Pilot Study for EGFRvIII-positive Glioblastoma Treatment Shows Promise

CAR T-Cell Therapy in EGFRvIII-Positive GBM

Carl H. June, MD

A chimeric antigen receptor (CAR) T-cell therapy used in patients with EGFRvIII-positive glioblastoma multiforme (GBM) during a pilot study showed promising results, according to two leading researchers in the field presenting at the 2015 Society of Neuro-Oncology (SNO) Annual Meeting.

Carl June, MD, director of Translational Research, Abramson Cancer Center at the University of Pennsylvania, reviewed trials of CAR T-cell therapy directed to the CD19 antigen in hematologic malignancies. The therapy demonstrated impressive efficacy in both chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) and studies in patients with EGFRvIII-positive GBM follow successful trials of the same therapy in hematological cancers.

Initial results from studies of CD19-directed CAR (CTL019) began in 2010, where from 3 patients with late-stage and incurable CLL showed durable remissions and resulted in sustained antibody delivery with a single infusion, June said. He noted mature findings from data on 14 patients who had an overall response rate of 57% in these heavily pretreated CLL patients, with 4 complete remissions and 4 partial remissions.

“And we now know, 5 years later, that the responses are durable,” June reported.

June and colleagues also recently reported on the therapy’s effectiveness in ALL where CTL019 was administered to 30 children and adults. Of those tested, 27 experienced complete remission which yielded a response rate higher than for CLL, June noted.²

Whether CAR T-cell therapy will prove as effective in solid cancers remains an open question, and June’s colleague at the University of Pennsylvania, Donald M. O’Rourke, MD, provided attendees at SNO with an update of clinical and correlative data from studies testing EGFRvIII-directed CAR T-cell therapy in GBM. O’Rourke directs the Human Brain Tumor Tissue Bank at PennMedicine, where he is also an associate professor of Neurosurgery.

O’Rourke presented early findings from a pilot study at the Abramson Cancer Center of autologous T cells redirected to EGFRvIII with a CAR in patients with EGFRvIII-positive glioblastoma (NCT02209376). The study’s primary objective is safety and feasibility of the treatment. Overall survival and progression-free survival at 1, 6, 12, and 24 months are secondary objectives.

Correlative immunologic studies are examining persistence of CART-EGFRvIII and bioactivity of CART-EGFRvIII in blood, and advanced MRI imaging is studying regional blood flow as a biomarker of EGFRvIII expression.

Eight patients have been accrued to the study. Surgery was performed on 5 of the 8 patients. O’Rourke focused on these in his update, because surgical specimens are available. He mentioned regional heterogeneity in the tumors’ EGFRvIII expression, though the significance of the quantification is unknown at this time.

He stressed that these are “very difficult, refractory patients. All of them have multifocal disease, and most of them have had a number of treatments.”

The therapy has been well tolerated, said O’Rourke. “Two patients did get treated with siltuximab, one for edema and the other for a seizure,” he said, adding that the IL-6 blockade was very effective in these patients. “These were the only major toxicities, which is an important point. The seizure was grade 3, and the edema was grade 4, but transient, and quickly reversed with steroids and a single dose of the IL-6 blockade.”

One patient emerged as an internal control, O’Rourke explained, because unlike the other patients in the cohort, [this patient did not exhibit] CAR expansion in the blood, and CAR sequences were detected in the brain, “this patient, for whatever reason, did not engraft peripherally. The kinetics were different, and we did not detect any subsequent EGFRvIII loss in the tumor specimen.”

O’Rourke said, the other patients, however, have shown varying degrees of clinical stability, adding that the kinetics of T-cell engraftment peripherally mirrored the experience with CD19.

“It’s really interesting, in that we also observed a peak of T-cell engraftment at about day 7." Notably, “In 4 of the 5 surgical cases, there was a significant reduction in the antigen after T-cell therapy,” and in 3 patients, near complete elimination of EGFRvIII was observed.

“These findings are consistent with targeted recruitment and activation of EGFRvIII CAR cells to GBM within a week following infusion, and this has implications for how we will use this therapy in the future.”

The therapy did not disrupt other mutations, such as PI3K, or EGFR wild-type, suggesting that “this is a very selective T-cell killer.” Also of interest, O’Rourke said, are indications that some of the activated EGFR alleles, which were coexpressed in these tumors before CAR-T cells, disappeared in addition to the vIII. “Potentially, although speculative, the therapy may be able to clear some of the other EGFR mutations that coexist with vIII, and we’re exploring that now.”

While reminding the audience that the findings are “very early,” O’Rourke concluded that, “screening for EGFRvIII and CART-EGFRvIII manufacturing is feasible in GBM. We believe that it is safe; there is a risk of seizures, but those on antiepileptic medications have not had seizures, and there was no EGFR wild type—directed toxicity in 8 of 8 patients.”

“We’ve established, we believe, the mechanism of action. CART-EGFRvIII cells expand in the blood and traffic to the brain; they’re detectable in brain tumors of 3 of 5 patients, and we’ve seen near complete antigen loss in 4 of 5 operative patients."

He added that immunohistochemistry studies showed induction of new T-cell infiltrates in tumor resection specimens, a finding that suggests antigenic spreading of bystander cells.

“We may need additional strategies to target other antigens beyond EGFRvIII to prevent tumor escape."

References

1. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015; doi: 10.1126/scitranslmed.aac5415.
2. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.