Children with diffuse midline gliomas (DMGs) – a type of brain cancer – continue to have a dismal prognosis, and most children die within one year of diagnosis. Recent studies have shown that the majority of these tumors carry a specific mutation referred to as H3.3K27M. Researchers have shown that this specific mutation is present in almost all DMG tumor cells but not in normal cells within the body, making this an attractive target for immunotherapy approaches that activate an immune response against the cancer cells. Immunotherapy has shown phenomenal improvements in the outcome of adults and children with specific types of cancers, such as melanoma and leukemia. However, we are just starting to implement such novel and promising approaches for DMGs in the clinic.

With this proposal, we will test the benefit of a specific immunotherapy approach referred to as adoptive T-cell transfer, which gives the patient a large number of killer T cells. More specifically, we will test an approach known as engineered T-cell receptor (TCR) therapy, in which killer T cells are engineered to be specific to a piece of protein on the surface of tumor cells.

We have been able to show in the laboratory that we can make T cells specifically recognizing DMG cells with the H3.3K27M – and that these specific T cells can kill tumor cells. Based on these exciting data, we propose to test this new therapy approach in the clinic. Participants who are newly diagnosed with an H3.3K27M DMG are eligible for this clinical trial. They will undergo collection of their own T cells, and these T cells will subsequently be engineered in the laboratory to recognize the specific H3.3K27M mutation. These modified T cells will then be given back to the participants once they have completed standard-of-care radiation therapy and a conditioning short chemotherapy course. We hypothesize that these modified T cells will now be able to kill the cancer cells carrying the specific H3.3K27M mutation.

Within this project, we will assess if such a therapy approach is feasible and safe. Precisely, we will test how many of these specifically modified T cells are able to be given back to participants without causing too many side effects. Further, we will perform specific tests from blood samples from trial participants to assess how long these modified T cells survive. To better understand responses, we will use advanced molecular technologies to assess the blood of participants. This information will help us to improve our ability to assign patients to the right therapies and make even more effective tumor-targeting T cells in the future.

This project has the potential to significantly impact the treatment approach for a disease for which we have not achieved any improvement for the last several decades and is the first of its kind for this devastating disease.

Malignant brain tumors carry a dismal prognosis despite surgery, chemotherapy, and radiation, hence new therapeutic approaches are needed. New strategies are being investigated using modified viruses (termed “vectors”) to infect cancer cells and deliver genes that serve as blueprints to make therapeutic proteins inside the cancer cells themselves.  

Until recently, most researchers used viral vectors that could deliver therapeutic genes to the initially infected tumor cells but are rendered incapable of infecting any additional cells. However, such ‘non-replicating’ vectors were found to have limited benefit, because not enough tumor cells could be reached.  

A newer approach is to use virus vectors that actively replicate themselves and can spread forth from the initially infected cancer cells within tumors, but not in normal tissues, thereby continuing to infect more cancer cells even as the cells continue to proliferate. These tumor-selectively spreading viruses are used to deliver a “suicide gene,” which converts a non-toxic ‘trigger’ compound (“prodrug”) into a DNA synthesis-blocking chemotherapy drug. Because this virus causes the chemotherapy drug to be generated selectively and directly within the infected tumor itself, there are few adverse side effects.  

The first version of this type of therapeutic virus has shown highly promising results in early-stage clinical trials and is currently being tested in an international Phase 2B/3 trial for recurrent brain cancer. 

We recently discovered that this approach can also activate the immune system to attack tumors. Hence, in this Alliance for Cancer Gene Therapy funded study, we examine whether brain tumors that show a high rate of new mutations, which can be recognized by the immune system, may be correlated with better responses to this treatment.  

We also propose to develop a new tumor-selectively spreading virus vector that delivers a different “suicide gene” which cross-links DNA and thereby generates new mutations for the immune system to attack, and we further propose to combine this mutagenic DNA cross-linking suicide gene therapy with strategies to overcome immune blockade (“checkpoint”) mechanisms within tumors.  

Finally, we will conduct preclinical studies to evaluate the safety of this new virus vector for use in a future clinical trial. If the proposed preclinical studies are successful in validating the safety, efficacy, and mechanism of action for this new immunogenic suicide gene therapy, combined with immune checkpoint inhibition, we anticipate that this approach can be rapidly translated to the clinic in collaboration with a biotech partner that is already testing our previously developed virus vector in clinical trials.  

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.