Clinical research: Treatment of patients with metastatic melanoma with ultra-low dose Paclitaxel (Taxol®): A Pilot Trial for “Proof of Principle”

Info

Location: Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Mannheim, Germany
Collaboration: Dr. Christoffer Gebhardt, Prof. Dr. Jochen Utikal, Prof. Dr. Viktor Umansky

 

It is well known that melanoma cancer cells, in contrast to other types of cancers, activate the immune system very well, so that our body can fight harder to reject these cancer cells adequately. Checkpoint inhibitors, such as Yervoy, Opdiva and Keytruda, are approved medication 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. What is more, it is presumed that cancer cells in general, next to activating the immune system, are also using another mechanism that can suppress the immune system at the same time. This suppression of the immune system, which prevents the body from fighting against cancer cells, might also occur due to chronic inflammation found in melanoma lesions that have progressed rapidly.

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. 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 recently shown that lowering the dose of chemotherapy drugs (including paclitaxel) and combining them with other treatment modalities may not only decrease the toxicity of chemotherapy but also boost the efficacy of different anticancer therapies by interfering with the immune reaction in our bodies in different ways.

The investigators suggest that low-dose paclitaxel would also be beneficial in humans. To confirm this assumption proper clinical studies should be performed.

Therefore, the Anticancer Fund decided to support a trial to evaluate the effects, safety and efficacy of palliative (end of life) treatment with ultra-low dose paclitaxel in patients with metastatic (spread) melanoma in stage IV or III that cannot be treated with surgery (unresectable). For this trial, 12 patients have been recruited.

Professional info

Location: Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Mannheim, Germany
Collaboration: Dr. Christoffer Gebhardt, Prof. Dr. Jochen Utikal, Prof. Dr. Viktor Umansky

 

The immunogenic capacity of human malignant melanoma is well documented. The  approved checkpoint inhibitors (antibodies blocking the negative checkpoints CTLA-4 or PD-(L)1) showed durable responses with long-term survival. However, this effect could be achieved only in a minority of patients, and the overall results of immunotherapeutic clinical trials are currently not satisfactory. This could be due to a profound immunosuppression mediated by tumor cells and chronic inflammation represented by soluble factors and regulatory leukocytes, in particular, myeloid-derived suppressor cells (MDSCs). Main mechanisms of MDSC-mediated immunosuppression in tumor-bearing hosts are dealing with the inhibition of antitumor T-cell responses through the up-regulated activity of inducible nitric oxide (NO) synthase and arginase-1. Using the ret transgenic mouse spontaneous melanoma model that closely resembles human melanoma regarding histopathology and clinical development, Umansky et al. found an accumulation of chronic inflammatory factors and MDSCs in melanoma lesions, which was associated with rapid tumor progression. Tumor-derived MDSCs showed a strong inhibition of T-cell anti-tumor reactivity (Umansky et al. Cancer Immunol Immunother 2012; 61(2):275-82).

It has been recently shown that lowering the dose of anti-tumor cytotoxic agents (including paclitaxel) and combining chemotherapy with other modalities may not only decrease the toxicity of chemotherapy but also up-regulate the efficacy of different anticancer therapies by altering differentiation and activity of immune regulatory and effector cells via drug-specific activation of signal transduction pathways. Upon administration of paclitaxel at ultra-low, non-cytotoxic dose in melanoma bearing ret transgenic mice, Umansky et al. demonstrated a reduction of numerous chronic inflammatory mediators in melanoma lesions in association with decreased MDSC frequencies and immunosuppressive functions reflected by decreased nitric oxide (NO) production and the ability to inhibit T cell proliferation. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of T-cell functions.
Thus, it has been hypothesized that neutralizing MDSC-induced immunosuppression upon ultra-low dose Paclitaxel (Taxol®)  will result in the restoration of CD8 T cell frequencies and anti-tumor activity leading to clinical benefits for melanoma patients (Sevko et al. J Immunol 2013; 190(5):2464-71).

To confirm this hypothesis proper clinical studies should be performed. The Anticancer Fund decided to support a pilot clinical trial to evaluate the biologic effects, safety and efficacy of palliative treatment with ultra-low dose paclitaxel (Taxol®) in patients with metastatic melanoma in stage IV or III unresectable. This study is led by Dr. Christoffer Gebhardt, Prof. Dr. Jochen Utikal, Prof. Dr. Viktor Umansky. This investigation involves one health care center in Germany.  12 patients are enrolled (NCT02332642).

For more information you can contact Dr. Umasky by e-mail: V [dot] Umansky@dkfz-heidelberg [dot] de