Massachusetts General Hospital (MGH) and University of Florida researchers study reveals a strategy that could make immune checkpoint inhibitors successful with glioblastomas—deadly primary brain tumors in adults. It involves the use of an investigational chemokine receptor 2 (CCR) antagonist called CCX872.

Not Effective to Date

Thus far ineffective, the use of immune checkpoint inhibitors are not commonly used to treat glioblastoma. That is until a recent preclinical research effort.

Introduction

A preclinical research study led by MGH and University of Florida centering on the use of immune checkpoint inhibitors in glioblastoma with mice has evidenced a promising strategy that could lead to a promising  breakthrough. But first a review of this promising approach hasn’t worked thus far with brain cancer.

The Collaborators

The collaboration was led by Jeffrey K. Harrison, PhD, Department of Pharmacology and Therapeutics, University of Florida and Rakesh K. Jain, PhD, Department of Radiation Oncology, MGH and Harvard Medical School

The Strategy

Immune checkpoint inhibitors and other immunotherapies haven’t been effective with glioblastoma because of cells called myeloid-derived suppressor cells (MDSCs) which tend to infiltrate the region around the glioblastoma tumors and contribute to immunosuppression, tumor progression and treatment resistance. Thus, the researchers found that by targeting these cells may boost the effectiveness of immune checkpoint inhibitors.

The Preclinical Study

Utilizing two mouse models of glioblastoma, the team targeted receptors—called chemokine receptors—vital for enabling MDSCs to infiltrate the glioblastoma tumor region. IN the mice that were bred to lack chemokine receptor 2 (CCR2) and develop glioblastoma, MDSCs weren’t able to execute on the infiltration and hence support the tumor. And with these targeted mice the use of immune checkpoint inhibitor stimulated a strong anti-cancer immune response and hence prolonged the mice survival. While with mice that had normal CCRT, by using a molecule that blocks the CCR2 had similar effects. The results were published in the Proceedings of the National Academy of Sciences and indicates that this combination therapy should be assessed in clinical trials of patients with glioblastoma—a disease with no cure.

Research Lead Comment

Rakesh K. Jain reported, “The CCR2 antagonist used in this study—called CCX872—has passed Phase IB safety trials in patients with pancreatic tumors, and clinical trials are ongoing to investigate the use of CCR2 inhibitors in several cancers.”  Jain continued, “Thus, the results of the study support targeting CCR2—expressing MDSCs as a means to enhance immunotherapies, warrant investigation of this combination therapy I clinical trials for patients with glioblastoma.”

What is CCX872?

Developed by ChemoCentryx CCX872 is their second inhibitor of the chemokine receptor since as CCR2. On their website they note in oncologic disease, tumors can profoundly subvert inflammatory and effector immune responses. In the tumor cellular microenvironment, CCR2 bearing cells are thought to largely have an immunosuppressive behavior. These are the so-called myeloid derived suppressor cells, (MDSCs). These cells effectively help tumors hide from the body’s cytotoxic immune response to tumor cells. Inhibiting CCR2, and thus the MDSCs controlled by CCR2, could therefore lead to the liberation of the cytotoxic immune response against the tumor cells and improved patient survival. They have been using CCX872 in an ongoing clinical development program for the treatment of patients with advanced pancreatic cancer, a deadly cancer.

Lead Research/Investigator

Jeffrey K. Harrison, PhD, Department of Pharmacology and Therapeutics, University of Florida

Rakesh K. Jain, PhD, Department of Radiation Oncology, MGH and Harvard Medical School

Source: Big News Network

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