Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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Exploring Combination Therapy for DIPG: SGI-110 and GAA Vaccine
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Diffuse intrinsic pontine glioma (DIPG) are some of the deadliest childhood brain tumors. The immune system protects the body by recognizing targets on harmful cells, but tumor cells can “switch off” the targets and hide from the immune system. We have been using a vaccine that can target pediatric brain tumor cells with precision. This is valuable because recently it has been found that activating the immune system without specifically targeting the DIPG may cause dangerous inflammation at the tumor site. We also recently found that a new drug called SGI-110 could “switch on” the targets on the tumor cells in a mouse model. So now we have a vaccine and a potentially target-enhancing drug. This project will test them together to see whether SGI-110 improves the success of the vaccine. We will test it in a new mouse model of DIPG that we created. We also will test which is better: to inject the SGI-110 under the skin or into the spinal fluid, which might help it avoid potentially degrading enzymes. If successful, our data would support an entirely new approach to treatment that will be tested in a clinical trial and may provide hope for children with DIPG.

Executive Summary

Scientific Merit
The overall goal of our proposed study is to evaluate the potential of SGI-110, a DNA methyltransferase (DNMT) inhibitor, to immunosensitize diffuse intrinsic pontine glioma (DIPG) cells to peptide vaccine immunotherapy. A clinical trial using SGI-110 as a monotherapy for DIPG patients is currently in development. A wealth of data from our group and others demonstrate that SGI-110 can overcome some of the key barriers facing peptide vaccine immunotherapy by increasing the expression of MHC, tumor antigens, and other immunosensitizing molecules. Additionally, based on recent supporting data in a non-human primate, we will examine whether intrathecal delivery of SGI-110 may allow for increased CSF exposure and be more effective than the commonly used subcutaneous route of administration. Following successful completion of this proposal, we plan to initiate a clinical trial combining our peptide vaccine immunotherapy with SGI-110. SGI-110 is a DNMT inhibitor that is highly stable compared with other DNMT inhibitors and allows for slow release of its active agent. Additionally, we will use our newly developed syngeneic DIPG-relevant models, including a model developed in AAD mice expressing HLA-A2.1.
          Immunotherapy has demonstrated significant promise and cures in multiple cancer types. Nevertheless, results with primary brain tumors have been far from ideal. Although the immunosuppressive landscape of DIPG is still an active area of investigation, it is well known that tumors, including those in the brain, reduce expression of MHC and immune-attracting molecules, to avoid immune-mediated killing. Numerous studies have shown that the use of DNMT inhibitors can immunosensitize tumor cells, but these inhibitors may be rapidly degraded in the patient. Therefore, our proposed study seeks to combine a stable DNMT inhibitor, SGI-110, with a promising immunotherapy approach that relies on antigen and MHC expression.

Feasibility
In March 2018, we received SGI-110 from Astex [under an agreement from the NCI Cancer Therapy Evaluation Program (CTEP)] and synthesized peptide for the murine vaccine. Over the course of 2018, we have developed 2 models of mouse syngeneic Histone 3.3 K27M-induced glioma to use for the proposal. The investigator successfully performed stereotactic implantation of glioma cells near mouse pons. With all reagents and mouse models in hand, we are ready to initiate and complete the proposed experiments within 1 year.

Expertise
The Principal Investigator (Dr. Gary Kohanbash, PhD) for this proposal has extensive experience in glioma immunobiology and peptide vaccine immunotherapy, including the development of a neoantigen-targeted peptide vaccine approach for children with DIPG. Ian Pollack, MD, Chief of Pediatric Neurosurgery at Children's Hospital of Pittsburgh and Distinguished Professor of Neurosurgery at the University of Pittsburgh, will serve a collaborator for this proposal to assist in project oversight and future clinical trial development. Additionally, Research Assistant Lauren McCarl has a bachelor’s degree in biochemistry and molecular biology and has been evaluating SGI-110 on glioma cells since March 2018.    

Description of Research Proposal

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.