Introduction
Several adolescents and young adults with diffuse midline gliomas had their tumors shrunk in a limited clinical trial using CAR T-cell treatment, an immunotherapy that fights cancer by using the patient’s own immune cells. Within a year after diagnosis, this rapidly spreading kind of brain and spinal cord cancer usually results in death.
Several trial participants remained alive for at least two years following treatment.
About 80% of younger patients with diffuse midline gliomas have a genetic mutation called the H3K27M mutant, which was present in the trial participants. The study’s lead researchers at Stanford University created the experimental CAR T-cell therapy to target GD2, a chemical that is produced in high quantities by diffuse midline gliomas with the H3K27M mutation.
The ongoing clinical trial’s results were released in Nature on November 13.
According to Stanford Medicine co-investigator Crystal L. Mackall, M.D., “this study breaks new ground.” “It proves that CAR T cells can give solid cancers actual, significant benefit, which many people didn’t think was possible.”
Nine out of eleven trial participants who got the GD2 CAR T-cell treatment experienced improvements in their neurological function. Seven of them saw tumor shrinking, with several cases showing very noticeable results. Patients’ symptoms improved as their tumors decreased, and many were able to regain basic abilities like hearing, walking, and tasting that they had lost due to the condition.
Two patients survived the study’s 2.5-year follow-up period, and participants lived a median of almost two years following therapy. Four years after his diagnosis, one of these patients’ tumors completely disappeared, and he is still cancer-free.
Rosandra N. Kaplan, M.D., of NCI’s Center for Cancer Research, who is not involved in this study but is also conducting a clinical trial for GD2 CAR T-cell treatment, said, “It’s really remarkable.” Nothing has ever been effective in treating this malignancy. I believe that a revolution in our knowledge of how to treat these people is about to begin.
A fortuitous partnership
Diffuse midline gliomas encompass a category of brain tumors, including diffuse intrinsic pontine glioma (DIPG), which are challenging to excise surgically due to their positioning in regions of the brain responsible for essential functions like breathing and heart rate regulation. Chemotherapy and radiation offer only temporary alleviation of symptoms. H3K27M-mutant diffuse midline glioma tumors are exceedingly rare and nearly always result in fatal outcomes.
“Our progress against these tumors has been minimal,” Dr. Mackall stated. She explained that the sole standard therapy is radiation, which aids in managing symptoms.
“These patients experience a limited lifespan and a gradual decline in essential functioning, leading to a downward trajectory from the moment of diagnosis,” she stated.
CAR T-cell therapy entails the collection of patients’ immune cells, which are then engineered to express a receptor on their surface (the CAR) that enables them to attach to and target cancer cells effectively. The cancer-fighting T cells are expanded to millions and subsequently reintroduced to the patient, with the objective that this robust assembly of immune cells will identify and eliminate the cancer cells.
Numerous CAR T-cell therapies have received approval for the treatment of blood cancers; however, this method presents greater challenges in solid tumors, such as brain cancers. This difficulty arises partly because the potential target molecules present on the surface of solid tumors are also found on healthy cells.
An earlier study conducted by Michelle Monje, M.D., Ph.D., from Stanford Medicine, revealed that diffuse midline glioma cells produce elevated levels of GD2, a molecule that is typically found at minimal levels in normal brain cells. Concurrently, Dr. Mackall initiated trials for a CAR T-cell therapy she developed, which specifically targets GD2, informed by research indicating its prevalence in tumors associated with neuroblastoma and osteosarcoma.
“It was genuinely one of those moments in science that was fortuitous,” Dr. Mackall remarked regarding their collaboration.
The researchers and their colleagues at Stanford subsequently demonstrated that the GD2 CAR T-cell therapy was capable of effectively penetrating the brain and completely eradicating tumors in a mouse model of diffuse midline glioma.
A modest trial yielded unexpected outcomes
This initial human study of GD2-targeted CAR T-cell therapy involved 11 children and young adults diagnosed with either DIPG or spinal diffuse midline glioma, who received an intravenous infusion of one of two distinct doses of GD2 CAR T cells. The lower dose resulted in reduced inflammation and will be utilized in a subsequent, larger clinical trial.
The CAR T-cell therapies authorized for hematological malignancies are typically administered as a single treatment; however, the Stanford team adopted an alternative strategy in this trial.
All nine patients who responded positively to their initial treatment subsequently received further infusions of GD2 CAR T cells. The treatment was administered directly into the brain through a specialized catheter, rather than via an intravenous infusion. Patients received treatments at intervals of 1 to 3 months, contingent upon the stability of their disease.
The trial investigators chose to administer additional doses in this manner, as prior studies in mice indicated that direct delivery of the treatment to the brain resulted in reduced inflammation and increased efficacy in eliminating cancer cells compared to systemic delivery via the bloodstream.
Following a follow-up period of 2.5 years post-initial treatment, tumors reduced in size by over 50% in 4 out of 9 patients who initially responded, including one patient whose tumor completely resolved and has not recurred.
All nine patients exhibited improvements in their neurological disabilities, with some regaining the ability to walk, hear, and taste.
A patient presented who was completely wheelchair-bound and unable to walk upon arrival. Dr. Mackall stated that following treatment, she began utilizing a cane for extended walks. Her cancer ultimately recurred; however, she experienced a significant period of approximately one and a half years during which her mobility improved markedly. That is invaluable. This instills optimism regarding the potential for positive change.
Adverse effects from the treatment encompassed neurological complications, including headaches, fever, and cerebrospinal fluid accumulation, frequently associated with tumor inflammation in the brainstem and spinal cord. The researchers indicated that these and other side effects could be managed through standard treatments and approaches.
Enhancing treatment response
Dr. Kaplan emphasized the necessity of understanding the differential responses of patients to the treatment.
All patients targeted GD2, yet responses varied among them. Dr. Kaplan stated that the response encompasses more than merely the target. The subsequent steps involve examining the influence of various components of the tumor microenvironment on treatment efficacy and utilizing this knowledge to enhance the overall immune response and duration of treatment effectiveness.
The Stanford clinical trial is currently in progress, involving additional patient groups receiving all treatments administered directly into the brain, with no intravenous treatments provided. Certain patients will not undergo chemotherapy before receiving CAR T-cell therapy. This “lymphodepleting” chemotherapy is administered to eradicate white blood cells that may target the infused T cells.
Dr. Mackall and her colleagues intend to initiate a larger phase 2 trial that will include patients from institutions beyond Stanford.
Dr. Kaplan is conducting a clinical trial to assess the efficacy of CAR T-cell therapy in patients with neuroblastoma and osteosarcoma exhibiting elevated GD2 expression.
Dr. Kaplan stated that the insights obtained from these studies will enhance other CAR T-cell therapies for solid tumors, several of which are currently undergoing clinical trials. One trial is currently evaluating a CAR T-cell therapy targeting the molecule B7-H3 in children with diffuse midline gliomas, while another trial is assessing a B7-H3 targeted CAR T-cell therapy in adults with glioblastoma.
