Beta blockers may improve response to immunotherapy in metastatic melanoma
Patients with metastatic melanoma who underwent treatment with immunotherapy derived a benefit when they also received beta blockers, according to study results.
Todd Schell, PhD, professor of microbiology and immunology at Penn State College of Medicine, and colleagues hypothesized that the stress-reducing properties of beta blockers may add to the benefits of immunotherapy for this patient population.
Researchers retrospectively assessed 195 patients with metastatic disease and observed a significant survival benefit among those treated with both immunotherapy and beta blockers.
The analysis included a parallel, follow-up study conducted in mice with melanoma. Results showed delayed tumor growth and prolonged survival among mice treated with the two drug classes.
HemOnc Today spoke with Schell about the results and their implications.
Question: Can you describe how you conducted the initial study?
Answer: Immunotherapy has dramatically improved the prognosis for patients with metastatic melanoma. However, the majority of patients do not yet benefit from this type of therapy. Kathleen Kokolus, PhD, a postdoctoral fellow in my laboratory, asked whether patients with metastatic melanoma who received immunotherapy would have different outcomes if they also were taking beta-blockers for an unrelated medical condition. Beta-blockers reduce the effects of the stress-induced hormones epinephrine and norepinephrine, which are known to inhibit the immune response. We evaluated 195 patients, 62 of whom were taking one of several different beta blockers. We found that patients taking pan beta blockers lived significantly longer than patients who were not taking beta blockers or patients who were taking beta1-selective blockers. In fact, approximately 70% of patients taking pan beta blockers were alive 5 years after receiving immunotherapy, compared with only 25% of the remaining patients.
Q: Can you explain how those findings led to the follow-up data set in mice ?
A: These retrospective results in our patient population prompted us to perform a prospective study in a mouse model of melanoma to test whether beta blockers could improve immunotherapy. We found that pan beta blocker alone did not alter tumor growth, but this drug significantly improved the ability of immunotherapy to reduce tumor growth and prolong survival of the mice. In addition, we found that the effect of the pan beta blocker to improve immunotherapy was reproduced by a beta 2-selective blocker, but not a beta 1-selective blocker. This result suggests that the main effect of pan beta blockers on immunotherapy is mediated by inhibiting the binding of stress hormones to beta 2-adrenergic receptors.
Q: Can you describe the mechanism of how certain beta blockers may improve efficacy of immunotherapy?
A: Pan beta blockers can reduce stress hormone binding to both the beta 1 and beta 2 adrenergic receptors. Our results in mice indicate that the main effect of pan beta blockers is to reduce the effects of stress hormones on beta 2 adrenergic receptors. Although both beta 1 and 2 adrenergic receptors are expressed on many cell types throughout the body, studies have shown that the negative effects of stress hormones on immune cells are mediated by beta 2 adrenergic receptors. Thus, pan beta blockers may directly increase the activity of immune cells against the tumors. In our study, approximately 3.5 times more patients were taking beta 1-selective blockers than pan beta blockers, suggesting that many patients with metastatic melanoma could benefit from taking pan beta blockers.
Q: If this approach does prove to be efficacious, what are the potential implications?
A: If our results are confirmed by clinical trials, prescription of pan beta blockers during immunotherapy could dramatically improve the number of patients with metastatic melanoma who derive long-term benefits, including longer survival. Because pan beta blockers are very inexpensive, their addition to immunotherapy would add only a minimal cost.
Q: Are there studies underway to confirm your findings?
A: We plan to open a clinical trial to determine how prescription of pan beta blockers will impact the response rate of patients who receive pembrolizumab (Keytruda, Merck), an FDA-approved immunotherapy for metastatic melanoma. In addition, we will use a genetic approach to determine whether the beneficial effect of pan beta blockers requires beta 2 adrenergic receptors.
Our next steps will be to identify which immune cells are affected by pan beta blockers and how they may be improved to respond to cancer. We also will determine whether beta blockers directly target the tumor cells themselves and whether similar results will be observed for cancers other than melanoma. – by Rob Volansky
For more information:
Todd Schell, PhD, can be reached at 500 University Drive, Mailbox H107, Hershey, PA 17033; email: email@example.com.
Disclosure: Schell reports no relevant financial disclosures. Please see the study for all other researchers’ relevant financial disclosures.