Abstract
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.