Old-School Chemotherapy in Immunotherapeutic Combination in Cancer, A Low-cost Drug Repurposed

Cancer Immunology Research

Volumn 4, Issue 5, 2016, Pages 377-382

  Eid, Rasha Abu ^a   Razavi, Ghazaleh Shoja E ^a   Mkrtichyan, Mikayel ^a,b   Janik, John ^a   Khleif, Samir N ^a  

^a MEDICAL COLLEGE OF GEORGIA   (United States)

^b FIVE PRIME THERAPEUTICS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPHOSPHAMIDE; ALKYLATING AGENT; IMMUNOLOGIC FACTOR;

ARTICLE; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; DRUG COST; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; MYELOID DERIVED SUPPRESSOR CELL; NEOPLASM; NONHUMAN; REGULATORY T LYMPHOCYTE; SUPPRESSOR CELL; DOSE RESPONSE; DRUG EFFECTS; DRUG REPOSITIONING; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS; PROCEDURES; T LYMPHOCYTE SUBPOPULATION;

ANTINEOPLASTIC AGENTS, ALKYLATING; CYCLOPHOSPHAMIDE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG REPOSITIONING; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOTHERAPY; NEOPLASMS; T-LYMPHOCYTE SUBSETS;

EID: 84976548411     PISSN: 23266066     EISSN: 23266074     Source Type: Journal    
DOI: 10.1158/2326-6066.CIR-16-0048     Document Type: Article

References (35)

1. de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 2005;44:1135-64.
2. Motoyoshi Y, Kaminoda K, Saitoh O, Hamasaki K, Nakao K, Ishii N, et al. Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide. Oncol Rep 2006;16:141-6.
3. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factorsecreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001;61:3689-97.
4. Keenan BP, Saenger Y, Kafrouni MI, Leubner A, Lauer P, Maitra A, et al. A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 2014;146:1784-94.e6.
5. Abu-Eid R, Samara RN, Ozbun L, Abdalla MY, Berzofsky JA, Friedman KM, et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol Res 2014;2:1080-9.
6. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862-8.
7. Roux S, Apetoh L, Chalmin F, Ladoire S, Mignot G, Puig PE, et al. CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumorinfiltrating DCs in rodent models of colon cancer. J Clin Invest 2008; 118:3751-61.
8. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004;34:336-44.
9. Mkrtichyan M, Najjar YG, Raulfs EC, Abdalla MY, Samara R, Rotem-Yehudar R, et al. Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Eur J Immunol 2011;41:2977-86.
10. Mkrtichyan M, Najjar YG, Raulfs EC, Liu L, Langerman S, Guittard G, et al. B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets. J Immunol 2012;189:2338-47.
11. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007; 56:641-8.
12. Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J, et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 2012;61:353-62.
13. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 2015;38:1-11.
14. Wada S, Jackson CM, Yoshimura K, Yen HR, Getnet D, Harris TJ, et al. Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. J Transl Med 2013;11:89.
15. Korbelik M, Banath J, Saw KM. Immunoregulatory cell depletion improves the efficacy of photodynamic therapy-generated cancer vaccines. Int J Mol Sci 2015;16:27005-14.
16. Zhao J, Cao Y, Lei Z, Yang Z, Zhang B, Huang B. Selective depletion of CD4+CD25+Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels. Cancer Res 2010;70:4850-8.
17. Dimeloe S, Frick C, Fischer M, Gubser PM, Razik L, Bantug GR, et al. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur J Immunol 2014;44:3614-20.
18. Govindaraj C, Scalzo-Inguanti K, Madondo M, Hallo J, Flanagan K, Quinn M, et al. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment. Clin Immunol 2013; 149:97-110.
19. van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 2009;58:1219-28.
20. Weir GM, Hrytsenko O, Stanford MM, Berinstein NL, Karkada M, Liwski RS, et al. Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response. Oncoimmunology 2014;3:e953407.
21. Mackiewicz J, Kotlarski M, Dondajewska E, Nowicka-Kotlarska A, Krokowicz L, Kazimierczak U. Cell-based Hyper-interleukin 6 or Hyper-interleukin 11 secreting vaccines combined with low dose cyclophosphamide in an orthotopic murine prostate cancer model. Contemp Oncol (Pozn) 2015;19:187-94.
22. Xuan W, Yan Y, Wan M, Wu X, Ji D, Wang L, et al. Antitumor activity of mHSP65-TTL enhanced by administration of low dose cyclophosphamide in pancreatic cancer-bearing mice. Int Immunopharmacol 2015;27:95-103.
23. Schiavoni G, Mattei F, Di Pucchio T, Santini SM, Bracci L, Belardelli F, et al. Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 2000;95:2024-30.
24. Matar P, Rozados VR, Gervasoni SI, Scharovsky GO. Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol Immunother 2002;50:588-96.
25. Viaud S, Flament C, Zoubir M, Pautier P, LeCesne A, Ribrag V, et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res 2011;71:661-5.
26. Niedbala W, Wei XQ, Campbell C, Thomson D, Komai-Koma M, Liew FY. Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor beta 2 expression via cGMP. Proc Natl Acad Sci U S A 2002;99:16186-91.
27. Loeffler M, Kruger JA, Reisfeld RA. Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase. Cancer Res 2005;65:5027-30.
28. Abu Eid R, Friedman KM, Mkrtichyan M, Walens A, King W, Janik J, et al. Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8 T-cell proliferation and survival. Oncoimmunology 2015;4:e1005448.
29. Sevko A, Sade-Feldman M, Kanterman J, Michels T, Falk CS, Umansky L, et al. Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J Invest Dermatol 2013;133:1610-9.
30. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 1982;155:1063-74.
31. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 2012; 18:1254-61.
32. Klein O, Davis ID, McArthur GA, Chen L, Haydon A, Parente P, et al. Lowdose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. Cancer Immunol Immunother 2015;64:507-18.
33. Berinstein NL, Karkada M, Oza AM, Odunsi K, Villella JA, Nemunaitis JJ, et al. Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. Oncoimmunology 2015;4:e1026529.
34. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 2015;33:1325-33.
35. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res 2014;2: 616-31.