In children, the most fatal cancers occur inside the brain. When a tumor grows in an area like the brainstem, like a diffuse intrinsic pontine glioma (DIPG), surgical removal risks damaging sensitive tissue that regulate essential functions like breathing. Even without surgery, treatment can still be highly invasive. Getting drugs across the blood-brain barrier often requires injections into the brain or cerebrospinal fluid, and chemotherapy is notoriously difficult for children to tolerate. Thus, patients are often stuck without good treatment options.
Now, a new Phase 1 trial led by researchers at Children’s National Hospital showed that a new autologous multi-antigen T cell therapy can be delivered intravenously and reach the brain through the bloodstream to fight off brain tumors in children. The results, published in Nature Medicine, are highly impressive in such a challenging space. While the aim of the trial was to establish the maximum safe and effective dose, the researchers found that several patients had a strong response to the treatment and have remained disease-free for years.
“We achieved the highest dose without too many side effects, making that the recommended dose moving forward for other trials. We also of course found that several patients responded well to the treatment, which is exciting, and gave rationale to build this strategy into the next two trials, which are opening at Children's now,” Eugene Hwang told DDN, a pediatric neuro-oncologist who co-led the trial with Children’s National Hospital cancer researcher Catherine Bollard.
Early hints at efficacy
Bollard helped develop the tumor-associated antigen T cell (TAA-T) program at Children’s National Hospital, which manufactures autologous T cells that target tumor-associated proteins using the patient’s own blood rather than using off-the-shelf T cells. The new T cell therapy for pediatric brain cancer patients is multi-antigen, targeting three proteins relevant to brain tumors: WT1 (Wilms’ tumor protein), PRAME (preferentially expressed antigen in melanoma), and survivin (BIRC5).
The trial results showed that the T cell therapy was well tolerated with low grade side effects in the 33 total patients. None of the dosage levels reached toxicity, and there were only two severe adverse events. In addition, the median overall survival for patients with newly diagnosed DIPG without lymphodepletion was 13.7 months. For patients with relapsed/recurrent nonbrainstem malignancies, median progression-free survival was 5 months from infusion of the multi-antigen T cell therapy. Further adding to the potential efficacy of the therapy, three patients remain disease-free at 31.8, 41.2, and 51.6 months without additional treatments, and one patient had a complete response.
“This study represents an important step toward developing safer and more effective T-cell therapies for children with devastating brain cancers,” said Bollard in the press release. “Even in this early-stage trial focused on safety, we were encouraged to see lasting clinical benefit in several patients who otherwise had very few options.”
Yet, the efficacy results remain exploratory until they are directly investigated in the next Phase 1 successor studies, which are under development now.
“We are currently developing the LIFT trial, which will use this strategy in combination with low-frequency ultrasound in order to improve delivery of the T cells to the tumors, as well as IMPACT, which is currently open and uses the same backbone, but instead tries to identify targets specific to each patient's tumor,” said Hwang.
Hope for the future
The researchers are hopeful that the strategies they’re adding to their next studies will help more children respond to the T cell therapy and remain disease-free for years to come. If so, the therapy could represent a massive win in an area with few efficacious treatment options — and also become one of the first T cell therapies to show success in solid tumors.
Hwang noted that it was wonderful to see the successful responses of some children to the therapy, although he added it’s still not enough time. Still, he called the work so far “another stepping stone to the dream of one day curing these children.”
