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

• Published in: International journal of molecular sciences Vol. 18; no. 10; p. 2134
• Main Author: Kareva, Irina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13-10-2017; MDPI
• Subjects: Administration, Metronomic; Animals; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Cancer; Cancer therapies; Cell death; Chemotherapy; combination therapy; Combined Modality Therapy; Cytotoxicity; Drug Resistance, Neoplasm; Humans; Immune checkpoint; immune checkpoint inhibitors; Immune response; Immune system; Immunomodulation - drug effects; Immunoregulation; Immunosuppressive agents; Immunotherapy; Lymphocytes; Lymphocytes T; Maximum Tolerated Dose; metabolic competition; Metastases; metronomic chemotherapy; Molecular Targeted Therapy; MTD; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Nutrients; Review; Suppressor cells; Synergistic effect; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Treatment Outcome; Tumor cells; tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; metronomic chemotherapy; combination therapy; metabolic competition; immune checkpoint inhibitors; tumor microenvironment; MTD
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18102134

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.