Research And Grants
CONNECT Consortium - $278,619
Dr. Rachid Drissi
Immuno-Modulation to Treat Poor-Prognosis Pediatric Brain Tumors
There is encouraging rationale to incorporate immunotherapy into the treatment of high-risk pediatric brain tumors. The addition of decitabine (DAC) and 4H2 (anti-PD1 in mice, the mouse equivalent of nivolumab) improved survival in high-grade glioma (HGG) mice and in ATRT models. Furthermore, our data showed accumulation of myeloid cells during tumor progression in our model and all the treatment groups exhibited reduced tumor growth and myeloid cells.
While our data demonstrate that DAC is an effective drug in our DIPG syngeneic model, its mode of action seems to be independent of T-cell activation-mediated killing as shown by immunohistochemistry and flow-based analysis of tumor infiltrating lymphocytes and myeloid cells. Therefore, the evaluation of the mechanism of action of DAC and 4H2 in our model is crucial for a clinical trial design involving these drugs. To this end, we plan to conduct CyTOF analysis to evaluate the presence of immune markers in collected tumors specimens and evaluate in vivo the mechanism of action of DAC and DAC+4H2.
We therefore hope to complete currently ongoing preclinical studies to ensure adequate numbers of mice are treated per arm so that we can press forward with adopting this as a critical arm within the previously mentioned molecularly-guided CONNECT phase II umbrella trial, TARGET. In addition, Dr. Annie Huang will also explore the efficacy of the combination of DAC and 4H2 in ATRT models for consideration of a future clinical trial through CONNECT.