Study of ultra-low dose paclitaxel in metastatic melanoma
Immuno-monitoring of patients with metastatic melanoma (AJCC stadium IV) under ultra-low dose paclitaxel (Taxol©): a pilot trial for “proof of principle” (ImmunoPAX).
Why this trial?
Malignant melanoma is a potentially fatal form of skin cancer characterized by a rapid development and spreading to different organs in the body. Despite the recent progress in new treatment options, the metastasized disease is usually not curable.
It is well known that melanoma cancer cells activate the immune system, so that our body can fight harder to destroy these cancer cells adequately. Checkpoint inhibitors, such as Yervoy©, Opdivo© and Keytruda©, are approved medications to treat melanoma, and work by helping the immune system to kill melanoma cancer cells. However, this effect can only be achieved in a minority of patients.
Moreover, it is presumed that cancer cells in general, next to activating the immune system, also suppress it at the same time. Suppressing the immune system prevents the body from fighting against cancer cells. The suppressive mechanisms at play, like myeloid-derived suppressor cells, are believed to be induced due to chronic inflammation found in melanoma lesions that have progressed rapidly.
Therefore, novel immunotherapeutic strategies that activate the body’s immune system to help to attack and destroy melanoma cells are urgently needed.
Why this intervention?
The team of Prof. Umansky showed that paclitaxel (a form of chemotherapy) in low doses can decrease substances associated to chronic inflammation and suppression of the immune system in mice and humans. Hence, paclitaxel in low dose can increase the activity of the immune system, making the body more susceptible to treatment and stronger to fight the cancer cells. The performed experiments in mice also showed tumor shrinkage and increased survival time.
The fact that the dose of paclitaxel is low is of major importance. Indeed, it has been shown that lowering the dose of chemotherapy drugs (including paclitaxel) and combining them with other treatment modalities may decrease the toxicity of chemotherapy. Furthermore, it may also boost the efficacy of other anticancer therapies by interfering with the body’s own immune reaction in different ways. Therefore, the investigators of this trial suggest that low-dose paclitaxel would also be beneficial in human melanoma patients.
This pilot trial aims at evaluating immuno-modulating effects, safety and efficacy of palliative (end of life) treatment with ultra-low dose paclitaxel in 12 patients with metastatic (spread) melanoma in stage IV or III that cannot be treated with surgery (unresectable). Patients will receive paclitaxel (Taxol©) intravenously once per week for 3 weeks (40.0 mg/m2).
The trial was completed in 2016. Analysis of the results show that, taking into account that the 9 participants had a poor overall prognosis, the treatment response was good (2 Partial Response, 1 Stable Disease, 6 Progressive Disease). In patients that responded to the treatment, paclitaxel decreased the frequency and immunosuppressive action of immunosuppressive cells (i.e. myeloid-derived suppressor cells (MDSCs)) in the peripheral blood and in skin metastases. In addition, paclitaxel influenced the production of inflammatory mediators in the blood serum of the melanoma patients. These results suggest that treatment with low-dose paclitaxel could improve the clinical outcome of patients with advanced melanoma by enhancing the bodies’ immune response to the tumour.
- Christoffer Gebhardt, MD, Universitätsmedizin Mannheim - Klinik für Dermatologie, Venerologie und Allergologie, Mannheim, Germany (Principal Investigator)
- Jochen Utikal, MD, Universitätsmedizin Mannheim - Klinik für Dermatologie, Venerologie und Allergologie, Mannheim, Germany (Deputy Principal Investigator)
- Viktor Umansky, MD, Universitätsmedizin Mannheim - Klinik für Dermatologie, Venerologie und Allergologie, Mannheim, Germany (Immuno-monitoring)
- Universitätsmedizin Mannheim, Mannheim, Germany
More info: NCT02332642
Christoffer Gebhardt, Sonja C. S. Simon, Rebekka Weber, Mirko Gries, Dong Hun Mun, Raphael Reinhard, Tim Holland-Letz, Viktor Umansky, Jochen Utikal. Potential therapeutic effect of low-dose paclitaxel in melanoma patients resistant to immune checkpoint blockade: A pilot study. Cellular Immunology, Volume 360, February 2021, 104274, doi: 10.1016/j.cellimm.2020.104274
Author: Kristine Beckers (Trial Manager)
Last update: October 2020