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Immunotherapy with a chimeric antigen receptor (CAR) T-cell treatment targeting disialoganglioside GD2 may have a sustained antitumor effect in at least a proportion of pediatric patients with relapsed or refractory high-risk neuroblastoma, as well as a favorable safety profile, a suggested.

GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 total patients with heavily pretreated neuroblastoma up to 30 months after infusion (median persistence 3 months), reported Franco Locatelli, MD, PhD, of IRCCS Ospedale Pediatrico Bambino Gesù in Rome, and colleagues.

Six weeks after infusion of GD2-CART01, 17 responded to treatment, for an overall response rate of 63%, with nine achieving a complete response and eight achieving a partial response, they noted in the

Of the remaining patients, five had stable disease and five did not respond. Five of the nine patients who had a complete response maintained that response at a median follow-up of 1.7 years.

"We observed a high incidence of response among our patients with refractory disease, a finding that indicates that GD2-CART01 has therapeutic potential against high-risk refractory or relapsed neuroblastoma," Locatelli and colleagues wrote.

In the entire cohort, the 3-year overall survival (OS) rate was 40% and the event-free survival (EFS) rate was 27%, while these rates were 60% and 36%, respectively, among patients who received the recommended dose of GD2-CART01. Among the patients who had a complete response after the first infusion, the OS rate was 66% and the EFS rate was 50% at 3 years.

Patients with low disease burden had significantly longer survival than those with a higher disease burden. At 3 years, the OS rate was 67% among patients with low disease burden compared with 0% among those with high disease burden, while EFS rates were 58% and 0%, respectively.

Of note, cytokine release syndrome (CRS) was one of the most common drug-related adverse events, occurring in 20 of 27 patients after the first infusion. However, 19 were mild cases (grade 1 or 2), and the single case of grade 3 CRS rapidly resolved after administration of tocilizumab (Actemra).

In a accompanying the study, Oladapo Yeku, MD, PhD, and Dan Longo, MD, both of the Mass General Cancer Center and Harvard Medical School in Boston, observed that the study has several notable features, including that it tested the use of CAR T-cell therapy in solid tumors, while most previous trials have evaluated CAR T cells in hematologic cancers.

They also noted that while currently approved CAR T cells for hematologic cancers include at least one costimulatory domain, "given the previous evidence of the poor efficacy of CAR T cells in the treatment of solid tumors," the investigators in this trial incorporated two others -- CD28 and 4-1BB.

Locatelli and colleagues said that the incorporation of these two costimulatory domains may account for the fact that all patients in the study had persistence of CAR T cells for more than 6 weeks, and in order to maintain tumor control, "it is essential that CAR T cells persist over time."

Severe hematologic toxic effects developed in all the patients -- grade 4 neutropenia in all 27 patients, grade 3 anemia in 19 patients, and grade 3 and 4 thrombocytopenia in four and 19 patients, respectively.

In order to address potential neurotoxic effects associated with GD2-CART01, Locatelli and team also incorporated the inducible caspase 9 suicide gene, which essentially worked as a "safety switch" that allowed adoptively transferred cells to be killed if they were associated with dangerous toxic effects.

This was used in a patient who experienced an altered state of consciousness and was then treated with rimiducid. It was subsequently determined that the patient's symptoms were caused by a cerebral hemorrhage and not from the CAR T-cell therapy, but the safety switch did eliminate circulating GD2-CART01, and GD2-specific CAR T cells subsequently re-expanded to detectable levels in this patient.

The 27 patients in the trial had a median age of 6.7 years, and two-thirds were male. Before enrollment, all the patients had disease resistance to at least two, and up to six, lines of treatment. Twenty-six patients had relapsed or refractory disease, and one had received GD2-CART01 during complete remission at the end of first-line therapy.

Of the patients with relapsed or refractory disease, 24 had active stage IV metastatic disease before treatment. Fourteen patients had previously been treated with an anti-GD2 monoclonal antibody.

GD2-CART01 was manufactured successfully in all patients, and three dose levels were evaluated (3, 6, and 10 × 10⁶ CAR-positive T cells/kg of body weight) in the phase I portion of the trial, with no dose-limiting toxic effects recorded. The recommended dose for the phase II portion of the study was 10 × 10⁶ CAR-positive T cells/kg.

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