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).
Funding
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 suggested that low-dose paclitaxel would also be beneficial in human melanoma patients.
Trial design
This pilot trial aimed 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 couldn't be treated with surgery (unresectable). Patients received paclitaxel (Taxol©) intravenously once per week for 3 weeks (40.0 mg/m2).
Results
The trial was completed in 2016, with 9 patients included. Analysis of the results showed that, taking into account that the 9 participants had a poor overall prognosis, the treatment response was good.
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.
Partners
Researchers:
- 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)
Sponsor:
- Universitätsmedizin Mannheim, Mannheim, Germany
Our role
Why we support this trial
Intervention has little or no commercial value
Expected survival benefit
Funding
References
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: March 2024