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Targeted CAR T-cell therapy may be ‘game changer’ for glioblastoma
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Chimeric antigen receptor T-cell therapy induced tumor regression in a patient with malignant glioblastoma, according to a brief report published in The New England Journal of Medicine.
“These recent results show a potential breakthrough treatment that may have a remarkable impact on patients with malignant brain tumors,” Christine E. Brown, PhD, faculty member in the departments of hematology and hematopoietic cell transplantation and immuno-oncology at City of Hope Comprehensive Cancer Center, told HemOnc Today. “The results of this case study demonstrate that even at the lowest dosage, this type of new therapy has tremendous promise and is a game changer in how brain tumors may be treated in the future. The most exciting thing about our study is that it proves a better treatment may be attainable. We can take a patient who has actively growing advanced, metastatic multifocal glioblastoma, and we can see regression of all lesions, including in the spine.”
Glioblastoma is the most common and aggressive brain cancer among adults in the United States, with about 12,000 people diagnosed each year and a median survival of about 15 months after diagnosis.
Based on previous clinical studies evaluating intracranial administration of CD8 T cells expressing a first-generation interleukin-13 receptor alpha 2 (IL13R2)–targeted CAR in patients with glioblastoma, Brown and colleagues modified the CAR T cells to improve antitumor potency and T-cell persistence. They incorporated a 4-1BB costimulation and a mutated IgG4-Fc linker to reduce off-target Fc-receptor interactions in the CAR; they also genetically engineered enriched central memory T cells.
In the study, a 50-year-old man with highly aggressive recurrent glioblastoma in the right temporal lobe received infusions of CAR T cells targeting IL13R2 for 220 days through two intracranial routes — the resected tumor cavity, followed by the ventricular system.
After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid.
During the six weekly intracavitary infusions, the treated tumor in the temporal-occipital region remained stable for more than 45 days after surgery without evidence of disease progression. However, MRI revealed progression of nonresected tumors in the left temporal lobe and new tumors near the resected lesions. In addition, researchers detected new metastatic lesions in the spine, causing leg numbness, suggesting that the infusions were not sufficient to control tumor progression at distant sites.
After the first three intraventricular infusions (day 133), the patient experienced a dramatic reduction in the size of all intracranial and spinal tumors. Following the fifth intraventricular infusion on day 190, all tumors had decreased by 77% to 100%. Five additional intraventricular infusions resulted in all tumors decreasing to a point where they were not measurable by MRI and were undetectable by PET.
From day 108 through 284, systemic dexamethasone was gradually eliminated and the patient returned to normal life and work activities.
This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy and none of the initial tumors recurred.
“As part of the City of Hope clinical trial to test the safety of CAR-T cell therapy delivered directly to brain tumors, the patient received multiple infusions that were well tolerated,” Brown said. “By injecting the reengineered CAR T cells directly into the tumor site and the ventricles, where the spinal fluid is made, the treatment could be delivered throughout the patient’s brain and also to the spinal cord where this particular patient had a large metastatic tumor. Regression was observed for both brain and spinal tumors, as well as increased numbers of immune cells in the cerebrospinal fluid, a clinical response that was sustained for 7.5 months after initiation of CAR T-cell therapy.”
The infusions were not associated with any toxic effects of grade 3 or higher. Grade 1 or 2 events observed within 72 hours of the T-cell infusions included headaches, fatigue, myalgia and olfactory auras.
The patient’s disease eventually recurred 228 days after the first CAR T-cell treatment, at four new locations that were distinct and nonadjacent to the previous seven tumors.
Brown said City of Hope is currently enrolling patients for this trial and eligibility criteria can be found on its clinical trials website.
“Based on the early successful results seen in the phase 1 trial for intracranial CAR T-cell therapy, we see enormous potential for a remarkable impact on a wide variety of patients,” Brown said. “We remain encouraged that this promising treatment also greatly improves quality of life by preserving patients’ neurological function and minimizing the toxic side effects of other treatments.” – by Chuck Gormley
For additional reading:
Information on the City of Hope clinical trial can be found at http://clinicaltrials.coh.org by entering “13384” in the keyword search.
Disclosure: Gateway for Cancer Research and others funded this study. Brown reports receiving royalties from pending patents related to CARs having mutations in the Fc spacer region and methods for their use (PCT/US2014/028961; licensed to Mustang Bio) and costimulatory CAR T cells targeting IL13Ra2 (PCT/US2015/051089; licensed to Mustang Bio), and a pending patent related to the administration of cellular immunotherapy for treatment of cancers in the central nervous system (62/292,152 and 62/309,348). Please see the full study for a list of all other researchers’ relevant financial disclosures.
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