IMMU-39. COMBINATION OF RADIOTHERAPY WITH A 4-1BB AGONIST ANTIBODY AND A TIM-3 APTAMER RESULTS IN ENHANCED SURVIVAL IN A DIPG MODEL

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric tumors. Despite advances in targeted treatments radiotherapy remains as the standard treatment being just palliative. The lack of effective therapies represents a critical unmet need for many pediatric solid tumors. Cancer immunotherapy is an ideal alternative choice since the immune response is highly specific; it would persist along time creating memory and will get rid of infiltrative cells even if they are far away. 4-1BB is a major costimulatory receptor promoting the survival and expansion of activated T cells. Aptamers are high-affinity single-stranded nucleic acid ligands that exhibit remarkable affinity and specificity to their targets, comparable or exceeding that of antibodies. TIM-3 is a negative regulator of lymphocyte function that is involved in T-cell exhaustion. In this work we examined the anti-tumor effect of radiotherapy in combination with an agonist 4-1BB antibody and an aptamer against TIM-3. Of importance neither of the treatments resulted in fatal toxicities. Moreover, Combination treatment of 4-1BB with radiotherapy resulted in a significant improvement in survival in mice bearing DIPG orthotopic tumors when compared with single treatment. In addition, this combination led to long-term survivors (90 days). Currently we are performing rechallenge experiments in these animals. Further combination of radiotherapy, with the 4-1BB antibody and the TIM-3 aptamer, that released the immune suppression, is currently under study. At this point the combination between the three approaches showed lack of toxicity. Survival studies are on-going. Mechanistic studies performed on day 16 showed an increase in CD8 effector cells, a decrease in T-regulators Foxp3+ cells and an increase in INF-gamma expression suggesting the triggering of an antitumor-immune response. These results suggest that immuno-therapies approaches in combination with radiotherapy would be worth to explore in the treatment of deadly DIPGs.