title: T-cell subsets in peripheral blood and tumors of patients treated with oncolytic adenoviruses.
abstract: The quality of the antitumor immune response is decisive when developing new immunotherapies for cancer. Oncolytic adenoviruses cause a potent immunogenic stimulus and arming them with costimulatory molecules reshapes the immune response further. We evaluated peripheral blood T-cell subsets of 50 patients with refractory solid tumors undergoing treatment with oncolytic adenovirus. These data were compared to changes in antiviral and antitumor T cells, treatment efficacy, overall survival, and T-cell subsets in pre- and post-treatment tumor biopsies. Treatment caused a significant (P < 0.0001) shift in T-cell subsets in blood, characterized by a proportional increase of CD8(+) cells, and decrease of CD4(+) cells. Concomitant treatment with cyclophosphamide and temozolomide resulted in less CD4(+) decrease (P = 0.041) than cyclophosphamide only. Interestingly, we saw a correlation between T-cell changes in peripheral blood and the tumor site. This correlation was positive for CD8(+) and inverse for CD4(+) cells. These findings give insight to the interconnections between peripheral blood and tumor-infiltrating lymphocyte (TIL) populations regarding oncolytic virotherapy. In particular, our data suggest that induction of T-cell response is not sufficient for clinical response in the context of immunosuppressive tumors, and that peripheral blood T cells have a complicated and potentially misleading relationship with TILs.
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Kristian
authors: K
authors: Taipale
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Ilkka
authors: I
authors: Liikanen
authors: Oncos Therapeutics, Ltd., Helsinki, Finland.
authors: Juuso
authors: J
authors: Juhila
authors: Oncos Therapeutics, Ltd., Helsinki, Finland.
authors: Aila
authors: A
authors: Karioja-Kallio
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Minna
authors: M
authors: Oksanen
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors: Riku
authors: R
authors: Turkki
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors: Nina
authors: N
authors: Linder
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors: Johan
authors: J
authors: Lundin
authors: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors: Ari
authors: A
authors: Ristimäki
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
authors: Anna
authors: A
authors: Kanerva
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Anniina
authors: A
authors: Koski
authors: Docrates Cancer Center, Helsinki, Finland.
authors: Timo
authors: T
authors: Joensuu
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Markus
authors: M
authors: Vähä-Koskela
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics Ltd., Helsinki, Finland. Electronic address: akseli.hemminki@helsinki.fi.
authors: Akseli
authors: A
authors: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D055815:Young Adult
references: Cancer Res. 2010 Nov 1;70(21):8368-77
references: 20940398
references: Cell Death Differ. 2014 Jan;21(1):69-78
references: 23811849
references: Science. 2006 Sep 29;313(5795):1960-4
references: 17008531
references: Cancer Immunol Immunother. 2012 Feb;61(2):289-293
references: 22237887
references: Ann Surg Oncol. 2010 Mar;17(3):718-30
references: 19915919
references: Hum Gene Ther. 2013 Dec;24(12):1029-41
references: 24099555
references: J Virol. 2008 Aug;82(15):7252-63
references: 18385237
references: N Engl J Med. 2008 Jun 19;358(25):2704-15
references: 18565863
references: Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):727s-732s
references: 17255301
references: Inflamm Res. 2013 Sep;62(9):823-34
references: 23868500
references: Mol Ther. 2010 Oct;18(10):1874-84
references: 20664527
references: Clin Cancer Res. 2011 Jul 1;17(13):4550-7
references: 21498393
references: Clin Cancer Res. 2013 Aug 15;19(16):4541-2
references: 23946419
references: Cancer Res. 2011 Nov 15;71(22):6997-7009
references: 21948969
references: Mol Ther. 2007 Feb;15(2):378-85
references: 17235317
references: Clin Cancer Res. 2013 May 15;19(10):2734-44
references: 23493351
references: Cancer Res. 2012 Apr 1;72(7):1621-31
references: 22323527
references: J Urol. 2009 Apr;181(4):1894-900
references: 19237175
references: Immunotherapy. 2013 Oct;5(10):1075-87
references: 24088077
references: Cancer. 2008 Sep 15;113(6):1387-95
references: 18671239
references: Cancer Immunol Immunother. 2012 Feb;61(2):255-263
references: 22120756
references: J Clin Pathol. 2012 Feb;65(2):159-63
references: 22049225
references: Neuro Oncol. 2011 Apr;13(4):393-400
references: 21339188
references: Cell Immunol. 2012 Sep;279(1):21-4
references: 23041206
references: Mol Ther. 2013 Jun;21(6):1212-23
references: 23546299
references: Immunity. 2013 Jul 25;39(1):61-73
references: 23890064
references: Mol Ther. 2011 Sep;19(9):1737-46
references: 21673660
references: Int J Oncol. 2012 Mar;40(3):764-72
references: 22134728
references: Clin Dev Immunol. 2011;2011:430394
references: 22110524
references: Nat Rev Cancer. 2008 Jan;8(1):61-70
references: 18075512
references: Mol Ther. 2012 Nov;20(11):2076-86
references: 22828500
references: Cancer Res. 2011 Feb 15;71(4):1263-71
references: 21303976
references: Vaccine. 2009 Jun 24;27(31):4225-39
references: 19481312
references: Scientifica (Cairo). 2014;2014:862925
references: 24551478
references: Cancer Res. 2012 May 1;72(9):2327-38
references: 22396493
references: Mol Ther. 2012 Jan;20(1):221-9
references: 22044933
references: Gene Ther. 2011 Sep;18(9):898-909
references: 21451575
references: Nat Rev Immunol. 2006 Apr;6(4):295-307
references: 16557261
references: Oncogene. 2010 Feb 25;29(8):1093-102
references: 19946335
references: J Immunol. 2013 Jun 15;190(12):6259-68
references: 23686484
references: Curr Pharm Biotechnol. 2012 Jul;13(9):1750-60
references: 21740355
references: Nat Rev Clin Oncol. 2011 Mar;8(3):151-60
references: 21364688
references: Nat Immunol. 2013 Oct;14(10):1014-22
references: 24048123
references: Cancer Res. 2010 Jun 1;70(11):4297-309
references: 20484030
references: J Clin Oncol. 2010 Jul 1;28(19):3167-75
references: 20516446