Research Projects

It is now recognized that oncolytic viruses, including Delta-24-RGD, are potent anti-cancer immunotherapeutic agents, which act through direct oncolysis and by inducing an anti-glioma immune response. This paradigm-shifting concept implies that oncolytic viruses, including Delta-24-RGD, alter the immune tumor microenvironment (TME) and may therefore induce synergistic effects when combined with other immunotherapy strategies. We have recently engineered natural killer (NK) cells (called eCB-NK-TF-/GC- cells) for glioblastoma (GBM) which are resistant to tumor- and corticosteroid-induced immunosuppression by inactivation of TGFb-Receptor 2 and the glucocorticoid receptor 2, respectively, which is being evaluated in a phase 1 clinical trial in patients with recurrent
GBM. When combined with NK cells, we found that treatment with Delta-24-RGD increased the recruitment, anti-cancer activity, survival, and memory of endogenous NK cells and extended the survival of glioma-bearing mice compared with controls.

To test whether Delta-24-RGD treatment will actively contribute to enhancing the activity and memory of off-the-shelf eCB-NK-TF-/GC- cells resulting in strong anti-tumor activity without undue toxicity in patients with GBM we will:

1. Leverage the post-treatment biological specimens obtained from the window-of-opportunity arm of our ongoing Phase 1 clinical trial to evaluate the fate of eCB-NK-TF-/GC- cells as a single agent and to determine the associated immune changes in the TME of patients with recurrent GBM (Aim 1);
2. Explore the combination of Delta-24-RGD and eCB-NK-TF-/GC- cells in a variety of preclinical animal models to evaluate the impact on the TME in GBM (Aim 2); and
3. Execute a phase I clinical trial with a window-of-opportunity arm of intratumorally administered Delta-24-RGD in combination with eCB-NK-TF-/GC-cells in patients with recurrent GBM (Aim 3). 

Immunotherapies have so far not benefited patients with glioblastoma (GBM), largely due to abundant immune-suppressive GBM-associated microglia/macrophages (GAMs). Although heterogeneous, GAMs almost ubiquitously exhibit pro-tumorigenic states with
defective phagocytosis. We reasoned that therapeutically reversing the immunosuppressive features of GAMs and restoring phagocytosis would promote anti-tumor activity by enhancing their ability to digest and process glioma cells and present tumor-specific antigens to activate the adaptive immune system. By analyzing human and mouse GBM samples by single cell RNA sequencing,
we found that suppression of Quaking (QKI) is a universal feature in human and mouse GAMs and contributes to the impairment of the phagocytic activity of GAMs. QKI forms a complex called QPR, by interacting with peroxisome proliferator-activated receptor b (PPARb) and retinoid X receptor a (RXRa). QPR regulates unsaturated fatty acids (UFAs) synthesis, influences membrane fluidity and driving phagocytosis. Conditional knockout of Qki or PPARb in GAMs greatly impairs the phagocytosis of GAMs and enhances gliomagenesis by decreasing immune cell infiltration. Conversely, activating QPR through small molecule agonists of PPARb (KD3010) or RXRa (bexarotene) greatly enhances the phagocytic ability of GAMs and suppresses GBM growth in syngeneic glioma mouse models, demonstrating the therapeutic potential of these agents.

To test whether activating QPR with small molecular agonists will restore GAM phagocytosis, normalize the defective immune microenvironment of GBM and consequently halt GBM progression, we will:

1. Decipher the molecular mechanisms underlying the effect of QPR activators on phagocytic activity in GAMs in vitro (Aim 1);
2. Investigate the molecular and cellular effects of KD3010/bexarotene on GAMs in pre-clinical in vivo animal models (Aim 2); and
3. Perform a window-of-opportunity clinical trial to evaluate the therapeutic potential of bexarotene in patients with recurrent GBM (Aim 3).

In all, these studies will define QPR agonists as a new class of immunotherapeutics that can provide new hope for curing GBM by
overcoming the immunosuppressive tumor microenvironment that drives this dreaded disease.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is responsible for significant morbidity and
mortality in the United States. Of the different subtypes of MB, Sonic Hedgehog (Shh) is the most common. Patients with Shh-a
(mostly adolescents) who have TP53 mutations have nearly 100% mortality, and those with Shh-d (mostly adults) experience significant morbidity from standard treatment with craniospinal radiation and have extremely poor outcomes with limited treatment options at
recurrence.  We recently identified a unique somatic point mutation in a non-coding small nuclear RNA (snRNA) called U1 in 50% of Shh medulloblastomas. This mutation, U1 (r.3A>G), is found in 97% of Shh-δ tumors and >65% of Shh-α tumors with TP53 mutations. The U1 snRNA is an essential component of the spliceosome, and tumors with this mutation exhibit a unique form of post-transcriptional hypermutation which results in the expression of thousands of novel epitopes that are not expressed in normal human tissue. Hypermutant cancers are often responsive to immune checkpoint inhibitors (ICI) therapy, and the thousands of novel epitopes arising from transcriptional hypermutation are likely to be good candidates for CAR T-cell therapy. Therefore, we will:

1. Conduct a phase II clinical trial of nivolumab and ipilimumab in patients with Shh MB and correlate the clinical outcomes with U1 mutation status (Aim 1);
2. Identify novel tumor antigenic epitopes, characterize the tumor microenvironment and delineate the molecular biology of cells along the differentiation hierarchy in U1-mutant Shh MBs through state-of-the-art transcriptomic profiling and analysis (Aim 2); and
3. Prioritize U1-mutation driven tumor antigenic epitopes and use these epitopes to design, develop and test CAR T cells in preclinical models of Shh MB (Aim 3). 

Core A: Administrative Core

Co-Directors: Frederick Lang, M.D., and Juan Fueyo, M.D.
SPORE Administrators: Joanna Drennen and Preeti Ramadoss, Ph.D.

The Administrative Core provides critical centralized administrative support to ensure the success of the entire SPORE. The specific objectives of the Administrative Core are to:

• Oversee and administer all SPORE activities.
• Oversee all SPORE Projects and core activities.
• Oversee the Developmental Research and Career Enhancement Programs.
• Promote integration and communication between the SPORE, the Brain Cancer Program, and the Cancer Center Support Grant.
• Ensure compliance with institutional, governmental, and NCI regulations.
• Communicate and consult with the NCI program officer and other staff to ensure timely preparation and submission of reports, publications, and important events that affect management of the SPORE.
• Oversee and administer all fiscal and budgetary activities of the SPORE.
• Manage and provide quality assurance, including data quality control, in cooperation with the Biostatistics and Bioinformatics Core.
• Coordinate meetings of the Executive Committee, Internal and External Advisory Boards, monthly investigator meetings, lectures, and symposia.
• Ensure compliance with and improvement of policies for recruitment of women and minorities.
• Coordinate with other Brain Cancer SPORE programs and investigators, as well as other organ site SPORE programs, to promote research communication in meetings, distribution of materials, electronic communications, and evaluation of progress reports.

Core B: Pathology and Biorepository Core

Co-Directors: Jason Huse, M.D., Ph.D., and Frederick Lang, M.D.

The Pathology and Biorepository Core is a key driver of the success of the MD Anderson Brain Cancer SPORE, which seeks to progress home-grown experimental treatment strategies to clinical trials to improve patient management. The core incorporates an innovative and near-comprehensive tissue procurement and processing pipeline and provides histopathological expertise and the wealth of experience gained over multiple funding cycles. The objectives of the core are to:

• Procure, bank, and supply relevant tissue and biomaterial to SPORE projects and the institutional brain tumor research community.
• Coordinate clinical trial-associated tissue and biomaterial banking, processing, and databasing.
• Support murine sample processing and higher-order human/murine tissue reagent development.
• Provide histopathological, immunohistochemical, and molecular pathology expertise.
• Facilitate collaboration across the SPORE network.
  

Core C: Biostatistics and Bioinformatics Core

Co-Directors: Ying Yuan, Ph.D., and James Long, Ph.D.

The Biostatistics and Bioinformatics Core for the MD Anderson Cancer Center SPORE in Brain Cancer is a comprehensive, multilateral resource for the design of basic science experiments and clinical trials, and appropriate statistical analysis of the resulting data. The Biostatistics and Bioinformatics Core incorporates sound experimental design principles that enhance interpretability of study results, performs data analyses using appropriate methodology, and contributes to interpretation of results through written reports and frequent interaction with project investigators. Thus, from inception to reporting, translational experiments benefit from SPORE resources which are used to augment existing MD Anderson Cancer Center Biostatistics and Bioinformatics resources. The Biostatistics and Bioinformatics Core collaborates with all project investigators to facilitate the timely publication of all data collected under the Brain Cancer SPORE program.

To serve all proposed SPORE Projects, as well as the Career Enhancement and Developmental Research Programs, the Biostatistics/Bioinformatics Core has the following objectives:

• Provide biostatistics and bioinformatics expertise in the design and conduct of laboratory experiments and clinical trials arising from the research.
• Provide biostatistics and bioinformatics analysis and interpretation of all data collected under the SPORE Projects, Developmental Projects and other cores.
• Collaborate and assist all project investigators with the publication of scientific results.
  

Core D: Animal Core 

Co-Directors: Candelaria Gomez-Manzano, M.D., and Juan Fueyo, M.D.

The purpose of the Brain SPORE Animal Core is to provide centralized and specialized animal modeling, thereby achieving uniformity and reproducibility that enables accurate comparisons between experiments, research groups, and projects in this Brain Cancer SPORE. To this end, the core will:

• Support specialized surgical methods to generate brain tumor models.
• Support all animal strains and tumor cell lines.
• Support specialized treatment delivery methods. Core D can support complex drug delivery regimens including intracranial injection, intra-thecal injections, intravenous and intra-arterial injections, and oral gavage.
• Support in vivo imaging and sample collection to assess therapeutic efficacy.

The combined expertise of the Animal Core personnel lends itself to productive collaboration with SPORE and non-SPORE investigators in developing new animal models and unique surgical methods for therapeutic delivery and data collection.