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Int. J. Mol. Sci. 2017, 18(10), 2134; doi:10.3390/ijms18102134

A Combination of Immune Checkpoint Inhibition with Metronomic Chemotherapy as a Way of Targeting Therapy-Resistant Cancer Cells

1
Mathematical and Computational Sciences Center, School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85287, USA
2
EMD Serono Research and Development Institute, Merck KGaA, Billerica, MA 02370, USA
Received: 11 September 2017 / Revised: 29 September 2017 / Accepted: 2 October 2017 / Published: 13 October 2017
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Abstract

Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by immune cell death induced by cytotoxic treatments. High-frequency low-dose (also known as metronomic) chemotherapy can help improve the activity of CTLs by providing sufficient stimulation for cytotoxic immune cells without excessive depletion. Additionally, therapy-induced removal of tumor cells that compete for shared nutrients may also facilitate tumor infiltration by CTLs, further improving prognosis. Metronomic chemotherapy can also decrease the number of immunosuppressive cells in the tumor microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Immune checkpoint inhibition can further augment anti-tumor immune responses by maintaining T cells in an activated state. Combining immune checkpoint inhibition with metronomic administration of chemotherapeutic drugs may create a synergistic effect that augments anti-tumor immune responses and clears metabolic competition. This would allow immune-mediated elimination of therapy-resistant cancer cells, an effect that may be unattainable by using either therapeutic modality alone. View Full-Text
Keywords: immune checkpoint inhibitors; combination therapy; metronomic chemotherapy; tumor microenvironment; metabolic competition; MTD immune checkpoint inhibitors; combination therapy; metronomic chemotherapy; tumor microenvironment; metabolic competition; MTD
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Kareva, I. A Combination of Immune Checkpoint Inhibition with Metronomic Chemotherapy as a Way of Targeting Therapy-Resistant Cancer Cells. Int. J. Mol. Sci. 2017, 18, 2134.

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