Focus: Pediatric Brain Cancer

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.

Brain tumors are the most common solid tumor in children and represent the leading cause of death from childhood cancer. Diffuse intrinsic pontine gliomas (DIPG) are a highly aggressive pediatric brain tumor of the brain stem, with a five-year survival rate of less than 1% and median survival of only 9 months. While significant improvement in survival has been achieved in treating other forms of brain cancer, the outcome for children with DIPG has remained poor, and has not changed in over three decades.  

The major challenge in the treatment of DIPG is its extremely invasive nature and delicate anatomical location in the brain stem, which precludes surgical removal. Previous research has shown that transplanted neural stem cells (NSC) possess remarkable tropic migratory capacity toward adult brain tumors, but the use of NSCs in clinics is severely limited by the ethical and technical challenges to obtain these cells in human. Furthermore, current approaches rely on viral-based vectors for delivery of therapeutic genes, which face safety concerns for broad clinical applications. While gene therapy targeting tumor apoptosis has been shown to be effective in eradicating adult brain tumors, pediatric brain tumors including DIPG, easily gain drug resistance to apoptosis inducing-based gene therapy alone.  

Through working at the interface of biology, material science, bioengineering and medicine, this Alliance for Cancer Gene Therapy funded research will develop a novel treatment regimen to enhance targeting and eradication of disseminated DIPG tumor by directing addressing the current critical bottlenecks in the field of cancer gene therapy.  

To overcome the critical barrier of cell availability by employing adipose-derived stem cells (ADSCs), an abundant and easily accessible autologous stem cells source as drug delivery vehicle for targeting DIPG cells in vivo.  

Unlike the conventional, viral vector-based cancer gene therapy, the proposed strategy employs non-viral gene delivery using biodegradable polymeric vectors, a platform well established in the applicant’s laboratory.  

To overcome drug resistance commonly observed in treating pediatric brain tumors, this approach employs a combined therapy by co-delivering non-viral engineered stem cells with nanoparticles containing chemotherapeutic drugs, which has been found to enhance the responsiveness of pediatric brain tumor cells to gene therapy.  

The outcomes of the proposed interdisciplinary approach may advance care for DIPG in ways that would not be possible using conventional treatment paradigms. This will lead to improved survival for patients of DIPG, one of the most deadly forms of pediatric brain cancer and may substantially reduce the associated socioeconomical burden on our society. While the proposed work will initially focus on DIPG as a model disease, the proposed strategy to enhance targeting and treating cancer metastasis may be adapted for treating a broad range of other cancer types as well. 

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