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Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Development of immunocompetent animal models for pediatric high-grade glioma and diffuse intrinsic pontine glioma
Translational
Brain Tumors (General), DIPG, Childhood (Brain Cancer)
Lay Summary

Brain tumors are the leading cause of cancer-related death in children, with high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) carrying the worst prognosis, with no chance of cure. Over the past years, the prognosis of other aggressive cancer types has improved thanks to scientific breakthroughs in the field of immunotherapy. In cancer, damaged cells have attained the ability to ‘escape’ the immune system, whereas they would normally be recognized as damaged, and destroyed by white blood cells.

The goal of immunotherapy is to help the immune system recognize and destroy cancer cells, as they would do with bacteria or virus-infected cells. This strategy has proven successful in the past years in treating advanced stages of, for example, lung cancer and melanoma. In pHGG and DIPG, however, this strategy has only been tried in small sets of patients, without much success, probably due to a lack of understanding of the immune response to these cancers. This lack of understanding is largely because of the absence of relevant animal models to study the immune system in pHGG and DIPG. This proposal aims apply cutting-edge technology to develop the necessary models to study immunotherapy for these devastating tumors.

Currently, most animal models to study pHGG and DIPG consist of so-called patient-derived xenograft models. In these, tumor cells from a patient are injected into the brain of mice to form a tumor. However, these tumors will be rejected by the immune system of the mouse, in a similar fashion as in which organs are rejected in patients if they are not receiving treatment to suppress the immune system. Therefore, we inject the tumor cells into the brain of mice that have been genetically engineered to have no functioning immune system. This allows for the study of many aspects of the disease, including efficacy of drugs, but has one severe limitation; the absence of the immune system precludes the use of these xenograft models for the study of immunotherapy.

Recent advances in our understanding of the development of pHGG and DIPG have allowed us to develop a new generation of mouse models for the study of these tumors. Based on the hypothesis that pHGG and DIPG originate during the development of the brain in the embryo, the Phoenix laboratory has developed a technique that allows us to introduce the typical genetic mutations found in these tumors in stem cells in the brain of embryonic mice. In this way, the mice develop pHGG and DIPG tumors that perfectly recapitulate the disease as it is found in humans. The major advantage of this technique is that it can be applied to generate tumors in mice that have an intact immune system, therefore allowing the study of immunotherapy. However, the technology is advanced and requires a high level of expertise in a specialized facility. Therefore, we here propose to develop stem cell cultures from these mouse tumors that are capable of forming tumors when injected in the brain of genetically identical (syngeneic) mice, a procedure that can be performed more easily. Since we will share these stem cell cultures with other research groups, more immunotherapy studies in relevant pHGG and DIPG models can be performed by various laboratories. Furthermore, the availability of such cell cultures will allow for the study of these cells in the laboratory, under controlled circumstances, before therapies are tested in the animals, limiting the amount of animals necessary.

In our proposal, we aim to develop brain tumor models for use in mice with intact immune systems, that represent all major subtypes of pHGG and DIPG that occur in patients. Additionally, we aim to evaluate the efficacy of nivolumab: the most used, and most promising, immunotherapeutic drug currently available in the clinic, using these models. The results of this study will allow the promise of immunotherapy to be extended to children suffering from these highly aggressive brain tumors.

Executive Summary

Tumors of the central nervous system are the number one cause of cancer-related death in children. Among these, high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) carry the worst prognosis, and to this day no curative treatment is available. In recent years, major steps forward have been made in the treatment of other aggressive cancers, with the introduction of effective immunotherapeutic strategies. However, the promise of immunotherapy has not yet been extended to pHGG and DIPG, as research is hampered by the lack of relevant preclinical models of these tumors that recapitulate the antitumor immune response.
In this proposal, we aim to fill this critical gap by developing immunocompetent models of pHGG and DIPG. For this purpose, we propose to use our recently developed intra-uterine electroporation (IUE) techniques to generate pHGG and DIPG tumors in mice that accurately reflect the genetic and phenotypic background of these tumors in children (Aim 1). The Phoenix laboratory has extensive experience in generating such models, and we expect to obtain the most important tumor models within 2-3 months after start of the project. Next, we will establish stem cell cultures from these tumors that are capable of engrafting in syngeneic immunocompetent animals (Aim 2), which will allow for the preclinical study of homogeneous, clinically relevant, pHGG and DIPG tumors in the presence of an intact immune system (Aim 3). Since tumor stem cell culture and intracranial implantations are routinely performed in our laboratories, we do not expect any difficulties in performing these experiments. Finally, we will use these newly developed models to perform a preclinical immunotherapy study using the checkpoint inhibitor nivolumab, to evaluate the potential of this form of therapy for the treatment of pHGG and DIPG and thereby steer future research in the right direction (Aim 4). These experiments will be performed in the last part of this project. Importantly, the models that will be created in this project will be shared with the international pHGG/DIPG community to enable other research groups to perform additional  immunotherapeutic studies in a preclinical setting.

In summary, this proposal combines the expertise of two laboratories that will both exploit their own strengths, with the Phoenix laboratory generating pHGG and DIPG models by intra-uterine electroporation, and the Hulleman laboratory generating stem cell cultures and xenograft mouse models. The Hulleman laboratory will also be responsible for the execution of the initial preclinical immunotherapy trials.

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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