A study from Children’s National Hospital explored a different type of T-cell therapy in children with aggressive brain tumors, including diffuse intrinsic pontine glioma (DIPG). The research was featured in New Scientist and the findings from the The Phase 1 ReMIND trial (ClinicalTrials.gov: NCT03652545) were published in Nature Medicine. The trial included children with newly diagnosed DIPG as well as patients with recurrent or treatment-resistant pediatric brain tumors.
The Cure Starts Now joined the Musella Foundation for a conversation with Dr. Eugene Hwang of Children’s National Hospital to take a closer look at the study, what researchers learned and where they hope to go next.
How TAA T-Cell Therapy Works
The study tested multi-targeted tumor-associated antigen, or TAA, T-cell therapy. Like CAR T-cell therapy, the treatment starts with a patient’s own T cells. But instead of genetically engineering those cells to recognize a specific target, researchers identify and expand naturally occurring T cells that can recognize the tumor. The cells are grown in the laboratory and then returned to the patient.
In this study, the T cells were trained to recognize three TAA targets: WT1, PRAME and survivin. Researchers chose multiple targets because cells within the same tumor are not necessarily identical. By going after several targets at once, the hope is to give the immune system more than one way to recognize and attack the cancer.
There was another important difference from many of the CAR T-cell approaches currently being studied for DIPG and DMG. These T cells were given through an IV rather than directly into the brain or cerebrospinal fluid.
Giving the T cells through the bloodstream has a potential advantage: it may help activate the patient’s broader immune system. The challenge is getting enough of those cells across the blood-brain barrier and into the tumor.
What did researchers learn?
This was a Phase 1 trial, so the primary goal was to study safety and determine whether the treatment could be successfully made and delivered. A study this early is not designed to determine whether a treatment is effective.
Overall, most children tolerated the treatment well, although there were important exceptions. Dr. Hwang discussed two patients who experienced more serious events, including one child with DIPG who died a few weeks after receiving the T cells. Investigators believed the death was most likely related to the tumor but classified it as possibly related to the treatment. Another patient experienced tumor swelling that may have contributed to side effects.
Researchers also saw outcomes that gave them reason to keep studying the approach. Among the children with DIPG, median overall survival was 13.7 months from diagnosis, with a few with much longer survival. While some patients lived longer than researchers might typically expect based on historical outcomes, Dr. Hwang was careful not to overstate what can be learned from a small Phase 1 trial. He described the therapy as a possible “stepping stone” rather than an answer on its own.
Some of the most interesting results came from patients with other recurrent pediatric brain tumors. Several remained alive years after treatment, and three of those had no evidence that their tumors were continuing to grow at the time of the study analysis. Those patients also raised an important question: Why did the treatment appear to help some patients more than others?
Learning from the patients who responded
One possibility researchers are looking at is tumor burden. Dr. Hwang noted that some of the patients who did particularly well had smaller amounts of tumor. His analogy was simple: if you have a large army of immune cells facing a smaller enemy, the immune cells may have a better chance of succeeding.
That could be especially relevant when thinking about DIPG, where surgically removing or reducing the tumor is generally not an option.
But there are still many unanswered questions. The patients had different tumors, received different treatments before entering the study and did not all receive the same number or dose of T cells. Even higher doses did not clearly translate into better outcomes. Dr. Hwang said there was some suggestion that higher doses performed better, but the study was too small to draw a firm conclusion.
The next step for DIPG/DMG
One of the biggest challenges with giving T cells through an IV is getting them into the brain. Children’s National is now taking what researchers learned from this trial and pairing the same TAA T cells with low-frequency ultrasound in a study called LIFT. The ultrasound is used with tiny microbubbles to temporarily open the blood-brain barrier in a targeted area, with the goal of helping more T cells reach the tumor.
The LIFT study is designed to address two major challenges in DIPG/DMG at once: helping more T cells reach the tumor and making the tumor’s immune environment more favorable for those cells to work. Dr. Hwang described DIPG/DMG as an especially difficult environment for immune cells, and researchers hope the combination can help overcome both barriers.
Researchers are also looking beyond a one-size-fits-all approach. Dr. Hwang discussed work at Children’s National that uses information from an individual patient’s tumor to identify the targets that may be most relevant for that particular cancer. Instead of using the same three targets for everyone, future T-cell products could potentially be tailored more closely to each patient.
Building on what we learn
One theme came up repeatedly throughout the conversation: the next advance in DIPG/DMG may not come from one treatment alone.
Researchers are studying TAA T cells, several types of CAR T cells, targeted therapies, radiation, ultrasound, vaccines and other approaches. Increasingly, the question is not only whether each one can help, but how different strategies might fit together. Dr. Hwang also emphasized that it is still too early to know how either TAA T-cell therapy or CAR T-cell therapy will ultimately fit into a curative treatment strategy.
This study does not tell us that TAA T-cell therapy is a cure for DIPG/DMG or other pediatric brain tumors. It does tell us that the approach can be given to children, that most patients tolerated it reasonably well and that there were enough encouraging outcomes to keep asking questions.
For Dr. Hwang and his team, that means figuring out why certain patients responded, how to get more T cells to the tumor and which other treatments might make those cells work better. Those are the questions researchers are now working to answer as they build on what was learned from this trial.
Watch Dr. Hwang explain these findings and what they could mean for future DIPG/DMG treatments: