Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer.
immunology
tumor
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
accepted:
24
02
2020
entrez:
20
3
2020
pubmed:
20
3
2020
medline:
1
9
2021
Statut:
ppublish
Résumé
Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC. Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan. Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs. The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy. UMIN000007321.
Sections du résumé
BACKGROUND
Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC.
METHODS
Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan.
RESULTS
Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs.
CONCLUSIONS
The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy.
TRIAL REGISTRATION NUMBER
UMIN000007321.
Identifiants
pubmed: 32188702
pii: jitc-2019-000316
doi: 10.1136/jitc-2019-000316
pmc: PMC7078938
pii:
doi:
Substances chimiques
Galactosylceramides
0
alpha-galactosylceramide
0
Banques de données
UMIN-CTR
['UMIN000007321']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Curr Clin Pharmacol. 2018;13(2):76-84
pubmed: 29992894
Cell. 2017 Nov 30;171(6):1259-1271.e11
pubmed: 29107330
J Clin Immunol. 2012 Oct;32(5):1071-81
pubmed: 22534863
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Blood. 2013 Jan 17;121(3):423-30
pubmed: 23100308
Cancer Sci. 2008 Apr;99(4):638-45
pubmed: 18294290
J Hematol Oncol. 2017 Apr 24;10(1):87
pubmed: 28434399
Blood. 2004 Jan 15;103(2):383-9
pubmed: 14512316
J Immunol. 1999 Sep 1;163(5):2387-91
pubmed: 10452972
Science. 2016 Mar 25;351(6280):1463-9
pubmed: 26940869
Lancet. 2014 Aug 23;384(9944):665-73
pubmed: 24933332
Cancer Sci. 2009 Jun;100(6):1092-8
pubmed: 19302288
Curr Opin Immunol. 2008 Jun;20(3):358-68
pubmed: 18501573
Lancet Oncol. 2014 Feb;15(2):143-55
pubmed: 24411639
Science. 1997 Nov 28;278(5343):1626-9
pubmed: 9374463
Cancer Chemother Pharmacol. 2001 Nov;48(5):356-60
pubmed: 11761452
J Exp Med. 2005 May 2;201(9):1503-17
pubmed: 15867097
J Immunol Res. 2015;2015:652875
pubmed: 26543874
Clin Cancer Res. 2005 Mar 1;11(5):1910-7
pubmed: 15756017
Semin Immunol. 2010 Apr;22(2):97-102
pubmed: 19939703
Nat Rev Immunol. 2012 Dec;12(12):845-57
pubmed: 23154222
Semin Oncol. 2015 Oct;42 Suppl 2:S11-8
pubmed: 26477470
Nat Med. 2018 Feb;24(2):144-153
pubmed: 29309059
Front Immunol. 2018 Sep 07;9:2021
pubmed: 30245690
Nat Immunol. 2003 Dec;4(12):1164-5
pubmed: 14639465
J Immunol. 2009 Feb 15;182(4):2492-501
pubmed: 19201905
N Engl J Med. 2016 Nov 10;375(19):1823-1833
pubmed: 27718847
Annu Rev Immunol. 2014;32:323-66
pubmed: 24499274
Mol Cancer Ther. 2015 Apr;14(4):847-56
pubmed: 25695955
N Engl J Med. 2015 Oct 22;373(17):1627-39
pubmed: 26412456
Cell. 2017 May 4;169(4):750-765.e17
pubmed: 28475900
Clin Cancer Res. 2017 Jul 15;23(14):3510-3519
pubmed: 28193627
Crit Rev Oncol Hematol. 2017 Aug;116:116-124
pubmed: 28693793
Nat Immunol. 2002 Sep;3(9):867-74
pubmed: 12154358
N Engl J Med. 2017 Dec 21;377(25):2500-2501
pubmed: 29262275
Cancer Immunol Immunother. 2012 Jul;61(7):1019-31
pubmed: 22146893
Lancet. 2016 Apr 30;387(10030):1837-46
pubmed: 26970723
J Thorac Oncol. 2007 Aug;2(8):694-705
pubmed: 17762335
Nature. 2017 Jan 18;541(7637):321-330
pubmed: 28102259
N Engl J Med. 2015 Jul 9;373(2):123-35
pubmed: 26028407
J Thorac Oncol. 2016 Jul;11(7):976-88
pubmed: 26944305
Clin Immunol. 2011 Mar;138(3):255-65
pubmed: 21185787
Immunity. 2018 Mar 20;48(3):453-473
pubmed: 29562195
Clin Immunol. 2011 Aug;140(2):167-76
pubmed: 21349771
Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6079-86
pubmed: 17028247
Cancer Immunol Immunother. 2008 Mar;57(3):337-45
pubmed: 17690880