Mutation-directed CAR T cell therapy feasible in recurrent glioblastoma
medwireNews: Treatment with autologous chimeric antigen receptor (CAR) T cells directed against the epidermal growth factor receptor variant III (EGFRvIII) mutation is feasible and well tolerated in patients with recurrent glioblastoma, indicates a first-in-human study.
But barriers to the clinical efficacy of the therapy exist, says the research team, including “the inhibitory tumor microenvironment, which becomes even more immunosuppressive after CAR T cells.”
Lead author Marcela Maus (Massachusetts General Hospital, Boston, USA) and colleagues chose the EGFRvIII mutation as it is “a tumor-specific, oncogenic, and immunogenic epitope” expressed in around 30% of newly diagnosed cases of glioblastoma.
In this phase I study, reported in Science Translational Medicine, 10 patients with EGFRvIII-expressing glioblastoma that had progressed after at least one prior line of therapy were given a single infusion of an autologous EGFRvIII-directed CAR T product within a week of progression.
There were no dose-limiting toxicities, and no evidence of off-target EGFR-directed effects – such as rash, diarrhea, or pulmonary symptoms – or systemic cytokine release syndrome.
Neurologic events were observed in three patients and included a seizure at day 9 in one patient and neurologic decline in two patients, at day 15 in one case and postoperatively in the other. Although such events are common in glioblastoma patients due to the nature of the disease, Maus et al say that they could also result from CAR T-induced immune responses in the confined intracranial space.
They were unable to formally assess efficacy as the majority (n=7) of study participants underwent surgery following infusion of the CAR T cells. But one patient was alive and required no further treatment for 18 months or more after the infusion. A further two patients were also alive at the time of analysis, but they showed signs of disease progression by imaging criteria.
The surgical intervention allowed the researchers to evaluate not only tissue-specific trafficking of CAR T cells and on-target effects, but also the tumor microenvironment in situ.
Analysis of tumor samples showed the presence of EGFRvIII–CAR T cells in the brain, with higher levels in the four patients who had surgery within 14 days of the infusion than in the three who underwent surgery at later timepoints.
And comparison of post-infusion samples with matched samples obtained before the infusion revealed a significant decline in the expression levels of EGFRvIII in five of the seven participants with available samples. Such a decrease in antigen expression in the remaining tumor bed and tissue is indicative of on-target effects, say Maus and colleagues.
But they also found that the expression of several immunosuppressive molecules, including indoleamine 2,3-dioxygenase 1, was “markedly increased” in post- versus pre-infusion samples, and noted elevations in the relative proportion of immunosuppressive FoxP3+ regulatory T cells after infusion.
These findings suggest that “CART-EGFRvIII activation induced a compensatory multifactorial immunosuppressive response in situ,” say the investigators, adding that it could potentially “be overcome with existing drugs that target immunosuppressive molecules.”
Study author Donald O’Rourke, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, USA, told the press: “This is an early stage trial, but we are encouraged by the fact that the cells got into the brain, proliferated, and reduced the level of antigen with very little toxicity to the patients. We can build on this as a therapeutic option for these patients. It gives us clues on what to do next.”
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