Phase III randomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in korea

Treatment Scheme

Treatment Scheme

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Summary

The study aims to evaluate the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of patients with glioblastoma. The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS.

Patients characteristics

Patients enrolled in the study were aged 18 to 70 years; had a Karnofsky performance status (KPS) of at least 60; newly diagnosed GBM World Health Organization [WHO] grade IV astrocytoma; with adequate hematologic, renal and hepatic function; and acceptable blood coagulation levels.
180 patients were randomized. 91 patients were randomized to the CIK immunotherapy group, and 89 patients were randomized to the control group. The median age at the time of randomization was 55.0 and 54.0 years, with a range 19 to 69 and 23 to 68 years in each group. Males comprised 56.0% and 57.3% in each group, and all patients had KPS > 60 at the start of the study treatment.

Methodology

Generation of CIK cells
For the autologous CIK immunotherapy group, peripheral blood (> 120 ml) was collected from each patient at least 2 weeks before administration. Mononuclear cells were separated and cultured for 12-21 days with IL-2 and immobilized monoclonal antibody to CD3 at 37°C. The CIK cell agent contained a total of 109~2 x1010 cells in 200 mL of fluid consisting of 1% human albumin in normal saline.
Immunotherapy group
Immunotherapy group received CIK cell agent intravenously over 60 min, and were then observed for at least 30 min. They were scheduled to receive CIK cell agent 14 times (4 times at a frequency of once a week, followed by 4 times every 2 weeks, and finally 6 times every 4 weeks). CIK cells were administered at an outpatient clinic.

Treatment

Standard TMZ chemoradiotherapy protocol
Standard TMZ treatment included concurrent radiotherapy (60 Gy administered as 2-Gy fractions 5 days per week) and chemotherapy with TMZ (75 mg per square meter of body-surface area per day for a maximum of 49 days). Maintenance treatment with TMZ began 4 weeks after the completion of radiotherapy at a starting dose of 150 mg per square meter for 5 consecutive days of a 28- day cycle, with an increase to 200 mg per square meter for subsequent cycles if treatment-related adverse events of grade 2 or higher were not noted. Maintenance TMZ was administered for up to 6 cycles.

Results

Efficacy outcomes
In intent-to-treat (ITT) set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group. The progression-free survival (PFS) rates with CIK immunotherapy group and control group were 28.3% and 22.6% at 1 year, and 18.4% and 13.4% at 2 years, respectively.In PP set, median PFS was 8.1 months (95% CI, 7.1 to 8.9 months) in the CIK immunotherapy group and 5.4 months (95% CI, 4.0 to 7.9 months) in the control group.
The median overall survival (OS) was 22.5 months (95% CI, 17.2 to 23.9 months) in the CIK immunotherapy group, as compared with 16.9 months (95% CI, 13.9 to 21.9 months) in the control group,There was no significant difference in the ORR including complete or partial response between groups (27.1% vs. 15.9%). However, a significant difference was found between groups in the DCR including complete response, partial response, and no change (82.4% vs. 63.4%).
Safety
Treatment-emergent adverse events (TEAEs) of any grade were reported in 84 (98.8%) of patients who received CIK immunotherapy group, and 83 (97.6%) of the control group. The incidences of total and ≥ grade 3 were higher in the CIK immunotherapy group than the control group. There is no significant difference in the rate of serious adverse events (41.2% vs. 36.5%, P = 0.5290), and in the rate of ≥ grade 3 adverse events (47.1% vs. 36.5%, P = 0.1616). The incidences of total and ≥ grade 3 adverse drug reactions (ADRs) associated with CIK immunotherapy group was 16 patients (18.8%) and 3 patients (3.5%), respectively (7 events). Each case involved neutropenia in 5 events from 1 patient, pneumonia in 1 case, and acute renal failure in 1 case.

Conclusion

The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

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Scientific article publishing date :9/27/2016

Immucura identifier BSC21_228EN

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