A New Immunotherapy Approach for Head and Neck Cancers

Head and neck squamous cell cancers develop in the epithelial cells (mucosa) lining the mouth, nose and throat. They are difficult to treat and require advanced expertise and a multidisciplinary approach because these anatomical areas are close together, contain many organs in a limited space alongside vital nerves and vessels, and are visibly exposed.

PD-1 and PD-L1 are immune checkpoints on cell surfaces, and inhibitors designed specifically for these molecules are a new generation of cancer immunotherapies.

Combined with chemotherapy, PD-1 inhibitor immunotherapy (nivolumab and pembrolizumab) has become a main treatment for recurrent or metastatic head and neck cancers. With its June 2019 FDA approval, pembrolizumab became standard for patients with advanced or recurrent, PD-L1-positive squamous cell head and neck cancer as first-line treatment. However, response rates are low, and observed response durations and hyperprogression (rapid cancer progression) risk suggest resistance to PD-1 inhibition. In addition, recurrence (relapse) is frequent. To overcome these problems and find a more effective treatment, scientists at the UCLA Jonsson Comprehensive Cancer Center and UCLA School of Dentistry joined forces. In a mouse-model study, they combined anti-PD1 immunotherapy with the BMI1 protein function-blocking agent PTC209. The results show successful suppression of cancer growth and spread, prevention of recurrence and elimination of cancer stem cells.

The Polycomb group (PcG) protein BMI1 controls cell differentiation and proliferation through epigenetic regulation and plays a critical role in cancer stem cell self-renewal.

The researchers used a mouse model mimicking the development and metastatic ability of head and neck squamous cell cancer, with an intact tumor microenvironment allowing tracking of BMI1-positive cancer stem cells. In the experiment, BMI1 protein was inhibited and inactivated through pharmacological or genetic techniques. In both cases, combination treatment with a PD1 inhibitor was used to test effectiveness against BMI1-positive cancer stem cells.

The researchers summarize the experimental results as follows: “Here, we found that combined anti-PD1 and cisplatin treatment suppressed head and neck squamous cell cancer growth while enriching BMI1-positive cancer stem cells in these cancers. In contrast, in experiments in which BMI1 protein was pharmacologically and genetically inactivated and a PD1 inhibitor was used, we demonstrated suppression of metastatic head and neck squamous cell cancer and a reduced recurrence risk.”

Inhibiting BMI1 eliminates BMI1 and cancer stem cells and stimulates the acquired immune response by attracting its important CD8+ T cells into the tumor environment and inducing a strong antitumor immune response.

In conclusion, this study provides evidence that immunotherapy targeting BMI1 proteins eliminates cancer stem cells by activating antitumor immunity, and is the first preclinical study. These results are promising for head and neck cancer patients treated with a PD1 inhibitor who subsequently develop resistance.