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Boosting the Potential of Checkpoint Inhibitors

Boosting the Potential of Checkpoint Inhibitors

Beta blockers, which are commonly used to treat hypertension, may be repurposed to improve the efficacy of anti-PD-1 checkpoint blockade in cancer patients, according to a recent study published in Cancer Research. The findings may explain, in part, why the efficacy of checkpoint inhibitors in controlling cancerous tumors often is short-lived.

The study showed that beta-2 adrenergic receptors (β-AR) control the functionality of key immune cells and in response to stressors, these receptors turn on the “flight or fight” response. The investigators employed three strategies (physiologic, pharmacologic, and genetic) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. They found that reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment. Reducing β-AR signaling led to increased intratumoral frequency of CD8+ T cells with an effector phenotype. It also decreased expression of PD-1.

“We continue to be impressed by the degree to which baseline stress affects the efficacy of cancer therapies, based on what we've seen in preclinical studies in mice,” said senior study author Elizabeth Repasky, PhD, a professor of immunology at Roswell Park Cancer Institute in Buffalo, New York. She and her colleagues previously demonstrated that the efficacy of chemotherapy was reduced by even relatively mild stress. But if this stress is chronic, that seems to be the key to driving cancer resistance.

“We found that the anti-tumor immune system is also sensitive to chronic stress, and if this stress is reduced, then the immune system is stronger. Excitingly, therapies that depend upon the immune system [checkpoint inhibitors] also work better when the system is less stressed,” Repasky told OncoTherapy Network.

The researchers pursued the implications of this novel finding with further laboratory studies, and demonstrated that the β-AR, also known as ADRB2, can be pharmacologically manipulated. Repasky said beta blockers reduce adrenergic signaling and this allows anti-tumor immune cells to become much stronger.

Marc Ernstoff, MD, chair of medicine at Roswell Park, plans to initiate a multicenter clinical study based on these findings. “A clinical trial is now designed to test the hypothesis of whether immune checkpoint inhibitors plus a beta blocker can improve the outcome of patients with metastatic melanoma. We hope to open this study by early 2018,” said Dr. Ernstoff.

He said a better understanding of immune pathways may provide insight into better designing rational combination of immune therapies. “Understanding the mechanism and pathway associated with stress’s impact on the immune system is one such area and a target, beta adrenergic receptor, has been identified that can easily be inhibited by repurposing commonly used and relatively safe drugs to improve cancer therapy in patients,” Dr. Ernstoff told OncoTherapy Network.

The researchers hope that by improving responses to checkpoint inhibitors, it may be possible to expand the numbers of patients who can benefit from these agents.

 
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