title: Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells.
abstract: BACKGROUND
  Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity.
  
  
  METHODS
  We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.
  
  
  RESULTS
  At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens.
  
  
  CONCLUSIONS
  Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00442130.
  
  
  BACKGROUND
  NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ute E
authors.initials: UE
authors.lastname: Burkhardt
authors.forename: Ursula
authors.initials: U
authors.lastname: Hainz
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Goldstein
authors.forename: Mildred
authors.initials: M
authors.lastname: Pasek
authors.forename: Masayasu
authors.initials: M
authors.lastname: Naito
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Anselmo
authors.initials: A
authors.lastname: Alonso
authors.forename: Naa Norkor
authors.initials: NN
authors.lastname: Hammond
authors.forename: Jessica
authors.initials: J
authors.lastname: Wong
authors.forename: Quinlan L
authors.initials: QL
authors.lastname: Sievers
authors.forename: Ana
authors.initials: A
authors.lastname: Brusic
authors.forename: Sean M
authors.initials: SM
authors.lastname: McDonough
authors.forename: Wanyong
authors.initials: W
authors.lastname: Zeng
authors.forename: Ann
authors.initials: A
authors.lastname: Perrin
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Christine M
authors.initials: CM
authors.lastname: Canning
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeng-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Richard C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: Mol Ther. 2008 Dec;16(12):2022-9
references.pmid: 18797450
references.citation: N Engl J Med. 2000 Dec 28;343(26):1910-6
references.pmid: 11136261
references.citation: Biol Blood Marrow Transplant. 2011 Sep;17(9):1395-403
references.pmid: 21296675
references.citation: Biol Blood Marrow Transplant. 2010 Nov;16(11):1467-503
references.pmid: 20699125
references.citation: Cancer. 2011 Oct 15;117(20):4679-88
references.pmid: 21455998
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2742-7
references.pmid: 12601144
references.citation: Cancer Res. 2000 Jun 15;60(12):3239-46
references.pmid: 10866317
references.citation: Blood. 2010 Oct 7;116(14):2438-47
references.pmid: 20595516
references.citation: J Clin Oncol. 2003 Sep 1;21(17):3343-50
references.pmid: 12947071
references.citation: Biol Blood Marrow Transplant. 2006 Oct;12(10):1056-64
references.pmid: 17084369
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: N Engl J Med. 2004 Aug 26;351(9):893-901
references.pmid: 15329427
references.citation: J Clin Oncol. 2008 Nov 1;26(31):5094-100
references.pmid: 18711173
references.citation: Oncoimmunology. 2012 Oct 1;1(7):1095-1103
references.pmid: 23170257
references.citation: J Exp Med. 2005 Oct 3;202(7):907-12
references.pmid: 16203864
references.citation: J Clin Invest. 2007 Jul;117(7):1902-13
references.pmid: 17557120
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
references.pmid: 8097319
references.citation: Blood. 2000 May 15;95(10):3011-9
references.pmid: 10807763
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4759-68
references.pmid: 19567591
references.citation: Blood. 2006 Feb 15;107(4):1332-41
references.pmid: 16249392
references.citation: N Engl J Med. 2011 Dec 29;365(26):2497-506
references.pmid: 22150006
references.citation: J Clin Oncol. 2001 Jan 1;19(1):145-56
references.pmid: 11134207
references.citation: Clin Cancer Res. 2010 May 15;16(10):2729-39
references.pmid: 20460482
references.citation: Cancer Immunol Immunother. 1999 May-Jun;48(2-3):123-31
references.pmid: 10414466
references.citation: Blood. 2008 Feb 15;111(4):2112-21
references.pmid: 18063750
references.citation: Cancer Immunol Immunother. 2013 Feb;62(2):347-57
references.pmid: 22926059
references.citation: Hum Gene Ther. 1999 Aug 10;10(12):1983-91
references.pmid: 10466632
references.citation: Blood. 1996 Jun 15;87(12):4990-7
references.pmid: 8652811
references.citation: Blood. 2009 Aug 27;114(9):1736-45
references.pmid: 19556425
references.citation: J Clin Oncol. 2007 Jun 20;25(18):2546-53
references.pmid: 17577033
references.citation: Immunol Rev. 2008 Apr;222:287-98
references.pmid: 18364009
references.citation: Blood. 2012 Mar 29;119(13):3142-50
references.pmid: 22267603
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4515-7
references.pmid: 19584145
references.citation: Cancer. 2008 Sep 1;113(5):975-84
references.pmid: 18646045
references.citation: Cancer Res. 2001 Jan 1;61(1):162-71
references.pmid: 11196155
references.citation: Adv Immunol. 2006;90:133-73
references.pmid: 16730263
references.citation: Cancer Res. 2004 Sep 1;64(17):6337-43
references.pmid: 15342423
references.citation: J Clin Oncol. 2008 Oct 20;26(30):4912-20
references.pmid: 18794548
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15825-30
references.pmid: 19717467
references.citation: Cancer Res. 2010 Feb 15;70(4):1344-55
references.pmid: 20124481
references.citation: Leukemia. 2013 Feb;27(2):362-9
references.pmid: 22955330
references.citation: Blood. 1990 Feb 1;75(3):555-62
references.pmid: 2297567
references.citation: Leukemia. 2005 Jun;19(6):1029-33
references.pmid: 15830011