Effective brain cancer therapies remain a critically unmet need in human healthcare. Advances in surgical, radiation and chemotherapeutic treatments have done little to change patients’ outcomes in the past 30 years. Clearly, new approaches are needed if we are to control these diseases. Many groups worldwide have been exploring the use of viruses that can selectively replicate in and kill tumor cells without harming normal cells; these so called “Oncolytic Viruses” (OV) have shown some remarkable results in late-stage clinical trials.  

Despite this clinical success most OVs are inherently neurotoxic and are not safe to use with brain cancer. Recently we have discovered a new OV variant (a Chimeric Maraba virus) that is non-neurotoxic when injected directly into the brain of mice and that is also effective in a rodent model of brain cancer in vivo and human glioblastoma tumor cells in vitro.  

A current impediment to further clinical development of this virus therapy is the manufacturing capability to supply this virus at a scale and quality suitable for requisite small rodent and non-human primate safety/toxicity studies, and to provide the eventual clinical stock that will be used in our upcoming phase I clinical trial.  

This Alliance for Cancer Gene Therapy funded grant will aid in the design and validation of a GMP-manufacturing process for this virus, and will provide the resources necessary to generate, characterize and validate the virus lots needed to supply the in vivo toxicity studies in support of our clinical trial application, and to conduct our clinical trial.  

Brain cancer continues to be an unmet clinical need requiring novel treatments that are not merely palliative (surgery, radiation and chemotherapy) but potentially curative. A potent OV that can safely target the brain can potentially treat primary, metastatic and recurrent brain cancer improving quality of life and extending survival rates for patients suffering from this deadly disease.   

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

Re-activating and directing a cancer patient’s immune system to reject their tumors and eradicate the cancer with minimal toxicity to the patient is the ultimate goal of the cancer immunotherapy field. The field has made great progress, with multiple immunomodulatory antibody therapies already approved and more in the therapeutic pipeline. Additional progress has been seen in recent successful cancer treatment using genetically modified T cell-based therapy. These advances in cancer immunotherapy represent the clinical translation of research into the signals that activate and inhibit cells of the immune system, particularly T cells.  

We believe that through understanding the molecular mechanisms by which recent translational approaches have been successful we can establish a strong foundation for the rational design of new approaches to T cell cancer immunomodulatory therapy.  

Specifically, we believe that by investigating connections between two of the signaling molecules targeted in developing antibody and cell based Immunotherapeutics, PD-1 and 4-1BB, and two transcription factors critical to effective and durable T cell immune responses, T-bet and Eomesodermin (Eomes), we will identify T cell molecules and signaling pathways representing promising future targets in cancer immunotherapy.  

Our prior work has described the functions of T-bet and Eomes in determining T cell behavior in immune responses. Our preliminary data show that Eomes is essential to cancer immunotherapeutic approaches targeting either PD-1 or 4-1BB on T cells. In the proposed project we will determine how Eomes contributes to T cell anti-tumor activity and determine what, if anything, is needed in T cells beyond Eomes to enact a strong and durable anti-cancer response. The Alliance for Cancer Gene Therapy funded research will provide new insights into the mechanisms of cellular cancer immuno-modulatory therapy that we will use to design and test novel cancer immunotherapeutic approaches.  

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

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.