta Alonso, director of the Advanced Therapies for Pediatric Solid Tumors Group at Cima University of Navarra, this "is an important study for an indication that currently has no cure."
"The study, a phase I trial, demonstrates that this type of study can be conducted in these patients. It also shows that we do not have to fear toxicities if we have ways to manage them, and they are accompanied by clinical improvement. Lastly, it indicates some efficacy and opens the door to future trials, suggesting the need for combinations for this type of tumors," she added.
On the other hand, Joaquín Arribas, head of the Growth Factors Group and ICREA research professor at the Vall d'Hebron Institute of Oncology (VHIO), highlighted that "this is a very comprehensive study that adds to two other studies already published showing the effectiveness of CAR-T therapy against central nervous system tumors."
He continued, stating that in a tumor with a very poor prognosis, with a median survival of 11 months, they observed very good responses (up to 30 months disease-free in one patient).