DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies.
Her-2/neu(+) tumor cells refractory to antibody or receptor tyrosine kinase inhibitors are emerging in treated patients. To investigate if drug resistant tumors can be controlled by active vaccination, gefitinib and antibody sensitivity of four neu(+) BALB/c mouse mammary tumor lines were compared. Significant differences in cell proliferation and Akt phosphorylation were observed. Treatment-induced drug resistance was associated with increased chromosomal aberrations as shown by spectral karyotyping analysis, suggesting changes beyond neu signaling pathways. When mice were immunized with pneuTM encoding the extracellular and transmembrane domains of neu, antibody and T-cell responses were induced, and both drug-sensitive and drug-resistant tumor cells were rejected. In T-cell-depleted mice, drug-sensitive tumors were still rejected by vaccination, but drug-refractory tumors survived in some mice, indicating their resistance to anti-neu antibodies. To further test if T cells alone can mediate tumor rejection, mice were immunized with pcytneu encoding full-length cytoplasmic neu that is rapidly degraded by the proteasome to activate CD8 T cells without inducing antibody response. All test tumors were rejected in pcytneu-immunized mice, regardless of their sensitivity to gefitinib or antibody. Therefore, cytotoxic T lymphocytes activated by the complete repertoire of neu epitopes were effective against all test tumors. These results warrant Her-2 vaccination whether tumor cells are sensitive or resistant to Her-2-targeted drugs or antibody therapy.
Whittington
Paula J
PJ
Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Piechocki
Marie P
MP
Heng
Henry H
HH
Jacob
Jennifer B
JB
Jones
Richard F
RF
Back
Jessica B
JB
Wei
Wei-Zen
WZ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D000077156:Gefitinib; D007621:Karyotyping; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D020032:Tyrphostins; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D019444:Vaccines, DNA; C101044:RTKI cpd
Biochemistry. 1990 Dec 18;29(50):11024-8
1980216
Oncogene. 2002 Jan 31;21(6):890-8
11840334
Clin Cancer Res. 2007 Sep 1;13(17):5133-43
17785568
Cancer Res. 2001 Oct 1;61(19):7196-203
11585755
Mol Cell Biol. 1991 Feb;11(2):833-42
1671296
Science. 1989 May 12;244(4905):707-12
2470152
Adv Cancer Res. 2002;85:101-44
12374283
Cancer Res. 2005 Sep 15;65(18):8471-8
16166327
Clin Cancer Res. 2008 Apr 15;14(8):2465-75
18413839
Nature. 1986 Jan 16-22;319(6050):226-30
3945311
Breast Cancer Res Treat. 2008 Dec;112(3):533-43
18188694
Chromosoma. 1993 May;102(5):325-32
8325164
Cancer Res. 2007 Jul 15;67(14):6825-43
17638894
Cancer Res. 2001 Jun 15;61(12):4892-900
11406568
Cancer Res. 2005 Jan 15;65(2):650-6
15695410
J Cell Physiol. 2006 Aug;208(2):461-72
16688757
Science. 1987 Jan 9;235(4785):177-82
3798106
Cancer Lett. 1992 Jul 10;64(3):203-9
1322235
Clin Cancer Res. 2004 Apr 1;10(7):2538-44
15073134
J Leukoc Biol. 1985 Nov;38(5):573-85
2413152
Cancer Res. 2002 Jul 15;62(14):4132-41
12124352
Semin Oncol. 2000 Oct;27(5 Suppl 9):20-6
11049053
Cell Immunol. 2006 Apr;240(2):96-106
16930573
Cancer Treat Rev. 2005 Jun;31(4):312-8
15979804
Genome. 2006 Mar;49(3):195-204
16604101
J Clin Oncol. 2003 Nov 1;21(21):3965-71
14507946
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Cancer Res. 2001 Oct 1;61(19):7184-8
11585753
J Clin Oncol. 1998 Feb;16(2):462-9
9469329
Semin Oncol. 1999 Aug;26(4 Suppl 12):51-9
10482194
J Immunol Methods. 2002 Jan 1;259(1-2):33-42
11730839
Cytogenet Cell Genet. 2001;93(3-4):195-202
11528112
Cancer Res. 2001 Dec 15;61(24):8887-95
11751413
Oncogene. 2002 Sep 12;21(41):6255-63
12214266
Cell. 1989 Jun 16;57(6):931-6
2567634
Br J Cancer. 2004 Aug 16;91(4):639-43
15266327
J Immunol. 2001 Sep 15;167(6):3201-6
11544306
EMBO J. 1994 Jul 15;13(14):3302-11
7913890
Int J Cancer. 1999 May 31;81(5):748-54
10328228
J Immunol. 2000 Nov 1;165(9):5133-42
11046045
N Engl J Med. 2005 Oct 20;353(16):1673-84
16236738
Int J Cancer. 2004 Mar 20;109(2):291-301
14750183
J Clin Oncol. 1999 Sep;17(9):2639-48
10561337
Cancer Genet Cytogenet. 2003 Apr 1;142(1):36-45
12660031
EMBO J. 1996 Jan 15;15(2):254-64
8617201