INTERFERON-ALPHA ENHANCES TEMOZOLOMIDE ANTI-GLIOMA EFFICACY: FROM BENCH TO BEDSIDE

O6-methylguanine DNA methyltranferase (MGMT) is one of the main mechanisms of chemoresistance for alkylating agents in malignant gliomas. Treatment for MGMT positive glioma is still challenge in clinical practice. We firstly tested anti-tumor efficacy of IFN-α combined with temozolomide (TMZ) in vitro and in vivo on 2 MGMT protein positive glioma cell lines. Then, we have launched a clinical trial “Adjuvant Temozolomide with Interferon-alpha in Newly Diagnosed High-grade Gliomas” (ClinicalTrials.gov ID:NCT01765088). The patients (WHO grade III/IV), received tumor resection and radiotherapy concurrent with TMZ, will be randomized assigning to receive up-to 12 cycles of standard TMZ chemotherapy alone or combined with IFN-α (3mIU on Day1,3,5 of each cycle). The proliferation analysis demonstrated that MGMT positive glioma stem cells (U251G and SKMG-4G), treated with TMZ or TMZ plus IFN-α resulted in inhibition rates of 16.13%±2.33% vis 57.95%±1.54% (U251G), and 57.74%±2.91%(SKMG-4G), respectively(p<0.05). The tumor growth repression rates of TMZ group, TMZ+IFN-α group on U251G xenografts were 16.7%±1.96% and 41.1%±8.66%，and on SKMG-4G xenografts were 35.2%±2.28% and 58.4%±4.34% respectively (Ρ<0.05). On clinical trail, 168 cases (WHO III, 81 cases and WHO IV, 87 cases) have been enrolled till March of 2016. Follow-up to end of 2016, 105 patients had tumor progression including 65 deaths. Survival analysis revealed that in grade III patients, OS and PFS in TMZ group and TMZ+ IFN-α group were 28 vis 36 months(p=0.16), and 16 vis 25 months(p=0.17), respectively; while in GBM patients, that were 24 vis 16 months(p=0.04), and 11 vis 9 months (p=0.17), respectively. Our results indicate that IFN-α could enhance anti-tumor efficacy of TMZ to high grade gliomas.