We investigated the impact of concurrent use of BB and ICB strategies on clinical outcomes for patients with advanced solid tumors. Although we did not detect a difference in OS between the non-BB and BB groups, we observed that in comparison with the non-BB group, patients in the BB group had improved disease control and longer median duration of therapy. After adjusting for clinically relevant covariates including age group, ECOG performance status, first line therapy and common comorbidities, the use of BB remained significantly associated with improved disease control. Our findings represent the first study to show the association of disease control with concomitant use of BB and ICB in a cohort of advanced solid tumors.
The interplay between adrenergic signaling and immune cells is well-described in animal model models. Specifically, BBs have been shown to prevent βAR-related immunosuppression, leading to the recruitment of effector CD8 + T-cells, an increased effector CD8 + to CD4 + regulatory T-Cell ratio, and a decreased expression of PD-1 (Bucsek, Qiao et al. 2017). Furthermore, in melanoma, a combination of anti-PD-1 and BB was associated with significantly more decrease in tumor volume, compared to the anti-PD-1 therapy alone. In this clinical context, two retrospective datasets for melanoma and NSCLC have each confirmed that the addition of BB was associated with improved OS (Kokolus, Zhang et al. 2018, Cortellini, Tucci et al. 2020, Wang, McQuade et al. 2020, Gandhi, Pandey et al. 2021, Oh, Guzner et al. 2021). In contrast, our study did not find an association between BB use and OS. The heterogeneity in tumor types within our cohort maybe accounting for the discrepancy, when compared to evidence in animal model systems and prior retrospective datasets in melanoma and NSCLC.
We also aimed to determine whether there was a difference in association between BB use and clinical outcomes by specific tumor type. We analyzed the four most common tumor types in our dataset: melanoma, NSCLC, HCC, and UC. We found that the addition of BB improved OS, compared to non-BB, only in the UC patients. However, when evaluating patients receiving ICB as first-line therapy for UC, the addition of BB was not associated with change in OS. Similarly, prior retrospective and prospective studies (Kokolus, Zhang et al. 2018, Gandhi, Pandey et al. 2021) suggesting enhanced activity of ICB when combined with BB in melanoma, our dataset demonstrated improved rates of disease control among melanoma patients receiving beta blockade. The mechanism for why BB use in melanoma was associated with increased disease control remains unknown. Prior research has detected increased βAR expression in biopsies of melanoma (Yang, Kim et al. 2009). Moreover, CTLA-4 monoclonal antibodies have more extensively been used in melanoma compared with other solid tumor types and might have unique synergy with beta blockade (Rotte 2019). Further research should explore how BB affects tumor response based on the distinct molecular mechanisms of ICB.
The final question we aimed to answer was the importance of beta-blockade selectivity in influencing clinical outcomes in patients receiving ICB. In previous studies of melanoma and NSCLC, patients with non-selective BB had improved clinical outcomes, compared to those on β1-selective blockers and those not on BB (Kokolus, Zhang et al. 2018, Oh, Guzner et al. 2021). Animal model systems substantiated that β2-adrenergic signaling may be driving the immune modulation through T-cell induced cytokine secretion and (Bucsek, Qiao et al. 2017, Kokolus, Zhang et al. 2018). In contrast, our study indicates that β1-selective BB improved clinical outcomes when compared to non-selective BB and no BB. The reason for this remains unclear – it is important to note that a substantial proportion of patients on BB were receiving β1-selective BB, thus potentially underpowering the non-selective BB group.
` Our study has several limitations. First, by including multiple cancer types we had significant tumor heterogeneity across our cohorts. Such heterogeneity can limit the ultimate application of our findings. Second, each individual tumor cohort was limited in its sample size and potentially underpowered. Finally, because we did not control for the use of chemotherapy with immunotherapy, we do not know how their interaction may have positively or negatively affected our final results. Despite these limitations, the external validity of our study is improved due the multitude of tumor types, similarity of demographics and gender between groups, and the inclusion distinct patient populations.
Ultimately, we provide evidence, consistent with prior studies, that BB may play a role in influencing the immune activity of ICB. BB are safe, low-cost, and widely available agents for serving as an adjunct to ICB therapy. The initial data from phase I study of propranolol and pembrolizumab provides an important safety signal to proceed with larger, prospective studies for validation (Gandhi, Pandey et al. 2021). This work also serves as a pioneering study to perform prospective studies in other tumor types such as UC. Additional research should incorporate detailed immune profiling and genomic analysis to identify predictors of response and to explore the underlying mechanism of this combinatorial approach.