title: MHC II lung cancer vaccines prime and boost tumor-specific CD4+ T cells that cross-react with multiple histologic subtypes of nonsmall cell lung cancer cells.
abstract: Nonsmall cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths in the United States. We are developing cell-based vaccines as a new approach for the treatment of NSCLC. NSCLC is broadly divided into 3 histologic subtypes: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Since these subtypes are derived from the same progenitor cells, we hypothesized that they share common tumor antigens, and vaccines that induce immune reactivity against 1 subtype may also induce immunity against other subtypes. Our vaccine strategy has focused on activating tumor-specific CD4(+) T cells, a population of lymphocytes that facilitates the optimal activation of effector and memory cytotoxic CD8(+) T cells. We now report that our NSCLC MHC II vaccines prepared from adeno, squamous or large cell carcinomas each activate CD4(+) T cells that cross-react with the other NSCLC subtypes and do not react with HLA-DR-matched normal lung fibroblasts or other HLA-DR-matched nonlung tumor cells. Using MHC II NSCLC vaccines expressing the DR1, DR4, DR7 or DR15 alleles, we also demonstrate that antigens shared among the different subtypes are presented by multiple HLA-DR alleles. Therefore, MHC II NSCLC vaccines expressing a single HLA-DR allele activate NSCLC-specific CD4(+) T cells that react with the 3 major classes of NSCLC, and the antigens recognized by the activated T cells are presented by several common HLA-DR alleles, suggesting that the MHC II NSCLC vaccines are potential immunotherapeutics for a range of NSCLC patients.
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Minu K
authors.initials: MK
authors.lastname: Srivastava
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bosch
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Wilson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ostrand-Rosenberg
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D045744:Cell Line, Tumor; D003429:Cross Reactions; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation; D022423:Myeloid Cells / Q000276:immunology; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D019496:Cancer Vaccines; D006684:HLA-DR Antigens
references.citation: Cancer Res. 2007 May 1;67(9):4499-506
references.pmid: 17483366
references.citation: Cancer Gene Ther. 2006 Jun;13(6):555-62
references.pmid: 16410826
references.citation: Cancer Immunol Immunother. 2008 Mar;57(3):389-98
references.pmid: 17724589
references.citation: Adv Immunol. 2000;75:159-208
references.pmid: 10879284
references.citation: J Exp Med. 1998 Dec 21;188(12):2357-68
references.pmid: 9858522
references.citation: CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30
references.pmid: 15661684
references.citation: Cancer Biol Ther. 2006 Feb;5(2):145-9
references.pmid: 16357522
references.citation: Expert Opin Biol Ther. 2007 Jan;7(1):89-102
references.pmid: 17150021
references.citation: Cancer Immunol Immunother. 2006 Dec;55(12):1553-64
references.pmid: 16491401
references.citation: Clin Cancer Res. 2003 Nov 15;9(15):5559-65
references.pmid: 14654536
references.citation: J Immunol. 2004 Jul 15;173(2):1085-93
references.pmid: 15240697
references.citation: Cancer Immunol Immunother. 2010 Jan;59(1):103-12
references.pmid: 19557412
references.citation: Cancer Res. 2004 Mar 1;64(5):1867-74
references.pmid: 14996751
references.citation: Cancer Immunol Immunother. 2008 Oct;57(10):1493-504
references.pmid: 18322683
references.citation: Cancer Res. 1998 Apr 1;58(7):1486-93
references.pmid: 9537252
references.citation: Nat Immunol. 2004 Sep;5(9):927-33
references.pmid: 15300249
references.citation: Science. 1994 Jul 1;265(5168):106-9
references.pmid: 8016643
references.citation: Clin Cancer Res. 1998 Sep;4(9):2279-89
references.pmid: 9748150
references.citation: Cancer Immunol Immunother. 2000 Apr;49(1):34-45
references.pmid: 10782864
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Expert Opin Emerg Drugs. 2006 Sep;11(3):445-59
references.pmid: 16939384
references.citation: Science. 2004 Jul 9;305(5681):200-5
references.pmid: 15247469
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: J Clin Oncol. 2005 Dec 10;23(35):9022-8
references.pmid: 16219932
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6674-81
references.pmid: 16170175
references.citation: J Immunol. 2009 Apr 15;182(8):4499-506
references.pmid: 19342621
references.citation: Immunol Rev. 1999 Aug;170:101-14
references.pmid: 10566145
references.citation: Cancer Res. 2006 Jan 15;66(2):1147-54
references.pmid: 16424052
references.citation: J Clin Oncol. 2004 Jul 15;22(14):2800-7
references.pmid: 15254047
references.citation: Lung Cancer. 2007 Sep;57(3):365-72
references.pmid: 17509725
references.citation: Immunology. 2007 Feb;120(2):148-59
references.pmid: 17274112
references.citation: Nature. 2003 Feb 20;421(6925):852-6
references.pmid: 12594515
references.citation: J Natl Cancer Inst. 2004 Feb 18;96(4):326-31
references.pmid: 14970281
references.citation: J Exp Med. 1982 Mar 1;155(3):768-82
references.pmid: 6801178
references.citation: J Exp Med. 1997 Jul 7;186(1):65-70
references.pmid: 9206998
references.citation: J Immunol. 2004 Mar 1;172(5):3289-96
references.pmid: 14978137
references.citation: EMBO J. 1996 Jan 15;15(2):418-28
references.pmid: 8617217
references.citation: Cancer Gene Ther. 2003 Nov;10(11):850-8
references.pmid: 14605671
references.citation: J Control Release. 2003 Aug 28;91(1-2):225-31
references.pmid: 12932654
references.citation: Science. 2003 Apr 11;300(5617):337-9
references.pmid: 12690201
references.citation: Nature. 1998 Jun 4;393(6684):480-3
references.pmid: 9624005
references.citation: J Exp Med. 1995 Feb 1;181(2):619-29
references.pmid: 7836917