Recently, the National Brain Tumor Society and Oligo Nation announced a $250,000 grant that will fuel a preliminary look at immunotherapy’s applications in the treatment of oligodendroglioma, a rare brain cancer that accounts for about 6 percent of all gliomas. In the United States, there are nearly 2,000 new oligodendroglioma diagnoses each year. Since the disease is relatively rare, little preclinical or clinical research has been completed. However, the fact that oligodendroglioma primarily affects younger individuals, typically in their 20s and 30s, has driven some research into the incurable disease.
The funded study, which is called Anti-CD47 Based Multimodality Immunotherapy Against Malignant Oligodendroglioma, will be headed by Dr. Samuel Cheshier, an assistant professor of neurosurgery at the Stanford University School of Medicine. This study will build upon multiple decades of work on the CD47 protein, which protects tumors from the innate immune system by creating disabling signals. CD47 is expressed in virtually all human cells, but researchers have found that it is overexpressed in several different tumors, including oligodendrogliomas. The protein is involved in several different cells processes, including adhesion, proliferation, migration, and apoptosis.
The Purpose of the Stanford Oligodendroglioma Trials
The Stanford team that will head the research has engineered an antibody capable of blocking the signal produced by CD47 that disables the innate immune system. Without this signal, macrophages can detect and destroy tumor cells. This immunotherapy has already entered Phase I studies to investigate its application in the treatment of multiple solid tumors and blood cancers. The new study is primarily aimed at determining the efficacy of this therapy in patients with oligodendroglioma. Preliminary results have been promising enough to warrant a more thorough investigation.
The funded study will look at three different approaches to determine efficacy. In the first, research will use multiple animal models to test the anti-CD47 antibody. These in vivo trials are the precursor to human clinical trials. The animal trials are scheduled to begin early next year.
The second approach will test anti-CD47 in combination with other immunotherapies currently available in the animal models to see if these combinations yield improved results. Immunotherapeutic compounds have improved patient outcomes in other clinical trials. The success of this arm will allow Phase II studies of combinations following the monotherapy trial. Anti-CD47 will be used in combination with anti-CD40 agents and epidermal growth factor receptor (EGFR) inhibitors.
The third approach will involve in vivo testing in combination with immuno-oncology treatments focused on the adaptive immune system, including checkpoint inhibitors that target PD-1, PDL-1, and CTLA-4. By triggering both innate and adaptive response to the tumor, researchers hope to create an even stronger anti-tumor effect.
The Underlying CD47 Research at Stanford
Earlier this year, the Stanford team published a study called MYC Regulates the Antitumor Immune Response Through CD47 and PD-L1 in Science. The study focuses on oncogenes, which play a key role in cell proliferation. When mutations in these genes occur, the cell can begin to divide uncontrollably, which leads to cancer. Myc is an oncogene that is mutated in a number of human cancers. The mutation causes the overexpression of transcription factor Myc. When the expression of the oncogene is blocked, regression can occur in certain tumors in animals. However, the regression only occurred in animals with intact immune systems. This fact led researchers to investigate the relationship between Myc and the immune system.
The study found that Myc regulated the expression of both CD47 and PD-L1, an important immune checkpoint. When Myc was suppressed in both mouse and human tumors, the researchers found a reduction in the levels of mRNA proteins produced by CD47 and PD-L1. Other immune regulators were unaffected. The researchers looked particularly at acute lymphoblastic leukemia tumors and liver cancer. The study also looked at genetic data from patients and posited a strong correlation between expression of CD47 and PD-L1 in the liver, kidney and colorectal tumors and Myc expression.
According to the study, Myc binds directly to the promoter regions of both PD-L1 and CD47. When Myc was inactivated in mouse cancer models, expression of CD47 and PD-L1 were lowered, which enhanced the anti-tumor response of the immune system. However, stimulating the constant expression of CD47 and PD-L1 allowed cells to consistently evade the immune system regardless of whether or not Myc was expressed. Thus, the researchers suggested a synergetic therapy that targets Myc, PD-L1, and CD47 to slow or stop tumor growth and encourage the immune attack.
These findings laid the foundation for the current anti-CD47 clinical trials and the upcoming study involving oligodendroglioma. At present, researchers still struggle to understand why some cancers are more sensitive to these immunotherapies than others are. Moving forward, understanding better the mechanisms by which these cancer immunotherapies work will help researchers develop more effective treatments that take into account both the biochemistry of the patient and the specific weaknesses of the tumor.