Research And Grants

Multilamellar H3K27M RNA aggregates targeting diffuse midline glioma, including diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma/midline gliomas (DIPG/DMG) are fatal brain cancers in desperate need of new treatments, and while immunotherapy has held intriguing promise, thus far its potential has not been fully realized. Messenger RNA, the messages that communicate instructions from DNA to the rest of the cell, have been harnessed to treat and prevent infections such as COVID-19; however, this modality has been unable to overcome DIPG/DMG's ability to evade the immune system or conquer the environment that protects the tumor.  

We have thus developed an innovative vaccine based on a unique packaging and presentation system (called lipid-nanoparticle aggregates, or LPAs) that layers the stimulating RNA into level after level of an onion-like cluster. Instead of injecting particles, this technology allows injection of clusters of particles wrapped around each other like onion layers.  This has now been shown to intensely stimulate pre-existing immune responses as well as to initiate new ones in a much more profound way than previous particle injection could.  In this proposal, we chose H3K27M RNA (the mutation which is the hallmark of almost all DIPG/DMGs) to elicit immune responses against these tumors; by using these H3K27M LPAs, we expect to rapidly reset the immune system and unlock immune cell attack against any cell harboring this mutation.  We have already seen that these unique LPA assemblies activate multiple cellular pathways resulting in huge waves of immune cells being recruited to tumor sites.  

This has been demonstrated in a trial for dogs with brain tumors, where vaccines with the same unique presentation package, but incorporating the total RNA library from tumor cells, had few side effects but had some remarkable responses.  A similar vaccine has also been given to four adults with newly-diagnosed glioblastoma.  Each of the adult patients had a significant, body-wide activation of the immune system, sometimes resulting in symptoms related to the immune activation.  In one of those adults, the tumor was taken out after vaccine because of concerns about tumor growth, but the mass instead revealed massive infiltration with attacking immune cells and little to no viable tumor.  It is particularly exciting to see each patient’s (dog or human) immune system so effectively stimulated with these approaches, which was also seen in the successful CAR T cell approach for leukemia, but intriguingly has not been seen in most previous pediatric brain cancer immunotherapies.

Logistically, these vaccines are suitable for large-scale production without the need for obtaining cells from the patient, and by targeting the H3K27M DMG alteration, can be essentially off-the-shelf vaccines that can be leveraged in multiple future combination strategies with a near-unlimited dosing schedule.

Thus, our current trial will be focused on DMG, including DIPG, and will be a safety and feasibility study.  The concept has already been preliminarily received favorably by the Pediatric Brain Tumor Consortium, a group comprised of sixteen of the leading pediatric brain cancer institutions in the United States and Canada.  In order to initiate the trial, FDA approval will be needed; however, the product itself will require starting funds in order to generate product approved for human use.  While there will be significant costs to generate vaccines for patients, for the execution of the trial and for the immune correlate tests that will help understand and rapidly optimize this treatment approach, this current application is solely for the funding in order to generate vaccine to obtain initial FDA approval so that we can move this trial forward quickly.