New Investigator Grant Awarded to Leo Wang

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the care of blood cancers and there is tremendous enthusiasm for using this new treatment to help children with diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). Ongoing clinical trials, including at City of Hope, have shown encouraging initial results. However, none of these trials has yet definitively cured a patient, and most patients unfortunately have both limited and transient responses. Improvements to this promising therapy are badly needed. Part of the challenge is that brain tumors are more complex than blood cancers and are more hostile to immune attack.
Fundamentally, successful immune therapy against DIPG/DMG must do three things. First, there must be immune cells that recognize and kill tumor cells. Second, those immune cells must be able to trigger an amplified immune response. Third, the tumor must be prevented from evading or dampening that immune response. This project addresses these challenges in several ways. First, structures called tertiary lymphoid structures (TLSes) are sometimes found in brain tumors, and their presence correlates with improved clinical outcomes. TLSes are lymph node-like structures that have been shown to optimize and amplify immune reactions, and we hypothesize that this improved immunity will lead to better responses. Thus, we propose to induce TLS formation in
DIPG/DMG to improve immune reactions. Second, we have shown that a drug called decitabine makes DIPG cells more amenable to immune attack; this drug does not penetrate the blood-brain barrier, and delivery into the cerebrospinal fluid (CSF) has only been tested in non-cancer conditions. We propose to test delivery of decitabine directly into the CSF to prevent DIPG/DMG cells from avoiding immune attack. Additionally, decitabine treatment increases the expression of a protein called IL13RA2, to which we have designed CAR T cells, currently being tested in clinical trial at City of Hope.

We hypothesize that combining TLSes with decitabine and CAR T cell therapy will further improve our ability to combat DIPG/DMG. We expect that successful completion of this project will greatly advance the field of CAR T cell therapy for pediatric brain tumors by creating advanced cellular therapies capable of sparking a potent and sustained antitumor immune response. We hope to move these promising new therapies into clinical trial within three years.