UCLA Study Reveals Inhibition of Gene Helps Overcome Resistance to Immunotherapy

UCLA Study Reveals Inhibition of Gene Helps Overcome Resistance to Immunotherapy

A UCLA Jonsson Comprehensive Cancer Center study reveals inhibition of gene helps overcome resistance to immunotherapy leading the team to believe that this could represent a new strategy for patients with advanced cancers that fail to respond to current cancer immunotherapies.

The Challenge

Many cancer immunology drives, which harness the body’s immune system to better attack cancer cells, have significantly changed the face of cancer treatment. People with aggressive cancers are now living longer, healthier lives thanks to these breakthroughs. Unfortunately, cancer immunology therapy only works on a select subset of patients.

The Breakthrough at UCLA

Now a new study from UCLA researchers help explain why some people with advanced cancer may not respond to one of the leading immunotherapies, PD-1 blockade, and how a  new combination approach may help overcome resistance to the immunotherapy drug.

The Study

In the study, UCLA revealed that genetic and pharmacological inhibition of the oncogene PAK4 overcomes resistance to anti-PD-1 therapy in preclinical research models.  The results were published in the new scientific journal Nature Cancer.

While previously known with involvement in cell migration and proliferation, UCLA researchers reveal that high PAK4 expression correlates with a lack of immune cells migrating into the tumors to destroy cancer cells.

The UCLA researchers used biopsies from people with advanced melanoma who received the immune checkpoint blocking antibody pembrolizumab. The team performed RNA sequencing to characterize the phenotype of the tumors. They saw that the tumors failed to respond to PD-1 blockade had a high expression of PAK4 and were not infiltrated by immune cells, meaning the immune cells had not found their way to the tumor to attack the cancer cells.

Inhibiting the PAK4

Then the researchers understood they needed to inhibit the PAK4 in cell lines by either using a drug inhibitor or a gene editing technique called CRISPR-Cas9. The scientists found that deleting PAK4 increased the migration of tumor specific immune cells and sensitized tumors to PD-1 blockage immunotherapy, reversing the resistance.

Moving Forward

The PAK4 inhibitor used in the study is already being tested in a Phase I trial. The combination treatment with an anti-PD-1 will be tested in a clinical trial setting in the future.    

Funding

The study was funded in part by the National Institutes of Health and the Parker Institute for Cancer Immunotherapy.

The UCLA Jonsson Comprehensive Cancer Center

The center has approximately 500 researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. Once of the nation’s largest comprehensive cancer centers, the UCLA Jonsson Comprehensive Cancer Center is dedicated to promoting research and translational basic science into leading-edge clinical studies.

Lead Research/Investigator                                

Gabriel Abril-Rodriguez, doctoral candidate department of pharmacology and medicine

Dr. Antoni Ribas, professor of medicine Geffen School and director the Jonsson Cancer Center’s Tumor Immunology Program