Effects of the Alkylating Agent Cyclophosphamide in Potentiating Anti-Tumor Immunity
Abstract
1. Introduction
2. Selective Depletion of Immune-Suppressive Cell Populations Within the TME
3. Influence of CPX on ICD in Cancer
4. CPX’s Impact on Myeloid Cell Activation
5. Direct Effects of CPX on Tumor Cells
6. CPX Stimulation of Type I IFN Release
7. CPX’s Influence on Th1 Immunity
8. Metronomic Low-Dose Administration of Chemotherapy
9. Metronomic Low-Dose Administration of CPX to Enhance Existing Cancer Immunotherapy in Preclinical Cancer Models
10. Metronomic Low-Dose Administration of CPX to Enhance Existing Cancer Immunotherapy in Clinical Trials
11. Discussion
12. Conclusions/Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ATP | adenosine triphosphate |
CR | complete response |
CRT | calreticulin |
CPX | cyclophosphamide |
DNA | deoxyribonucleic acid |
HMGB1 | high-mobility group box protein 1 |
ICD | immunogenic cell death |
IFN | interferon |
IL | interleukin |
JAK/STAT | Janus kinase/signal transducers and activators of transcription |
MAPK | mitogen-activated protein kinase |
MDSC | myeloid-derived suppressor cell |
MHC class I | major histocompatibility complex class I |
MHC class II | major histocompatibility complex class II |
NF-κB | nuclear factor kappa B |
NK cell | natural killer cell |
ORR | overall response rate |
OS | overall survival |
PFS | progression-free survival |
PD-1 | programmed cell death protein 1 |
PD-L1 | programmed death-ligand 1 |
PI3K/Akt | phosphoinositide 3-kinase/Akt |
TGF-β | transforming growth factor beta |
Th1 | T helper 1 |
TME | tumor microenvironment |
TNF-α | tumor necrosis factor alpha |
Treg | regulatory T cell |
VEGF | vascular endothelial growth factor |
VEX | treatment regimen of metronomic cyclophosphamide, vinorelbine, and capecitabine |
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Phase and No. of Patients | Cancer | Chemotherapy | Immunotherapy/Target | Primary Outcome | Identifier No. | Reference |
---|---|---|---|---|---|---|
Phase II, 40 patients | Recurrent ovarian cancer | MN CPX | Pembrolizumab (anti-PD-1) and bevacizumab (anti-VEGF) | 3 (7.5%) had CRs, 16 (40.0%) had PRs, and 19 (47.5%) had stable disease post-treatment, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 months. | NCT02853318 | [43] |
Phase II, 35 patients | Metastatic castration-resistant prostate cancer | MN CPX | Personalized tumor peptide vaccine | Patients with positive immune responses showed significantly longer survival than those with negative responses, with median OS of 27.1 months and 15.4 months, respectively. | UMIN000005329 * | [45] |
Phase II, 43 patients | Metastatic breast cancer | MN CPX, MN vinorelbine, MN capecitabine | Toripalimab (anti-PD-1) | The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. | NCT04389073 | [42] |
Phase I, 21 patients | Metastatic melanoma | MN CPX | Autologous dendritic cell vaccine | Well tolerated and favorable safety profile. | NCT00978913 | [46] |
Phase II, 13 patients | Desmoplastic small round cell tumor, neuroblastoma, and high-grade glioma | MN CPX | Nivolumab (anti-PD-1) | Well tolerated and favorable safety profile but limited clinical benefit. | NCT02813135 | [47] |
Phase I, 16 patients | Relapsed and refractory pediatric solid tumors | MN CPX, MN capecitabine and vinblastine | Nivolumab (anti-PD-1) | Well tolerated and low toxicity. | NCT03585465 | [48] |
Phase II, 20 patients | Head and neck squamous cell carcinoma | MN CPX and radiation | Avelumab (anti-PD-L1) | Favorable tolerability but limited clinical benefit. | EudraCT 201700035339 * | [49] |
Phase II, 20 patients | Soft tissue sarcoma | MN CPX | Oncolytic virus | Well tolerated and low toxicity. | NCT02630368 | [50] |
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Gephart, B.D.; Coulter, D.W.; Solheim, J.C. Effects of the Alkylating Agent Cyclophosphamide in Potentiating Anti-Tumor Immunity. Int. J. Mol. Sci. 2025, 26, 6440. https://doi.org/10.3390/ijms26136440
Gephart BD, Coulter DW, Solheim JC. Effects of the Alkylating Agent Cyclophosphamide in Potentiating Anti-Tumor Immunity. International Journal of Molecular Sciences. 2025; 26(13):6440. https://doi.org/10.3390/ijms26136440
Chicago/Turabian StyleGephart, Benjamin D., Don W. Coulter, and Joyce C. Solheim. 2025. "Effects of the Alkylating Agent Cyclophosphamide in Potentiating Anti-Tumor Immunity" International Journal of Molecular Sciences 26, no. 13: 6440. https://doi.org/10.3390/ijms26136440
APA StyleGephart, B. D., Coulter, D. W., & Solheim, J. C. (2025). Effects of the Alkylating Agent Cyclophosphamide in Potentiating Anti-Tumor Immunity. International Journal of Molecular Sciences, 26(13), 6440. https://doi.org/10.3390/ijms26136440