Ependymoma research is the reason Tanner Seebaum Foundation exists. We are fortunate to have the opportunity to support the promising research taking place at Children’s Hospital Colorado with Pediatric Neuro-Oncologist Dr. Nick Foreman and his team. Research for effective treatments of Ependymoma tumors is highly technical and typically under-funded. Below is a note from Dr. Foreman and below that are descriptions of research funded by Tanner Seebaum Foundation.
A Summary of Funded Ependymoma Research
As reported by Dr. Nick Foreman, Fall 2016
The Tanner Seebaum Foundation (TSF), for over 10 years has supported the development of new, innovative therapies for Ependymoma brain tumors. The need for such therapies in recent years has become acute as outcomes for the most common type of Ependymoma, known as Group A remains very poor; even with the use of surgery and re-radiation at recurrence. This type of Ependymoma is the overwhelmingly predominant type in very young children.
My laboratory has been interested in the development of immunotherapy for Ependymoma over many years. TSF has supported this effort from its early stages in helping my team with understanding how to better treat Group A Ependymoma through focusing on immune system responses. In particular, we have sought to find out how monocyte immune responses allow tumors to grow and become invasive. Moreover, in Group A Ependymoma, T cells (an important part of the immune system) become “exhausted” and inactive. Based on this, the idea occurred to the research team at an early stage to explore treating Group A Ependymom by “flipping” the immune type from pro-tumor to anti-tumor type as a means to dramatically improve outcomes. In order to make this idea practical and move it from concept to the clinic was the work of many years, but now a reality with the support of TSF.
We have now opened in the clinic at Children’s Hospital Colorado our second phase immunotherapy trial using an antibody therapy delivered directly to the fluid around the brain and spinal cord, with concurrent immune cell stimulation. We have evidence in the laboratory this approach will “flip” the monocytes making them anti-tumor. This second phase trial is considered to be innovative to the extent the federal authorities want close and extensive monitoring in all centers where the trial will open. Centers such as Boston Children’s, St. Jude’s, Lucie Children’s in Chicago and Arnold Palmer Hospital in Orlando are eager to open this trial and are convinced of its merits. This has only become possible with the recent large donation by TSF to enable this close monitoring.
Looking towards the future, we envision continued improvement in this immunotherapy over successive trials until it achieves the successes that have been seen with immunotherapy in disease with adult head and neck treatments where it is replacing conventional chemotherapy altogether. The laboratory has shown, with TSF support, that the T cell exhaustion can be reversed with the new check point inhibitors. These agents are recently approved in certain adult tumors. Using the data from our laboratory, there is now a real possibility that these agents will be available for an Ependymoma early phase trial, allowing them to be added to the our immunotherapy offerings in the future.
On a different note, we have succeeded in our persistent effort and with TSF support in at last establishing two Ependymoma cell lines that allow for expanded research of this tumor. These two cell lines have the cytogenetic abnormality where they have gained as extra arm of 1q+. This gain of 1q+ is associated with a very poor outcome in children with Ependymoma. We have screened a large number of approved medications against these lines comparing how well they responded to such treatments compared to other lines we have established from such tumors as Glioblastoma, Medulloblastoma, AT/RT and DIPG. We have found one, called axitinib, to which these 1q+ ependymoma lines are uniquely sensitive. We are in the process of prosposing to a national consortium a trial of this agent against Ependymoma.
None of this work would have been possible without the support of TSF. We are fully committed to finding new and effective therapies against childhood Ependymoma and improving outcomes. Our mission, together with TSF, is to ensure that families should no longer be in fear of relapse which currently remains all too common in childhood Ependymoma – especially in very young children.
In addition to promising new research, Tanner Seebaum Foundation has also funded other important studies and trials since 2006. A summary of this work follows.
Identification of gene mutations that cause Ependymoma recurrence. Standard therapy for Ependymoma is surgery and radiation, with approximately 50% of patients suffering from recurrence within 3 years. Work looking at genetic mutations in tumor diagnosis has been attempted, but nothing is known about the genetic changes or mutations that may have occurred in the tumor when it returns. This is in part due to the lack of genetic information. This study focuses on NextGen Sequencing to read the entire genetic code, or DNA sequence, in Ependymoma at initial presentation and compare this to the genetic information and compare this to genetic code tumor at recurrence in the same patient.
Immunohistochemical analysis of immune related factors in Ependymoma. Based on microarray analysis already performed by our lab, we have found that immune response-related genes are highly over-expressed in non-recurrent Ependymoma when contrasted against recurrent Ependymoma. In order to further study the role of the immune system in Ependymoma that respond to treatment, we will perform an immunohistochemical analysis of recurrent and non-recurrent Ependymoma. Analysis will be performed on 16 Ependymoma specimens (8 recurrent and 8 non-recurrent) and interpretation of results will be performed with the help of neuro-pathology collaborators.
Molecular and cellular profiling of the Ependymoma tumor microenvironment. The brain tumor microenvironment is largely unexplored, yet recent evidence suggests that it has a critical role in Ependymoma tumor growth and patient outcome. Leveraging the prior support obtained from the Tanner Seebaum Foundation in year one of this project (where we examined the basic science behind the immune system role in attacking Ependymoma tumors), we are now expanding our base of knowledge regarding how to use the immune system in a therapeutic context. We have begun systematically characterizing cellular and molecular components of the microenvironment of tumor specimens from Ependymoma patients. Using gene expression microarray, histology and bioinformatics techniques, we are creating a pool of information that our team will use and share with other researchers on the Anschutz Medical Campus as well as around the world. The data will allow us to measure the abundance and differential gene expression in cellular microenvironment constituents of whole tumor microarray data. This project also includes a translational study, whereby we correlate the data with patient diagnosis and outcome, allowing us to determine future research directions and devise innovative treatments for Ependymoma patients. In addition, we plan to use a recently developed DNA sequencing technique called pyrosequencing that will enable us to identify how the immune system recognizes and kills Ependymoma cells in those patients with a good outcome. We believe that pyrosequencing can identify a unique target that is present only on Ependymoma tumor cells. This, in turn, would provide the basis for new therapies that would direct the immune system to attack only the Ependymoma target and not the surrounding cells. This approach was recently shown to be clinically effective in treating lymphoma patients for whom other treatment options were ineffective. If we can succeed in “arming” the body’s T-cells to attach the tumor, we can move quickly into making clinical grade T-cells for therapeutic use. We plan to set up both a national trial and a smaller local trial that uses immune therapy alone (in contrast to immune therapy in conjunction with more traditional therapies) for those diagnosed with the lowest risk form of Ependymoma (those in whom we already know the immune system will play a role in fighting the tumor). One result of these studies will be new immune-only therapies that will avoid radiation for low and moderate risk patients without diminishing their survival rate.
Phase II study of the intrathecal use of Herceptin in the treatment of pediatric Ependymoma. This study will enroll children in the first study to test the use of Herceptin in a pediatric context for the treatment of recurrent Ependymoma. The grant will offset the significant expense of actually enrolling children and implementing the study. Once enrolled, participants will receive Herceptin and as a value-added measure. The Herceptin costs will be covered by the manufacturer.
Protoeomic analysis of recurrent versus non-recurrent Ependymoma. Using a technique called proteomics we will compare levels of proteins, key factors in the growth of tumors, between those Ependymoma that responded to treatment and those that did not. This technique has the advantage that it measures almost every protein in the tumor, unlike other techniques which are only capable of measuring one protein at a time. This technique accelerates the discovery of factors important in the growth of Ependymoma and our understanding of how treatment for the tumor works in those patients that are cured. This will help the medical profession devise better treatments for those patients whose tumors are likely to re-grow.
Trial of GM-CSF in Ependymoma. We have confirmed that there is a connection between the number of a type of immune cell invading the tumor and the length of survival in children with Ependymoma. We have recently shown in the lab that we can drive up these beneficial immune cells using an immune system stimulating compound, GM-CSF, in patient samples obtained from surgery. Given these results, we have designed a clinical trial to give prior GM-CSF to children requiring surgery as second look or at first relapse to see if we can increase the number of the beneficial immune cells in patient tumors.
Understanding abnormal NF-kappa-B activity as a driver of tumor development. Dr. Foreman seeks to better understand how abnormal NF-kappa-B activity drives tumor development in Ependymoma, with the hope that he can help develop new treatments to block that activity in Ependymoma patients.
High-throughput screening to identify effective treatment strategies for high-risk Ependymoma. We are currently supporting the immunotherapy trial for Ependymoma, the concept for which was developed in Dr. Foreman’s lab and is now led, as the clinical Principal Investigator, by Dr. Dorris at Children’s Hospital Colorado. This immunotherapy trial is restricted to first relapse patients and TSF is extremely interested in, and committed to, supporting trials for children in second and subsequent relapses to discover effective combinations of agents.