IM-01 PI3K GAMMA INHIBITOR FOR OVERCOMING TREATMENT RESISTANCE IN COMBINATION THERAPY OF TEMOZOLOMIDE AND ANTI-PDL1 ANTIBODY FOR GLIOBLASTOMA PATIENTS

PURPOSE: Multidisciplinary therapies including immunotherapy in glioblastoma (GBM) patients often cause long survivor, while early relapse of GBM still remains. We should find factors associated with the immunotherapy-resistance for overcoming it. We previously reported that the infiltration of PD-1 positive cells and M2 macrophages (M2M&phi) increased in recurrent specimens compared to the initial specimens of GBMs treated with chemo-radiotherapy and autologous formalin-fixed tumor vaccine. Here we evaluate whether combination of novel immunotherapies, anti-PD-L1 antibody and M2M&phi inhibitor (IPI-549) inhibits growth of temozolomide (TMZ)-treated glioma cells rather than monotherapy. METHODS: Using murine glioma initiating cells (TS) and TMZ-resistant TS (TMZRTS) cells, PD-L1 expression and cytokine production associated with M2M&phi were evaluated. TMZRTS cells were implanted in mice flank, followed by anti-PD-L1 antibody and / or IPI-549 administration. RESULTS: Relative cell proliferation rate of TMZRTS cells was lower than TS cells, while PD-L1 mRNA expression was higher. Treatment with PD-L1 antibody caused marked infiltration of M2M&phi in glioma tissue. The combination therapy strongly inhibited tumor growth in TMZRTS murine model. CONCLUSION: The anti-PD-L1 antibody treatment altered tissue microenvironment including marked infiltration of macrophages in glioma tissue, probably associated with clinical immunotherapy-resistance in GBM. Combination therapy with anti-PD-L1 antibody and M2M&phi inhibitor could overcame it.