Immune checkpoint inhibitors and mistletoe therapy

Few studies are available on the simultaneous or sequential combination of immune checkpoint inhibitors (ICI) and mistletoe preparations. As toxicities occurred in advanced and metastatic tumour diseases despite improved response rates under ICI, sequential as well as simultaneous combination of mistletoe extracts together with ICI (pembrolizumab, nivolumab, atezolizumab, durvalumab and other) have been investigated.

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.

A positive indication of synergistic effects is provided by a health services research 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, randomized, 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 spring 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) [331].
These findings suggest that the combination may exert its effects through mechanisms such as immunomodulation, reduction of ICI resistance, and/or changes in the tumor microenvironment, although these mechanisms have not yet been studied. These promising results require further validation through prospective, randomized controlled trials.