Immune checkpoint inhibitors and mistletoe therapy
There are not many studies on the simultaneous or sequential combination of immune checkpoint inhibitors (ICI) and mistletoe preparations.
Safety/Toxicity
Additional mistletoe therapy may reduce the adverse effects of the specific immunotherapy. First clinical experiences with ICI and add-on mistletoe are available for patients with bronchial carcinoma and melanoma. In a real-world data study one patient group (advanced and metastatic lung carcinoma or melanoma) received only ICI while the other received additional mistletoe therapy in order to determine the rate of side effects in both groups [68,302]. The results suggest that additional mistletoe therapy does not alter the rate of ICI side effects.
Another real-world data study involving 405 oncology patients showed that the discontinuation rate of immunotherapy due to side effects was not higher in the combination group with mistletoe therapy compared to the control group (combination ICI + mistletoe: 4.9% vs. ICI: 6.4%), indicating good tolerability of the combined treatment [343].
Another positive indication of synergistic effects is provided by a real-world data study in which add-on mistletoe therapy significantly reduced the number of discontinued treatments in the context of targeted therapy by half, including immune checkpoint inhibitors [67].
Further systematic prospective studies are currently being conducted. For example, in the recently completed prospective, controlled "Phoenix III study," patients with lung cancer were treated with PD-1 inhibitors and mistletoe therapy [70]. The publication of the results is still pending and is expected in sommer 2025.
Efficacy
Two publications from real-world data research are available on the efficacy of the combined immunotherapy and mistletoe therapy in advanced or metastatic lung cancer (non-small cell lung cancer, NSCLC) [332, 340]. They showed that the combination of immune checkpoint inhibitors and mistletoe therapy was associated with a seven-month increase in survival time (13.8 months vs. 6.8 months; p < 0.001) compared to PD-1/PD-L1 therapy alone. In particular, for PD-L1-positive patients, the addition of mistletoe preparations significantly and statistically reduced the risk of death. In one study, the risk reduction was approximately 75% (p = 0.02) [340], while in another study, it was around 56% (p < 0.001) [332].
Another real-world data study involving 312 patients with advanced or metastatic NSCLC showed that the 3-year survival rate was significantly higher in the group receiving additional mistletoe therapy (34.3% vs. 17.2%, p = 0.02). The effect was particularly pronounced in female patients: the 5-year survival rate was 50.1% compared to 12% in the control group (p = 0.0021), with a significant reduction in the risk of death by 91.2% (aHR: 0.088, 95% CI: 0.009–0.783) [343].
These findings suggest that the combination therapy – possibly through mechanisms not yet empirically studied, such as immunomodulation, reduction of ICI resistance, and/or changes in the tumor microenvironment – enhances the effectiveness of ICI therapy without increasing the rate of side effects. These promising results require further validation through prospective, randomied controlled trials.
