title: MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial.
abstract: BACKGROUND
  Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.
  
  
  METHODS
  We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.
  
  
  RESULTS
  After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7⁻ CD45RA⁺/⁻) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1⁻CD160⁻TIM3⁻LAG3⁻2B4⁺/⁻). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.
  
  
  CONCLUSIONS
  Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Verena
authors.initials: V
authors.lastname: Voelter
authors.forename: Julien
authors.initials: J
authors.lastname: Laurent
authors.forename: Hélène
authors.initials: H
authors.lastname: Bichat
authors.forename: Athina
authors.initials: A
authors.lastname: Stravodimou
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Frédéric
authors.initials: F
authors.lastname: Triebel
authors.affiliation: Department of Oncology, Service of Medical Oncology, CHUV BH-06 1011 Lausanne, Switzerland. Serge.Leyvraz@chuv.ch.
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
authors.forename: Alexandre
authors.initials: A
authors.lastname: Harari
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000008:administration & dosage*; D017690:Cell Transplantation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D058965:MART-1 Antigen / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D058965:MART-1 Antigen; C548667:MLANA protein, human; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human
references.citation: Nat Med. 2004 Sep;10(9):909-15
references.pmid: 15340416
references.citation: Cancer Immunol Immunother. 2012 Jun;61(6):817-26
references.pmid: 22080404
references.citation: J Immunol. 2009 Apr 1;182(7):4217-25
references.pmid: 19299720
references.citation: Cancer Res. 2013 Nov 15;73(22):6597-608
references.pmid: 24048821
references.citation: J Immunother. 2007 Feb-Mar;30(2):240-50
references.pmid: 17471171
references.citation: J Clin Invest. 2011 Jun;121(6):2350-60
references.pmid: 21555851
references.citation: Vaccine. 2003 Feb 14;21(9-10):862-8
references.pmid: 12547595
references.citation: J Immunol. 2000 Jun 1;164(11):5583-9
references.pmid: 10820232
references.citation: J Immunol. 2007 Sep 15;179(6):4202-11
references.pmid: 17785860
references.citation: J Immunol. 1999 Jan 15;162(2):989-94
references.pmid: 9916724
references.citation: Int J Cancer. 2010 Aug 15;127(4):759-67
references.pmid: 20518016
references.citation: J Clin Oncol. 2006 Nov 1;24(31):5060-9
references.pmid: 17075125
references.citation: Cancer Res. 2009 May 15;69(10):4335-45
references.pmid: 19435913
references.citation: J Immunother. 2010 Oct;33(8):848-58
references.pmid: 20842051
references.citation: J Transl Med. 2013 Jun 18;11:149
references.pmid: 23777306
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: J Exp Med. 2005 Oct 3;202(7):907-12
references.pmid: 16203864
references.citation: Nat Immunol. 2011 Jun;12(6):492-9
references.pmid: 21739672
references.citation: Cytometry A. 2011 Feb;79(2):167-74
references.pmid: 21265010
references.citation: J Immunother. 2010 Sep;33(7):723-34
references.pmid: 20664354
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Clin Cancer Res. 2009 Oct 1;15(19):6225-31
references.pmid: 19755389
references.citation: Eur J Immunol. 1999 Dec;29(12):3867-76
references.pmid: 10601994
references.citation: Nature. 1999 Oct 14;401(6754):708-12
references.pmid: 10537110
references.citation: J Virol. 2010 Apr;84(8):3868-78
references.pmid: 20130059
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: J Clin Invest. 2005 Mar;115(3):739-46
references.pmid: 15696196
references.citation: J Virol. 2009 Apr;83(7):2862-71
references.pmid: 19176626
references.citation: Nat Med. 2011 Mar;17(3):372-6
references.pmid: 21336285
references.citation: Cancer Lett. 2006 Apr 8;235(1):147-53
references.pmid: 15946792
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
references.pmid: 12427970
references.citation: J Transl Med. 2010 Jul 23;8:71
references.pmid: 20653948
references.citation: J Clin Invest. 2007 Aug;117(8):2197-204
references.pmid: 17657310
references.citation: Clin Dev Immunol. 2012;2012:485781
references.pmid: 22548114
references.citation: Trends Immunol. 2003 Dec;24(12):619-22
references.pmid: 14644131
references.citation: Cancer Res. 2006 Apr 15;66(8):4450-60
references.pmid: 16618772
references.citation: J Immunol. 2002 Apr 15;168(8):3874-80
references.pmid: 11937541
references.citation: Clin Cancer Res. 2011 Jul 1;17(13):4550-7
references.pmid: 21498393
references.citation: Science. 2013 Nov 22;342(6161):971-6
references.pmid: 24264990
references.citation: Immunol Rev. 2006 Jun;211:236-54
references.pmid: 16824132
references.citation: PLoS Pathog. 2013;9(7):e1003423
references.pmid: 23853580
references.citation: Nat Rev Clin Oncol. 2009 May;6(5):256-8
references.pmid: 19390551
references.citation: J Immunol. 2005 Mar 1;174(5):2591-601
references.pmid: 15728465
references.citation: J Exp Med. 2009 Feb 16;206(2):463-75
references.pmid: 19171765