Monica Bertagnolli: Hope for Patients with Diffuse Midline Gliomas and a Tribute to Gabriella Miller

Monica Bertagnolli, 17th Director of the National Institutes of Health, shared on LinkedIn:

“The part of the brain generally known as the midline is a dense region where connections between the two sides of our brain and between the brain and the rest of the body are located. This is a relay center that coordinates motor functions, regulates arousal, attention and sensation, and houses the beginning of distinct cranial nerves that control specific regions of the body, like the expressions of the face, movement of limbs, and function of the bowel and bladder. Diffuse midline gliomas (DMGs) are aggressive tumors of these midline structures that wreak havoc on the lives of all affected. These tumors are more common in children but also occur in adults.

During my time at NCI, I had the great honor of meeting Ellyn Miller, mother of Gabriella Miller. Gabriella, a beautiful, courageous and thoroughly charming soul, was diagnosed at age 9 with a Diffuse Intrinsic Pontine Glioma (DIPG), a subtype of DMG. By the time Gabriella passed away at age 10, she had galvanized a nationwide community of supporters of cancer research ranging from passionate individuals to nonprofit foundations to dedicated congressional champions. One of the most powerful statements in all of cancer activism is found in a video of Gabriella speaking, near the end of her life, where she looks directly into the camera and says with great passion ‘Talking is bull****.  We need actions.’ I am profoundly grateful to Gabriella and to her family for this reminder that precious lives depend upon biomedical research.

We have made progress since Gabriella’s diagnosis. Research teams across the nation received NIH funding from the Gabriella Miller Kids First Research Act and the Childhood Cancer STAR Act, and many private foundations also support this work. Today I am pleased to report on new results from researchers that recently arrived in print in the journal Nature.

This manuscript details results from a phase I clinical trial for patients with DMGs containing a mutation of the H3K27M gene that causes tumors to express high levels of the disialoganglioside DG2. This mutation is a defining feature of DMGs, including the DIPG subtype that is the most common cause of death due to brain cancer in children. Researchers at Stanford University developed T lymphocytes expressing a chimeric antigen receptor directing these cells to bind tumors with DG2 on their surface (GD2-CART). These special T lymphocytes are created using a patient’s own cells, then delivered back to the patient both intravenously and directly into the central nervous system by intracerebroventricular infusion. These GD2-CART cells then become activated by their interaction with the tumor, initiating a cascade of intracellular signaling events that release cytotoxic molecules such as perforin and granzymes which penetrate and destroy cancer cells.  They also induce other immune responses that augment tumor-killing.

The phase 1 study described in the manuscript by Monje, et al. was designed to determine whether GD2-CART infusions could be safely given to patients with DMG who had already received standard radiation therapy. A total of 11 patients ages 4-30 years were treated. Eight of these patients had tumors that were progressing clinically or increasing in size by MRI at the time of treatment. In addition to determining how well the treatment was tolerated, the study included a preliminary assessment of anti-tumor response by evaluating changes in tumor size by MRI and improvement in neurological function.

Nine of the eleven patients who received DG2-CART infusions showed clinical benefit, with either measurably decreased tumor volume or improvement in symptoms. One patient with DIPG who had severe sensory and motor deficits prior to treatment had a dramatic clinical recovery and complete regression of tumor radiographically. This patient had no evidence of disease progression based on clinical or MRI assessments at the time of the report, 30 months following initial treatment. Another patient who was paraplegic before infusion showed a greater than 90% reduction in tumor volume and recovered bowel and bladder function and the ability to walk with a cane after treatment.  There were toxicities associated with the infusions similar to those seen with other CAR T cell trials, including transient tumor inflammation-associated neurotoxicity, particularly following initial infusion. None of these toxicities required patients to discontinue treatment.

The median survival of patients with DMG treated with standard radiation therapy is typically 11 months from diagnosis, and fewer than 1% of those affected are alive at 5 years. At the time of this report, median overall survival for patients treated on the DG2-CART study was 20.6 months from diagnosis.

No definite conclusions can be drawn concerning the generalizability of these results to all patients with DMG, as the study did not compare participants to those undergoing standard treatment alone. However, the results of this phase 1 study warrant cautious optimism. For the patient who was restored to functional health at 30 months following treatment, DC2-CART therapy is nothing less than a medical miracle – and a miracle that we all fervently hope will last.

What now? Next will be intensive study of each of the trial participants, seeking patient-specific features associated with clinical benefit.  This study provides a very promising beginning and renews our commitment to pursue immunotherapy as an approach that will conquer this terrible disease. More studies will be initiated, and more courageous patients and their families will join in the slow and often heartbreaking process of seeking a cure, now with greater hope for success.”