Post-doctoral Fellowship Grant Awarded to Iker Ausejo Mauleon

CAR-T cell therapy, a promising approach to treating Diffuse Midline Gliomas (DMG), is facing challenges
in reaching its full potential. These engineered immune cells often become exhausted and don't last long
enough in the tumor environment to effectively attack the cancer. This could be because the DMG tumor
microenvironment (TME) lacks inflammation, making it unsuitable for CAR-T cells to function properly.

Additionally, prolonged activation of the CAR-T cells causes them to express receptors like PD-1 and TIM-
3, which slow down their activity and lead to exhaustion. This project aims to overcome these obstacles by

combining CAR-T cells with a TIM-3-blocking antibody. Pre-clinical studies demonstrated that blocking
TIM-3 can make the tumor environment more supportive and inflammatory, which would help CAR-T cells
work more efficiently and avoid exhaustion. The goal is to develop a safe and effective therapy for DMG,
especially since young patients are at risk of experiencing motor and cognitive side effects from CAR-T cells
treatments. We will evaluate how well the CAR-T/TIM-3 combination works in eliminate tumors and its
safety in pre-clinical orthotopic models of DMG. In addition, we will closely examine any side effects on
motor and cognitive function, looking at brain inflammation and immune cell activity. If issues like cognitive
impairment arise, we will explore potential neuroprotective treatments, including our previously patented
method. Overall, this project aims to enhance CAR-T cell therapy for DMG with a synergic therapy that has
been previously demonstrated anti-glioma effect, making it both more effective and safer for patients,
particularly in protecting brain function.