Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Metronomic Chemotherapy Mechanisms of Action
2.1. Anti-Angiogenic Effect
2.2. Immunomodulating Effects of mCT
2.3. mCT Directly Targets Tumor (Stem) Cells
2.4. mCT Mechanism of Actions Depend on Dose and Time-Exposure
3. Synergistic Role of mCT with Immune Checkpoint Inhibitors
Refs. | Treatment Drugs mCT + ICI | Tumor Type | Immunologic Outcome | Efficacy |
---|---|---|---|---|
[106] | Cyclophosphamide + anti-PD-1 | Triple negative breast cancer | No increase of PD-1 or CD4+/CD8+ T cell | Not reported |
[47] | Cisplatin/docetaxel + anti-PD-1 | Squamous cell lung carcinoma | Increased macrophage Increased TIL (CD45+, CD3+, CD8+) | Not reported |
[108] | Carboplatin + anti-PD-1 | Lung cancer | Increased PD-1 expression Increased CD8+ T cell infiltration | Reduced tumor growth No adverse effect (mice body weight) |
[101] | Gemcitabine + anti-PD-L1 | Squamous cell lung carcinoma | Increased M1-like macrophage Increased CD8+ T cell infiltration Decreased M2-like macrophage | Complete inhibition of tumor growth |
[109] | Multipeptide vaccine + XX+ anti-PD-1 | Melanoma | Decreased Treg Increased INF-γ | Complete tumor inhibition |
[110] | Gemcitabine + anti-PD-1 | Lung cancer | Increased CD8+ T cell Decreased IL-10 Decreased Treg | Milder leucopenia Highest antitumor efficacy |
4. Conclusions, Remarks, and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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mCT | ICI | Study Title | Status | Phase | Clinical Trial n° |
---|---|---|---|---|---|
Cyclophosphamide | Ipilimumab | A Phase I Clinical Trial of Combined Cryotherapy and Intra-tumoral Immunotherapy with Autologous Immature Dendritic Cells in Men with Castration-Resistant Prostatic Cancer and Metastases to Lymph Nodes and/or Bone Pre- or Post-Chemotherapy | Completed | I | NCT02423928 |
Cyclophosphamide | Nivolumab/Ipilimumab | Autologous Dendritic Cells and Metronomic Cyclophosphamide in Combination with Checkpoint Blockade for Relapsed High-Grade Gliomas in Children and Adolescents | Recruiting | I | NCT03879512 |
Vinblastine Cyclophosphamide Capecitabine | Nivolumab | Nivolumab in Combination with Metronomic Chemotherapy in Pediatrics Refractory/Relapsing Solid Tumors | Recruiting | I and II | NCT03585465 |
Gemcitabine Doxorubicin Docetaxel | Nivolumab | GALLANT: Metronomic Gemcitabine, Doxorubicin, Docetaxel, and Nivolumab for Advanced Sarcoma | Recruiting | II | NCT04535713 |
Temozolomide | Nivolumab | Temozolomide + Nivolumab in MGMT Methylated Oesophagogastric Cancer (ELEVATE) | Recruiting | II | NCT04984733 |
Temozolomide | Nivolumab + Ipilimumab | A Longitudinal Assessment of Tumor Evolution in Patients with Brain Cancer. | Recruiting | I | NCT03425292 |
Cyclophosphamide | Pembrolizumab | Phase 2 Study of an Immune Therapy, DPX-Survivac with Low Dose Cyclophosphamide Administered with Pembrolizumab in Patients with Persistent or Recurrent/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) | Active, not recruiting | II | NCT03349450 |
Vinorelbine | Atezolizumab | VinMetAtezo Study: Trial to Evaluate Safety and Efficacy of Vinorelbine with Metronomic Administration in Combination with Atezolizumab as Second-line Treatment for Patients with Stage IV NSCLC | Completed | II | NCT03801304 |
Decitabine | PD-1 Antibody (SHR-1210) | Combined Chemotherapy and PD-1 Antibody (SHR-1210) with or without Low dose Decitabine Priming for Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL): Two Stage, Phase I/II Trial | Unknown | I and II | NCT03346642 |
Gemcitabine | Nivolumab | Low dose Gemcitabine Combined with Nivolumab for Second-line and Above-line Treatment of Non-small Cell Lung Cancer Metastatic | Not yet recruiting | IV | NCT04331626 |
Cyclophosphamide | Pembrolizumab | CHEMOIMMUNE Study: Evaluation of Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide (Safety Run-in Phase) | Completed | II | EudraCT n. 2016-002736-33 |
Cyclophosphamide | Avelumab | CONFRONT Phase I-II Trial: Multimodality Immunotherapy with Avelumab, Short-Course Radiotherapy, and Cyclophosphamide in Patients with Relapsed/metastatic Head and Neck Cancer | Ongoing | I and II | EudraCT n. 2017-000353-39 |
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Muraro, E.; Vinante, L.; Fratta, E.; Bearz, A.; Höfler, D.; Steffan, A.; Baboci, L. Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors. Cancers 2023, 15, 2471. https://doi.org/10.3390/cancers15092471
Muraro E, Vinante L, Fratta E, Bearz A, Höfler D, Steffan A, Baboci L. Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors. Cancers. 2023; 15(9):2471. https://doi.org/10.3390/cancers15092471
Chicago/Turabian StyleMuraro, Elena, Lorenzo Vinante, Elisabetta Fratta, Alessandra Bearz, Daniela Höfler, Agostino Steffan, and Lorena Baboci. 2023. "Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors" Cancers 15, no. 9: 2471. https://doi.org/10.3390/cancers15092471
APA StyleMuraro, E., Vinante, L., Fratta, E., Bearz, A., Höfler, D., Steffan, A., & Baboci, L. (2023). Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors. Cancers, 15(9), 2471. https://doi.org/10.3390/cancers15092471