Regents of the University of Minnesota - Twin Cities Archives

2019

Scholar Grant

Chris Moertel

Minneapolis, MN

Title: Employing the CD200 Checkpoint to Optimize Immunotherapy for Pediatric Brain Tumors

Executive Summary:
Background: Immunotherapy has revolutionized cancer therapy. On the forefront are drugs targeting the cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) and the programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1) couple. Use of these drugs alone has modest effect and combination therapy significantly enhances survival, but these drugs may cause serious immune-related reactions. Our proposal aims to exploit a newly discovered immune checkpoint, CD200. We discovered this important molecule in patients treated on our phase I brain tumor vaccine trial and proved its existence in other brain tumors, including glioblastoma and ependymoma. Through additional observations, we showed that CD200 is expressed in brain tumor cells and tumor-associated blood vessels.

Project Aims: The CD200 checkpoint regulates the immune system through an inhibitory receptor, shutting down an immune response through ties with the PD-1 and CTLA4 checkpoints. In addition, the CD200 checkpoint surmounts the effects of CD200, PD-L1 and CTLA4 through a separate interaction with its activation receptor. We developed a CD200 peptide ligand that targets the CD200 activation receptor. We demonstrated that the use of this peptide i) overpowered the suppressive CD200 and PD-L1 solubilized by tumors, ii) activated an anti-tumor response and iii) downregulated both CD200 inhibitory receptors and PD-1 on immune cells. We believe this is how we achieved a 67% disease free survival at 30 months in a trial treating pet dogs diagnosed with high-grade gliomas. We have developed a new concept for brain tumor immunotherapy that will be accomplished through the following aims:
1) Optimize a novel peptide ligand activating immune responses against CNS-derived tumors.
2) Elucidate the molecular crosstalk between CD200, PD-1 and CTLA4.
Outcomes: At the conclusion of this project, we will have developed an optimal CD200-directed peptide for brain tumor immunotherapy. We will then show that this peptide has a direct effect on the CD200 checkpoint pathway and also shuts down the important PD-1 and CTLA4 pathways that are important for tumor survival.

Goals
– Our findings will develop a new and important avenue for immunotherapy of human cancer.
– Because brain tumors are the number one cause of cancer death in children, we will focus our therapy on this disease first.
– Our findings will elucidate an important mechanism of interaction between cancer and the human immune system.

Benefits to Pediatric Cancer: We believe that the destruction of the CD200 immune checkpoint fortress has the potential to finally achieve victory for brain tumor immunotherapy. Checkpoint inhibitor therapy has already proven to be effective in prolonging life for people afflicted with malignant melanoma and other cancers, so we believe this a realistic goal. We also believe our CD200-directed platform has the potential to impact other pediatric cancers.

2018

Scholar Grant

Peter Gordon

Minneapolis, MN

Targeted Therapy of the Rare, Chemo-resistant Leukemia Cells that Contribute to Relapse

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents ~25% of pediatric cancer diagnoses. Unfortunately, up to 20% of children in remission at the end of the first month of chemotherapy will ultimately relapse and potentially die of leukemia. Accordingly, relapse is the most common cause of treatment failure in childhood ALL and relapsed ALL is as common as most pediatric solid tumors and acute myeloid leukemia in childhood.

The majority of leukemia cells in a patient are highly sensitive to chemotherapy as 98% of patients achieve a complete morphologic and cytogenetic remission after the first month of chemotherapy. This corresponds to an up to a 10,000-fold reduction in leukemia burden. As a result, ALL relapse results from the rare, residual leukemia cells that persist following the first month of multi-agent chemotherapy.

We have established a mouse model of human leukemia that allows us to identify, isolate, and characterize these rare, chemoresistant leukemia cells that escape chemotherapy and contribute to leukemia relapse. Moreover, through our preliminary characterizations of these cells, we have identified drugs that may either directly target unique vulnerabilities in these cells or re-sensitize these cells to cytotoxic chemotherapy. In this proposal, we will use our mouse leukemia model system to test the ability of these drugs to specifically eradicate these rare, chemo-resistant leukemia cells in vivo and improve the therapy of ALL. Successful completion of these Aims would provide pre-clinical support for a novel approach for improving leukemia therapy by decreasing relapse risk and could advance quickly to clinical testing.

-Relapse is the most common cause of treatment failure in childhood ALL
-We will test novel strategies to eradicate the rare, chemo-resistant leukemia cells that contribute to relapse.
-Successful completion of these Aims could transform the care of patients with ALL.