Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Cancer Drug Targets
  4. Fast Track Articles
  5. Fast Track Article
image of A Combination Therapy of Cyclophosphamide and Immunomodulating Agents in Cancer

Abstract

Cyclophosphamide is a precursor of alkylating nitrogen mustard and was initially claimed to have antineoplastic and immunosuppressive properties. However, the role of cyclophosphamide as an immune activator has also been reported, depending on the dosage used. The application of lower-dose cyclophosphamide has emerged as a potential approach to cancer treatment. Cyclophosphamide selectively depletes regulatory T cells (Tregs), which dampens the immunological response, thereby rebalancing the immune system to allow other immune cells to act more efficiently. Cyclophosphamide can be either a friend or a foe in cancer treatment, depending on the therapeutic regime. The following questions remain to be answered: Can the cyclophosphamide be used in the presence of other agents? Is there any single immunotherapeutic agent that acts synergistically with cyclophosphamide to effectively alter the immunosuppressive tumor microenvironment? This review emphasizes the role of cyclophosphamide as an immune modulator, both alone and in combination with other immunotherapeutic agents, for effective cancer treatment in preclinical and clinical settings.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096314791240830111909
2024-10-08
2025-04-09

  • From This Site

    /content/journals/ccdt/10.2174/0115680096314791240830111909
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Marin J.J.G. Romero M.R. Blazquez A.G. Herraez E. Keck E. Briz O. Importance and limitations of chemothera-py among the available treatments for gastrointestinal tu-mours. Anticancer. Agents Med. Chem. 2009 9 2 162 184 10.2174/187152009787313828 19199863
    [Google Scholar]
  2. Alfarouk K.O. Stock C.M. Taylor S. Walsh M. Mudda-thir A.K. Verduzco D. Bashir A.H.H. Mohammed O.Y. Elhassan G.O. Harguindey S. Reshkin S.J. Ibrahim M.E. Rauch C. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int. 2015 15 1 71 10.1186/s12935‑015‑0221‑1 26180516
    [Google Scholar]
  3. Zeien J. Qiu W. Triay M. Dhaibar H.A. Cruz-Topete D. Cornett E.M. Urits I. Viswanath O. Kaye A.D. Clinical implications of chemotherapeutic agent organ toxicity on perioperative care. Biomed. Pharmacother. 2022 146 112503 10.1016/j.biopha.2021.112503 34922113
    [Google Scholar]
  4. D’Alterio C. Scala S. Sozzi G. Roz L. Bertolini G. Para-doxical effects of chemotherapy on tumor relapse and metas-tasis promotion. Semin. Cancer Biol. 2020 60 351 361 10.1016/j.semcancer.2019.08.019 31454672
    [Google Scholar]
  5. Galluzzi L. Buqué A. Kepp O. Zitvogel L. Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 2015 28 6 690 714 10.1016/j.ccell.2015.10.012 26678337
    [Google Scholar]
  6. Li K. Zhang Z. Mei Y. Li M. Yang Q. Wu Q. Yang H. He L. Liu S. Targeting the innate immune system with na-noparticles for cancer immunotherapy. J. Mater. Chem. B Mater. Biol. Med. 2022 10 11 1709 1733 10.1039/D1TB02818A
    [Google Scholar]
  7. Basu A. DNA damage, mutagenesis and cancer. Int. J. Mol. Sci. 2018 19 4 970 10.3390/ijms19040970 29570697
    [Google Scholar]
  8. Mills K.A. Chess-Williams R. McDermott C. Novel in-sights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothe-lial dysfunction in vitro. Arch. Toxicol. 2019 93 11 3291 3303 10.1007/s00204‑019‑02589‑1 31598736
    [Google Scholar]
  9. Alhmoud J.F. Woolley J.F. Al Moustafa A.E. Malki M.I. DNA damage/repair management in cancers. Cancers (Basel) 2020 12 4 1050 10.3390/cancers12041050 32340362
    [Google Scholar]
  10. Ghiringhelli F. Menard C. Puig P.E. Ladoire S. Roux S. Martin F. Solary E. Le Cesne A. Zitvogel L. Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effec-tor functions in end stage cancer patients. Cancer Immunol. Immunother. 2007 56 5 641 648 10.1007/s00262‑006‑0225‑8 16960692
    [Google Scholar]
  11. Vardanyan R.S. Hruby V.J. Antineoplastics. Synthesis of Essential Drugs. Elsevier 2006 389 418 10.1016/B978‑044452166‑8/50030‑3
    [Google Scholar]
  12. Chibber S. Hassan I. Farhan M. Salman M. Naseem I. White light augments chemotherapeutic potential of cyclo-phosphamide: an in vitro study. Biometals 2013 26 1 23 31 10.1007/s10534‑012‑9591‑1 23100198
    [Google Scholar]
  13. Motoyoshi Y. Kaminoda K. Saitoh O. Hamasaki K. Na-kao K. Ishii N. Nagayama Y. Eguchi K. Different mecha-nisms for anti-tumor effects of low- and high-dose cyclo-phosphamide. Oncol. Rep. 2006 16 1 141 146 10.3892/or.16.1.141 16786137
    [Google Scholar]
  14. Hughes E. Scurr M. Campbell E. Jones E. Godkin A. Gallimore A. T‐cell modulation by cyclophosphamide for tumour therapy. Immunology 2018 154 1 62 68 10.1111/imm.12913 29460448
    [Google Scholar]
  15. Rivera-Lazarín A.L. Martínez-Torres A.C. The bovine dia-lyzable leukocyte extract, immunepotent CRP, synergically enhances cyclophosphamide-induced breast cancer cell death, through a caspase-independent mechanism. EXCLI J. 2023 22 131 145 10.17179/excli2022‑5389
    [Google Scholar]
  16. Santos G.W. Owens A.H. Jr 19S and 17S antibody produc-tion in the cyclophosphamide- or methotrexate-treated rat. Nature 1966 209 5023 622 624 10.1038/209622a0 5921198
    [Google Scholar]
  17. Winkelstein A. Mechanisms of immunosuppression: effects of cyclophosphamide on cellular immunity. Blood 1973 41 2 273 284 10.1182/blood.V41.2.273.273 4541036
    [Google Scholar]
  18. Falvo P. Orecchioni S. Hillje R. Raveane A. Mancuso P. Camisaschi C. Luzi L. Pelicci P. Bertolini F. Cyclophos-phamide and vinorelbine activate stem-like CD8+ T cells and improve anti-PD-1 efficacy in triple-negative breast cancer. Cancer Res. 2021 81 3 685 697 10.1158/0008‑5472.CAN‑20‑1818 33268528
    [Google Scholar]
  19. Choi J. Rod-in W. Jang A. Park W.J. Arctoscopus japoni-cus lipids enhance immunity of mice with cyclophosphamide-induced immunosuppression. Foods 2023 12 17 3292 3292 10.3390/foods12173292 37685225
    [Google Scholar]
  20. Elazab M.F.A. Younes A.M. Gaafar A.Y. Abu-Bryka A.Z. Abdel-Daim M.M. Immunosuppressive effect of cy-clophosphamide in Nile tilapia (Oreochromis niloticus). Environ. Sci. Pollut. Res. Int. 2021 28 16 20784 20793 10.1007/s11356‑020‑11893‑8 33405143
    [Google Scholar]
  21. Leong W.I. Ames R.Y. Haverkamp J.M. Torres L. Kline J. Bans A. Rocha L. Gallotta M. Guiducci C. Coffman R.L. Janatpour M.J. Low-dose metronomic cyclophospha-mide complements the actions of an intratumoral C-class CpG TLR9 agonist to potentiate innate immunity and drive potent T cell-mediated anti-tumor responses. Oncotarget 2019 10 68 7220 7237 10.18632/oncotarget.27322 31921384
    [Google Scholar]
  22. Webb E.R. Moreno-Vicente J. Easton A. Lanati S. Tay-lor M. James S. Williams E.L. English V. Penfold C. Beers S.A. Gray J.C. Cyclophosphamide depletes tumor in-filtrating T regulatory cells and combined with anti-PD-1 ther-apy improves survival in murine neuroblastoma. iScience 2022 25 9 104995 104995 10.1016/j.isci.2022.104995 36097618
    [Google Scholar]
  23. Oparaugo N.C. Ouyang K. Nguyen N.P.N. Nelson A.M. Agak G.W. Human regulatory T cells: Understanding the role of tregs in select autoimmune skin diseases and post-transplant nonmelanoma skin cancers. Int. J. Mol. Sci. 2023 24 2 1527 1527 10.3390/ijms24021527 36675037
    [Google Scholar]
  24. Fehérvari Z. Sakaguchi S. Development and function of CD25+CD4+ regulatory T cells. Curr. Opin. Immunol. 2004 16 2 203 208 10.1016/j.coi.2004.01.004 15023414
    [Google Scholar]
  25. Heylmann D. Bauer M. Becker H. van Gool S. Bacher N. Steinbrink K. Kaina B. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implica-tions for the immune response. PLoS One 2013 8 12 e83384 10.1371/journal.pone.0083384 24376696
    [Google Scholar]
  26. Akimova T. Beier U.H. Wang L. Levine M.H. Hancock W.W. Helios expression is a marker of T cell activation and proliferation. PLoS One 2011 6 8 e24226 10.1371/journal.pone.0024226 21918685
    [Google Scholar]
  27. Thornton A.M. Lu J. Korty P.E. Kim Y.C. Martens C. Sun P.D. Shevach E.M. Helios + and Helios − Treg subpopu-lations are phenotypically and functionally distinct and ex-press dissimilar TCR repertoires. Eur. J. Immunol. 2019 49 3 398 412 10.1002/eji.201847935 30620397
    [Google Scholar]
  28. Chougnet C. Hildeman D. Helios—controller of Treg stabil-ity and function. Transl. Cancer Res. 2016 5 S2 Suppl. 2 S338 S341 10.21037/tcr.2016.07.37 30656143
    [Google Scholar]
  29. Baine I. Basu S. Ames R. Sellers R.S. Macian F. Helios induces epigenetic silencing of IL2 gene expression in regula-tory T cells. J. Immunol. 2013 190 3 1008 1016 10.4049/jimmunol.1200792 23275607
    [Google Scholar]
  30. Yu W. Ji N. Gu C. Wang Y. Huang M. Zhang M. Coex-pression of Helios in Foxp3+ Regulatory T Cells and Its Role in Human Disease. Dis. Markers 2021 2021 1 9 10.1155/2021/5574472 34257746
    [Google Scholar]
  31. Peng S. Lyford-Pike S. Akpeng B. Wu A. Hung C.F. Hannaman D. Saunders J.R. Wu T.C. Pai S.I. Low-dose cyclophosphamide administered as daily or single dose en-hances the antitumor effects of a therapeutic HPV vaccine. Cancer Immunol. Immunother. 2013 62 1 171 182 10.1007/s00262‑012‑1322‑5 23011589
    [Google Scholar]
  32. Zhong H. Lai Y. Zhang R. Daoud A. Feng Q. Zhou J. Shang J. Low Dose Cyclophosphamide Modulates Tumor Microenvironment by TGF-β Signaling Pathway. Int. J. Mol. Sci. 2020 21 3 957 10.3390/ijms21030957 32023984
    [Google Scholar]
  33. Scurr M. Pembroke T. Bloom A. Roberts D. Thomson A. Smart K. Bridgeman H. Adams R. Brewster A. Jones R. Gwynne S. Blount D. Harrop R. Hills R. Gallimore A. Godkin A. Low-Dose Cyclophosphamide Induces Anti-tumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer. Clin. Cancer Res. 2017 23 22 6771 6780 10.1158/1078‑0432.CCR‑17‑0895 28855352
    [Google Scholar]
  34. Nakahara T. Uchi H. Lesokhin A.M. Avogadri F. Riz-zuto G.A. Hirschhorn-Cymerman D. Panageas K.S. Merghoub T. Wolchok J.D. Houghton A.N. Cyclophos-phamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs. Blood 2010 115 22 4384 4392 10.1182/blood‑2009‑11‑251231 20154220
    [Google Scholar]
  35. van der Most R.G. Currie A.J. Mahendran S. Prosser A. Darabi A. Robinson B.W.S. Nowak A.K. Lake R.A. Tu-mor eradication after cyclophosphamide depends on concur-rent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol. Immunother. 2009 58 8 1219 1228 10.1007/s00262‑008‑0628‑9 19052741
    [Google Scholar]
  36. Ghiringhelli F. Larmonier N. Schmitt E. Parcellier A. Cathelin D. Garrido C. Chauffert B. Solary E. Bonnotte B. Martin F. CD4 + CD25 + regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which al-lows immunotherapy of established tumors to be curative. Eur. J. Immunol. 2004 34 2 336 344 10.1002/eji.200324181 14768038
    [Google Scholar]
  37. Li P. Chen F. Zheng J. Yang Y. Li Y. Wang Y. Chen X. Cyclophosphamide abrogates the expansion of CD4+Foxp3+ regulatory T cells and enhances the efficacy of bleomycin in the treat-ment of mouse B16-F10 melanomas. Cancer Biol. Med. 2021 18 0027 10.20892/j.issn.2095‑3941.2021.0027
    [Google Scholar]
  38. Ge Y. Domschke C. Stoiber N. Schott S. Heil J. Rom J. Blumenstein M. Thum J. Sohn C. Schneeweiss A. Beckhove P. Schuetz F. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunologi-cal effects and clinical outcome. Cancer Immunol. Immunother. 2012 61 3 353 362 10.1007/s00262‑011‑1106‑3 21915801
    [Google Scholar]
  39. Noordam L. Kaijen M.E.H. Bezemer K. Cornelissen R. Maat L.A.P.W.M. Hoogsteden H.C. Aerts J.G.J.V. Hen-driks R.W. Hegmans J.P.J.J. Vroman H. Low-dose cyclo-phosphamide depletes circulating naïve and activated regula-tory T cells in malignant pleural mesothelioma patients syner-gistically treated with dendritic cell-based immunotherapy. OncoImmunology 2018 7 12 e1474318 10.1080/2162402X.2018.1474318 30524884
    [Google Scholar]
  40. Mery B. Ménétrier-Caux C. Montané L. Pembrolizumab in lymphopenic metastatic breast cancer patients treated with metronomic cyclophosphamide: A clinical and translational prospective study. Breast Cancer 2023 15 311 325 10.2147/BCTT.S400055
    [Google Scholar]
  41. Sikandar B. Qureshi M.A. Naseem S. Khan S. Mirza T. Increased Tumour Infiltration of CD4+ and CD8+ T-Lymphocytes in Patients with Triple Negative Breast Cancer Suggests Susceptibility to Immune Therapy. PubMed 2017 18 7 1827 1832 10.22034/apjcp.2017.18.7.1827 28749113
    [Google Scholar]
  42. Zsiros E. Lynam S. Attwood K.M. Wang C. Chilakapati S. Gomez E.C. Liu S. Akers S. Lele S. Frederick P.J. Odunsi K. Efficacy and Safety of Pembrolizumab in Combi-nation With Bevacizumab and Oral Metronomic Cyclophos-phamide in the Treatment of Recurrent Ovarian Cancer. JAMA Oncol. 2021 7 1 78 85 10.1001/jamaoncol.2020.5945 33211063
    [Google Scholar]
  43. Arce Vargas, F.; Furness, A.J.S.; Solomon, I.; Joshi, K.; Mekkaoui, L.; Lesko, M.H.; Miranda Rota, E.; Dahan, R.; Georgiou, A.; Sledzinska, A.; Ben Aissa, A.; Franz, D.; Werner Sunderland, M.; Wong, Y.N.S.; Henry, J.Y.; O’Brien, T.; Nicol, D.; Challacombe, B.; Beers, S.A.; Turajlic, S.; Gore, M.; Larkin, J.; Swanton, C.; Chester, K.A.; Pule, M.; Ravetch, J.V.; Marafioti, T.; Peggs, K.S.; Quezada, S.A.; Spain, L.; Wotherspoon, A.; Francis, N.; Smith, M.; Strauss, D.; Hayes, A.; Soultati, A.; Stares, M.; Spain, L.; Lynch, J.; Fotiadis, N.; Fernando, A.; Hazell, S.; Chandra, A.; Pickering, L.; Rudman, S.; Chowdhury, S.; Swanton, C.; Jamal-Hanjani, M.; Veeriah, S.; Shafi, S.; Czyzewska-Khan, J.; Johnson, D.; Laycock, J.; Bosshard-Carter, L.; Goh, G.; Rosenthal, R.; Gorman, P.; Muru-gaesu, N.; Hynds, R.E.; Wilson, G.; Birkbak, N.J.; Watkins, T.B.K.; McGranahan, N.; Horswell, S.; Mitter, R.; Escudero, M.; Stewart, A.; Van Loo, P.; Rowan, A.; Xu, H.; Turajlic, S.; Hiley, C.; Abbosh, C.; Goldman, J.; Stone, R.K.; Denner, T.; Matthews, N.; Elgar, G.; Ward, S.; Biggs, J.; Costa, M.; Begum, S.; Phillimore, B.; Chambers, T.; Nye, E.; Graca, S.; Al Bakir, M.; Hartley, J.A.; Lowe, H.L.; Herrero, J.; Lawrence, D.; Hayward, M.; Panagiotopoulos, N.; Kolvekar, S.; Falzon, M.; Borg, E.; Simeon, C.; Hector, G.; Smith, A.; Aranda, M.; Novelli, M.; Oukrif, D.; Janes, S.M.; Thakrar, R.; Forster, M.; Ahmad, T.; Lee, S.M.; Papa-datos-Pastos, D.; Carnell, D.; Mendes, R.; George, J.; Navani, N.; Ahmed, A.; Taylor, M.; Choudhary, J.; Summers, Y.; Califano, R.; Taylor, P.; Shah, R.; Krysiak, P.; Rammohan, K.; Fontaine, E.; Booton, R.; Evison, M.; Crosbie, P.; Moss, S.; Idries, F.; Joseph, L.; Bishop, P.; Chaturved, A.; Quinn, A.M.; Doran, H.; Leek, A.; Harrison, P.; Moore, K.; Waddington, R.; Novasio, J.; Blackhall, F.; Rogan, J.; Smith, E.; Dive, C.; Tugwood, J.; Brady, G.; Roth-well, D.G.; Chemi, F.; Pierce, J.; Gulati, S.; Naidu, B.; Langman, G.; Trotter, S.; Bellamy, M.; Bancroft, H.; Kerr, A.; Kadiri, S.; Webb, J.; Middleton, G.; Djearaman, M.; Fennell, D.; Shaw, J.A.; Le Quesne, J.; Moore, D.; Nakas, A.; Rathinam, S.; Monteiro, W.; Marshall, H.; Nelson, L.; Bennett, J.; Riley, J.; Primrose, L.; Mar-tinson, L.; Anand, G.; Khan, S.; Amadi, A.; Nicolson, M.; Kerr, K.; Palmer, S.; Remmen, H.; Miller, J.; Buchan, K.; Chetty, M.; Gomersall, L.; Lester, J.; Edwards, A.; Morgan, F.; Adams, H.; Davies, H.; Kornaszewska, M.; Attanoos, R.; Lock, S.; Verjee, A.; MacKenzie, M.; Wilcox, M.; Bell, H.; Iles, N.; Hackshaw, A.; Ngai, Y.; Smith, S.; Gower, N.; Ottensmeier, C.; Chee, S.; Johnson, B.; Alzetani, A.; Shaw, E.; Lim, E.; De Sousa, P.; Barbosa, M.T.; Bowman, A.; Jorda, S.; Rice, A.; Raubenheimer, H.; Proli, C.; Cufari, M.E.; Ronquillo, J.C.; Kwayie, A.; Bhayani, H.; Hamilton, M.; Bakar, Y.; Mensah, N.; Ambrose, L.; Devaraj, A.; Buderi, S.; Finch, J.; Azcarate, L.; Chavan, H.; Green, S.; Mashinga, H.; Ni-cholson, A.G.; Lau, K.; Sheaff, M.; Schmid, P.; Conibear, J.; Ezhil, V.; Ismail, B.; Irvin-sellers, M.; Prakash, V.; Russell, P.; Light, T.; Horey, T.; Danson, S.; Bury, J.; Edwards, J.; Hill, J.; Matthews, S.; Kitsanta, Y.; Suvarna, K.; Fisher, P.; Keerio, A.D.; Shackcloth, M.; Gosney, J.; Postmus, P.; Feeney, S.; Asante-Siaw, J. Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity 2017 46 4 577 586 10.1016/j.immuni.2017.03.013 28410988
    [Google Scholar]
  44. Roghanian A. Stopforth R.J. Dahal L.N. Cragg M.S. New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B). J. Leukoc. Biol. 2018 103 6 1077 1088 10.1002/JLB.2MIR0917‑354R 29406570
    [Google Scholar]
  45. Roghanian A. Hu G. Fraser C.S. Singh M. Foxall R.B. Meyer M. Lees E. Huet H. Glennie M.J. Beers S.A. Lim S. Ashton-Key M. Thirdborough S.M. Cragg M.S. Chen J. Cyclophosphamide enhances cancer antibody immu-notherapy in the resistant bone marrow niche by modulating macrophage FcγR expression. Cancer Immunol. Res. 2019 7 11 1876 1890 10.1158/2326‑6066.CIR‑18‑0835
    [Google Scholar]
  46. Kantoff P.W. Higano C.S. Shore N.D. Berger E.R. Small E.J. Penson D.F. Redfern C.H. Ferrari A.C. Dreicer R. Sims R.B. Xu Y. Frohlich M.W. Schellhammer P.F. Sip-uleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 2010 363 5 411 422 10.1056/NEJMoa1001294 20818862
    [Google Scholar]
  47. Walter S. Weinschenk T. Stenzl A. Zdrojowy R. Pluzan-ska A. Szczylik C. Staehler M. Brugger W. Dietrich P.Y. Mendrzyk R. Hilf N. Schoor O. Fritsche J. Mahr A. Maurer D. Vass V. Trautwein C. Lewandrowski P. Flohr C. Pohla H. Stanczak J.J. Bronte V. Mandruzzato S. Biedermann T. Pawelec G. Derhovanessian E. Yamagishi H. Miki T. Hongo F. Takaha N. Hirakawa K. Tanaka H. Stevanovic S. Frisch J. Mayer-Mokler A. Kirner A. Rammensee H.G. Reinhardt C. Singh-Jasuja H. Multipep-tide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient surviv-al. Nat. Med. 2012 18 8 1254 1261 10.1038/nm.2883 22842478
    [Google Scholar]
  48. Walter S. Weinschenk T. Reinhardt C. Singh-Jasuja H. Single-dose cyclophosphamide synergizes with immune re-sponses to the renal cell cancer vaccine IMA901. OncoImmunology 2013 2 1 e22246 10.4161/onci.22246 23482454
    [Google Scholar]
  49. Tanaka A. Sakaguchi S. Regulatory T cells in cancer immu-notherapy. Cell Res. 2017 27 1 109 118 10.1038/cr.2016.151 27995907
    [Google Scholar]
  50. Saleh R. Elkord E. FoxP3+ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett. 2020 490 174 185 10.1016/j.canlet.2020.07.022 32721551
    [Google Scholar]
  51. McCarthy P.M. Valdera F.A. Smolinsky T.R. Adams A.M. O’Shea A.E. Thomas K.K. Van Decar S. Carpenter E.L. Tiwari A. Myers J.W. Hale D.F. Vreeland T.J. Peo-ples G.E. Stojadinovic A. Clifton G.T. Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials. Front. Immunol. 2023 14 1090533 10.3389/fimmu.2023.1090533 36960052
    [Google Scholar]
  52. Pol J.G. Atherton M.J. Stephenson K.B. Bridle B.W. Workenhe S.T. Kazdhan N. McGray A.J.R. Wan Y. Kroemer G. Lichty B.D. Enhanced immunotherapeutic pro-file of oncolytic virus-based cancer vaccination using cyclo-phosphamide preconditioning. J. Immunother. Cancer 2020 8 2 e000981 10.1136/jitc‑2020‑000981 32792361
    [Google Scholar]
  53. Gao J. Wang W. Pei Q. Lord M.S. Yu H. Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy. Acta Pharmacol. Sin. 2020 41 7 986 994 10.1038/s41401‑020‑0400‑z 32317755
    [Google Scholar]
  54. Yang F. Shi K. Hao Y. Jia Y. Liu Q. Chen Y. Pan M. Yuan L. Yu Y. Qian Z. Cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner. Bioact. Mater. 2021 6 10 3036 3048 10.1016/j.bioactmat.2021.03.003 33778186
    [Google Scholar]
  55. Berinstein N.L. Karkada M. Oza A.M. Odunsi K. Vil-lella J.A. Nemunaitis J.J. Morse M.A. Pejovic T. Bentley J. Buyse M. Nigam R. Weir G.M. MacDonald L.D. Quinton T. Rajagopalan R. Sharp K. Penwell A. Samma-tur L. Burzykowski T. Stanford M.M. Mansour M. Sur-vivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. OncoImmunology 2015 4 8 e1026529 10.1080/2162402X.2015.1026529 26405584
    [Google Scholar]
  56. Bracci L. Moschella F. Sestili P. La Sorsa V. Valentini M. Canini I. Baccarini S. Maccari S. Ramoni C. Be-lardelli F. Proietti E. Cyclophosphamide enhances the anti-tumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin. Cancer Res. 2007 13 2 644 653 10.1158/1078‑0432.CCR‑06‑1209 17255288
    [Google Scholar]
  57. Jameson S.C. Maintaining the norm: T-cell homeostasis. Nat. Rev. Immunol. 2002 2 8 547 556 10.1038/nri853 12154374
    [Google Scholar]
  58. Kravtsov D.S. Erbe A.K. Sondel P.M. Rakhmilevich A.L. Roles of CD4+ T cells as mediators of antitumor immunity. Front. Immunol. 2022 13 972021 10.3389/fimmu.2022.972021 36159781
    [Google Scholar]
  59. Poncette L. Bluhm J. Blankenstein T. The role of CD4 T cells in rejection of solid tumors. Curr. Opin. Immunol. 2022 74 18 24 10.1016/j.coi.2021.09.005 34619457
    [Google Scholar]
  60. Dorff T.B. Blanchard M.S. Adkins L.N. Luebbert L. Leggett N. Shishido S.N. Macias A. Del Real M.M. Dhapola G. Egelston C. Murad J.P. Rosa R. Paul J. Chaudhry A. Martirosyan H. Gerdts E. Wagner J.R. Still-er T. Tilakawardane D. Pal S. Martinez C. Reiter R.E. Budde L.E. D’Apuzzo M. Kuhn P. Pachter L. Forman S.J. Priceman S.J. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 2024 30 6 1636 1644 10.1038/s41591‑024‑02979‑8 38867077
    [Google Scholar]
  61. Murad J.P. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. Mol. Ther. 2021 29 7 2335 2349 10.1016/j.ymthe.2021.02.024
    [Google Scholar]
  62. Lickefett B. Chu L. Ortiz-Maldonado V. Warmuth L. Barba P. Doglio M. Henderson D. Hudecek M. Kremer A. Markman J. Nauerth M. Negre H. Sanges C. Staber P.B. Tanzi R. Delgado J. Busch D.H. Kuball J. Luu M. Jäger U. Lymphodepletion – an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle. Front. Immunol. 2023 14 1303935 10.3389/fimmu.2023.1303935 38187393
    [Google Scholar]
  63. Singh S. Chakrabarti R. Challenges of Using IFNγ in Clinical Settings. Cancer Res. 2023 83 13 2093 2095 10.1158/0008‑5472.CAN‑22‑0571 37403627
    [Google Scholar]
  64. Moschella F. Torelli G.F. Valentini M. Urbani F. Buc-cione C. Petrucci M.T. Natalino F. Belardelli F. Foà R. Proietti E. Cyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients’ blood cells: implications for cancer chemoimmuno-therapy. Clin. Cancer Res. 2013 19 15 4249 4261 10.1158/1078‑0432.CCR‑12‑3666 23759676
    [Google Scholar]
  65. Kwa M. Li X. Novik Y. Oratz R. Jhaveri K. Wu J. Gu P. Meyers M. Muggia F. Speyer J. Iwano A. Bonakdar M. Kozhaya L. Tavukcuoglu E. Budan B. Raad R. Goldberg J.D. Unutmaz D. Adams S. Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer. Breast Cancer Res. Treat. 2018 168 1 57 67 10.1007/s10549‑017‑4570‑4 29124456
    [Google Scholar]
  66. Rossmann E. Österborg A. Löfvenberg E. Choudhury A. Forssmann U. von Heydebreck A. Schröder A. Mellstedt H. Mucin 1-specific active cancer immunotherapy with tecemotide (L-BLP25) in patients with multiple myeloma: An exploratory study. Hum. Vaccin. Immunother. 2014 10 11 3394 3408 10.4161/hv.29918 25483677
    [Google Scholar]
  67. Agarwal P. Qi H. Munjal K. Gai J. Ferguson A. Parkin-son R. Harrison J. Rodriguez C. Anders R.A. Thompson E.D. Burkhart R. He J. Narang A. De Jesus-Acosta A. Zheng L. Jaffee E.M. George B. Laheru D.A. Yarchoan M. Osipov A. Overall survival (OS) and pathologic response rate from a phase II clinical trial of neoadjuvant GVAX pancreas vaccine (with cyclo-phosphamide) in combination with nivolumab and stereotactic body radiation therapy (SBRT) followed by definitive resection for patients with borderline resectable pancreatic adenocarcinoma (BR-PDAC). J. Clin. Oncol. 2023 41 (16_suppl)(Suppl.) e16309 e16309 10.1200/JCO.2023.41.16_suppl.e16309
    [Google Scholar]
  68. Patel T.H. van Rhee F. Al Hadidi S. Cereblon E3 Ligase Modulators Mezigdomide and Iberdomide in Multiple Myeloma. Clin. Lymphoma Myeloma Leuk 2024 S2152-2650(24)00238-6 10.1016/j.clml.2024.06.004 39003099
    [Google Scholar]
  69. Veneziani A. Lheureux S. Alqaisi H. Bhat G. Colombo I. Gonzalez E. Newton S. Msan A. Quintos J. Ramsahai J. Grant R.C. Dhani N.C. Wang L. Bowering V. Oza A.M. Pembrolizumab, maveropepimut-S, and low-dose cyclophospha-mide in advanced epithelial ovarian cancer: Results from phase 1 and expansion cohort of PESCO trial. J. Clin. Oncol. 2022 40 (16_suppl)(Suppl.) 5505 5505 10.1200/JCO.2022.40.16_suppl.5505
    [Google Scholar]
  70. Kastritis E. Palladini G. Minnema M.C. Wechalekar A.D. Jaccard A. Lee H.C. Sanchorawala V. Gibbs S. Mollee P. Venner C.P. Lu J. Schönland S. Gatt M.E. Suzuki K. Kim K. Cibeira M.T. Beksac M. Libby E. Valent J. Hungria V. Wong S.W. Rosenzweig M. Bumma N. Huart A. Dimopoulos M.A. Bhutani D. Waxman A.J. Goodman S.A. Zonder J.A. Lam S. Song K. Hansen T. Manier S. Roeloffzen W. Jamroziak K. Kwok F. Shimazaki C. Kim J.S. Crusoe E. Ahmadi T. Tran N. Qin X. Vasey S.Y. Tromp B. Schecter J.M. Weiss B.M. Zhuang S.H. Ver-meulen J. Merlini G. Comenzo R.L. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N. Engl. J. Med. 2021 385 1 46 58 10.1056/NEJMoa2028631 34192431
    [Google Scholar]
  71. Tang F. Zhong Q. Yang Z. Li H. Pan C. Huang L. Ni T. Deng R. Wang Z. Tan S. Nie Y. Zhang Y. Low-dose cyclophosphamide combined with IL-2 inhibits tumor growth by decreasing regulatory T cells and increasing CD8+ T cells and natural killer cells in mice. Immunobiology 2022 227 3 152212 10.1016/j.imbio.2022.152212 35436750
    [Google Scholar]
  72. Castano A.P. Mroz P. Wu M.X. Hamblin M.R. Photody-namic therapy plus low-dose cyclophosphamide generates an-titumor immunity in a mouse model. Proc. Natl. Acad. Sci. USA 2008 105 14 5495 5500 10.1073/pnas.0709256105 18378905
    [Google Scholar]
  73. Barbon C.M. Yang M. Wands G.D. Ramesh R. Slusher B.S. Hedley M.L. Luby T.M. Consecutive low doses of cy-clophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immuniza-tion. Cell. Immunol. 2010 262 2 150 161 10.1016/j.cellimm.2010.02.007 20206921
    [Google Scholar]
  74. Lv J.Y. Hu T.Y. Wang R.Y. Zhu J.M. Wang G. Deci-phering the anti-angiogenic effect of en-dostatin/cyclophosphamide to normalize tumor micrangium through notch signaling pathway in colon cancer. World J. Surg. Oncol. 2015 14 1 10 10.1186/s12957‑015‑0761‑9 26762567
    [Google Scholar]
/content/journals/ccdt/10.2174/0115680096314791240830111909
Loading
A Combination Therapy of Cyclophosphamide and Immunomodulating Agents in Cancer
Bentham Science Publishers ; https://doi.org/10.2174/0115680096314791240830111909
/content/journals/ccdt/10.2174/0115680096314791240830111909
/content/journals/ccdt/10.2174/0115680096314791240830111909
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: combination therapy ; modulator ; Cyclophosphamide ; cancer ; immunotherapy

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test