title: Immunomodulatory effects of cyclophosphamide and implementations for vaccine design.
abstract: Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.
authors: INSERM, U1015, 94805 Villejuif, France.
authors: Antonella
authors: A
authors: Sistigu
authors: Sophie
authors: S
authors: Viaud
authors: Nathalie
authors: N
authors: Chaput
authors: Laura
authors: L
authors: Bracci
authors: Enrico
authors: E
authors: Proietti
authors: Laurence
authors: L
authors: Zitvogel
references: Annu Rev Immunol. 1989;7:145-73
references: 2523712
references: Cancer Res. 2002 May 15;62(10):2731-5
references: 12019144
references: Am J Pathol. 1997 Feb;150(2):641-51
references: 9033277
references: Clin Cancer Res. 2002 Dec;8(12):3696-701
references: 12473578
references: Blood. 2010 Mar 25;115(12):2554-5; author reply 2556-7
references: 20339108
references: Clin Cancer Res. 2008 Mar 1;14(5):1455-63
references: 18316569
references: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8947-52
references: 17517626
references: Nature. 2006 May 11;441(7090):235-8
references: 16648838
references: Nat Med. 2007 Jan;13(1):54-61
references: 17187072
references: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9190-5
references: 16754847
references: Science. 2002 Oct 25;298(5594):850-4
references: 12242449
references: J Immunol. 2008 Apr 1;180(7):4679-86
references: 18354191
references: J Clin Oncol. 2005 Apr 1;23(10):2346-57
references: 15800326
references: J Exp Med. 2005 Oct 17;202(8):1075-85
references: 16230475
references: Nat Med. 2006 Feb;12(2):207-13
references: 16444266
references: Cancer Res. 2009 Aug 15;69(16):6607-14
references: 19679552
references: J Exp Med. 2002 Aug 19;196(4):541-9
references: 12186845
references: J Exp Med. 1999 Nov 15;190(10):1417-26
references: 10562317
references: Am J Pathol. 2004 Dec;165(6):1853-63
references: 15579430
references: J Immunol. 2007 Mar 1;178(5):2763-9
references: 17312119
references: Nat Med. 1998 May;4(5):627-30
references: 9585241
references: Nat Med. 2004 Sep;10(9):909-15
references: 15340416
references: J Surg Oncol. 1998 Apr;67(4):221-7
references: 9579368
references: Science. 2003 Feb 14;299(5609):1057-61
references: 12522256
references: Cell. 2010 Mar 19;140(6):798-804
references: 20303871
references: J Immunol. 1999 Nov 15;163(10):5211-8
references: 10553041
references: J Clin Oncol. 2009 Dec 10;27(35):5911-8
references: 19805669
references: Immunol Today. 1992 Oct;13(10):379-81
references: 1418371
references: Immunol Cell Biol. 2008 May-Jun;86(4):353-62
references: 18268517
references: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13141-6
references: 9789055
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: J Clin Invest. 2010 Feb;120(2):457-71
references: 20093776
references: Blood. 2009 Jun 11;113(24):6102-11
references: 19366986
references: N Engl J Med. 2009 Nov 5;361(19):1838-47
references: 19890126
references: Blood. 2000 Mar 15;95(6):2024-30
references: 10706870
references: Cancer Immunol Immunother. 1990;32(3):154-60
references: 2126987
references: Vaccine. 2009 Apr 6;27(16):2230-9
references: 19428837
references: Blood. 2010 Jun 3;115(22):4384-92
references: 20154220
references: Eur J Immunol. 2005 Dec;35(12):3424-32
references: 16285010
references: Cancer Res. 2001 May 1;61(9):3689-97
references: 11325840
references: J Immunol. 2002 May 1;168(9):4272-6
references: 11970966
references: Immunol Today. 1996 Mar;17(3):138-46
references: 8820272
references: Immunol Rev. 2006 Dec;214:229-38
references: 17100888
references: Clin Transl Sci. 2008 Dec;1(3):228-39
references: 20357913
references: J Clin Invest. 1998 Jan 15;101(2):429-41
references: 9435316
references: J Clin Oncol. 1990 Nov;8(11):1858-67
references: 2230873
references: Eur J Immunol. 1993 Oct;23(10):2517-25
references: 8405052
references: Cancer Res. 1984 Mar;44(3):1275-80
references: 6229330
references: J Exp Med. 2005 Jan 17;201(2):233-40
references: 15657292
references: Cancer Res. 2001 Oct 15;61(20):7530-5
references: 11606390
references: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19402-7
references: 20962281
references: J Exp Med. 2001 Sep 17;194(6):823-32
references: 11560997
references: J Exp Med. 2010 Jun 7;207(6):1273-81
references: 20479115
references: Cancer Immunol Immunother. 2010 Jan;59(1):137-48
references: 19590872
references: Nat Immunol. 2002 Mar;3(3):215-7
references: 11875459
references: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1178-83
references: 9448305
references: J Immunol. 2008 Jun 15;180(12):7887-97
references: 18523252
references: Immunology. 1988 Sep;65(1):87-92
references: 2972604
references: J Neurooncol. 2010 Aug;99(1):123-8
references: 20043189
references: Cancer Immunol Immunother. 2005 Jul;54(7):663-70
references: 15918076
references: Cancer Res. 2006 Aug 1;66(15):7741-7
references: 16885377
references: Science. 1986 Sep 19;233(4770):1318-21
references: 3489291
references: J Exp Med. 2010 Jun 7;207(6):1247-60
references: 20479116
references: J Clin Invest. 1987 Apr;79(4):1082-90
references: 3494044
references: Blood. 2005 Apr 1;105(7):2862-8
references: 15591121
references: Cancer Cell. 2010 Feb 17;17(2):121-34
references: 20138013
references: Cancer Res. 2004 Mar 15;64(6):2192-8
references: 15026362
references: Cancer Invest. 1988;6(3):337-49
references: 3167614
references: Ann Oncol. 2002 Jan;13(1):73-80
references: 11863115
references: Nature. 2003 Feb 13;421(6924):744-8
references: 12610626
references: Nat Rev Immunol. 2002 Mar;2(3):151-61
references: 11913066
references: Cancer Res. 2003 Dec 1;63(23):8408-13
references: 14679003
references: J Clin Oncol. 1994 May;12(5):1036-44
references: 8164027
references: Nat Immunol. 2001 Apr;2(4):293-9
references: 11276199
references: J Immunol. 2006 Jan 1;176(1):61-7
references: 16365396
references: Cell. 2008 May 30;133(5):775-87
references: 18510923
references: Cancer Res. 2011 Feb 1;71(3):661-5
references: 21148486
references: N Engl J Med. 2008 Jun 19;358(25):2704-15
references: 18565863
references: Nat Rev Immunol. 2004 Dec;4(12):941-52
references: 15573129
references: Curr Opin Immunol. 2006 Feb;18(1):85-91
references: 16326087
references: Blood. 2009 Aug 6;114(6):1141-9
references: 19470694
references: Eur J Cancer. 2000 May;36(8):1060-6
references: 10885612
references: J Exp Med. 2005 May 16;201(10):1591-602
references: 15883172
references: Methods Find Exp Clin Pharmacol. 1987 Sep;9(9):569-77
references: 2963936
references: Immunol Rev. 2010 Mar;234(1):18-31
references: 20193009
references: Clin Cancer Res. 2003 Feb;9(2):606-12
references: 12576425
references: Immunol Today. 1991 Mar;12(3):A49-53
references: 1648926
references: Clin Cancer Res. 2007 Jul 1;13(13):3951-9
references: 17606729
references: Immunity. 2008 Jan;28(1):29-39
references: 18164222
references: Cancer Res. 2009 Jan 15;69(2):609-15
references: 19147575
references: Cancer Res. 1990 Sep 1;50(17):5358-64
references: 2143687
references: Methods Mol Biol. 2010;651:131-55
references: 20686965
references: Clin Dev Immunol. 2010;2010:517493
references: 21076523
references: J Immunol. 2006 Nov 15;177(10):6603-12
references: 17082572
references: Cancer Sci. 2010 Sep;101(9):1947-54
references: 20550524
references: Cancer Immunol Immunother. 2002 Jan;50(11):588-96
references: 11807622
references: J Immunol. 2009 Oct 1;183(7):4169-75
references: 19767566
references: Clin Cancer Res. 2004 Nov 15;10(22):7466-74
references: 15569976
references: Cancer Res. 1999 Jul 1;59(13):3128-33
references: 10397255
references: Curr Opin Immunol. 2004 Oct;16(5):558-64
references: 15341999
references: J Exp Med. 2010 Jun 7;207(6):1283-92
references: 20479118
references: J Exp Med. 2009 May 11;206(5):1103-16
references: 19414558
references: Nat Med. 2007 Sep;13(9):1050-9
references: 17704786
references: J Urol. 1998 Jul;160(1):214-9
references: 9628653
references: Cancer Immunol Immunother. 2010 Jul;59(7):979-87
references: 20352428
references: Cancer. 1996 Aug 1;78(3):542-7
references: 8697402
references: Cancer Res. 2011 Feb 1;71(3):768-78
references: 21156650
references: Cancer Res. 2009 Aug 15;69(16):6590-7
references: 19679551
references: Oncol Rep. 2009 Mar;21(3):793-9
references: 19212641
references: Cancer Res. 2001 Dec 15;61(24):8643-6
references: 11751377
references: Int J Cancer. 2009 Jan 1;124(1):130-9
references: 18839429
references: J Immunol. 2006 Jan 15;176(2):705-10
references: 16393950
references: J Immunother. 2007 Jan;30(1):40-53
references: 17198082
references: J Immunol. 2010 Feb 15;184(4):1737-47
references: 20083664
references: J Clin Invest. 2010 Apr;120(4):1111-24
references: 20234093
references: Cancer Immunol Immunother. 2010 May;59(5):769-77
references: 19940990
references: J Exp Med. 2006 Oct 2;203(10):2271-9
references: 16982811
references: Trends Immunol. 2007 Feb;28(2):45-7
references: 17197240
references: J Clin Invest. 2008 Nov;118(11):3751-61
references: 18830416
references: Cancer Immunol Immunother. 2004 Mar;53(3):204-16
references: 14722672
references: Anticancer Res. 2010 Oct;30(10):4317-23
references: 21036758
references: Clin Exp Immunol. 1976 Nov;26(2):346-54
references: 991462
references: Lancet. 2009 Feb 21;373(9664):673-83
references: 19231634
references: Nat Rev Immunol. 2010 Apr;10(4):248-56
references: 20336152
references: Nat Med. 2006 Feb;12(2):214-9
references: 16444265
references: Cancer Res. 2005 Apr 15;65(8):3437-46
references: 15833879
references: J Immunol. 2009 Feb 15;182(4):2030-40
references: 19201856
references: J Immunol. 2010 Oct 1;185(7):4063-71
references: 20805420
references: Cell Death Differ. 2008 Jan;15(1):51-7
references: 17948028
references: Cancer Res. 1986 May;46(5):2572-7
references: 3697996
references: Immunol Rev. 2001 Aug;182:18-32
references: 11722621
references: Cancer Res. 2006 Jan 15;66(2):601-4
references: 16423984
references: J Immunol. 2000 Sep 15;165(6):3105-10
references: 10975823
references: J Immunol. 2006 Mar 1;176(5):2722-9
references: 16493027
references: Curr Opin Immunol. 2011 Feb;23(1):146-52
references: 20970973
references: J Immunol. 2008 May 15;180(10):6477-83
references: 18453565
references: Cancer Immunol Immunother. 2007 May;56(5):641-8
references: 16960692
references: Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):644-53
references: 17255288
references: Cancer Res. 1984 Nov;44(11):5439-43
references: 6488195
references: J Cancer Res Clin Oncol. 2006 May;132(5):293-301
references: 16421755
references: Eur J Immunol. 2004 Feb;34(2):336-44
references: 14768038
references: Dtsch Med Wochenschr. 1958 Mar 21;83(12):453-8
references: 13537667
references: J Immunol. 1995 Aug 1;155(3):1151-64
references: 7636184
references: Ann N Y Acad Sci. 2010 Jan;1183:38-57
references: 20146707
references: Horm Metab Res. 2008 Feb;40(2):75-81
references: 18283624
references: J Biol Chem. 2007 Nov 30;282(48):34605-10
references: 17884812
references: J Clin Oncol. 2008 Nov 10;26(32):5233-9
references: 18809613
references: J Exp Med. 1980 Jan 1;151(1):69-80
references: 6444236
references: Strahlentherapie. 1959;Suppl 43:243-53
references: 13829664
references: Eur J Immunol. 2002 Nov;32(11):3267-75
references: 12555672
references: Cell Immunol. 2010;261(2):134-43
references: 20036354
references: Int J Cancer. 1997 Aug 7;72(4):619-24
references: 9259401
references: Eur Respir J. 2006 Dec;28(6):1170-7
references: 16899480
references: J Immunol. 2002 Sep 1;169(5):2756-61
references: 12193750
references: Int J Cancer. 2005 Nov 20;117(4):574-86
references: 15912532
references: Nat Immunol. 2005 Nov;6(11):1069-70
references: 16239919
references: J Exp Med. 2001 Jun 4;193(11):1285-94
references: 11390435
references: Cancer Res. 2000 Apr 1;60(7):1878-86
references: 10766175
references: J Cell Biochem. 2007 Oct 1;102(2):291-300
references: 17729239
references: Cancer Res. 2010 Sep 15;70(18):7084-92
references: 20823160
references: J Immunol. 2010 Nov 15;185(10):6348-54
references: 20952674
references: Cancer Res. 1982 Nov;42(11):4862-6
references: 7127320
references: Nat Immunol. 2006 Apr;7(4):363-5
references: 16550200
references: J Immunol. 2010 Feb 1;184(3):1630-41
references: 20026736
references: Cell. 2006 Sep 22;126(6):1121-33
references: 16990136