title: Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution.
abstract: T-cell receptor (TCR) with unique major histocompatibility complex (MHC)-unrestricted antigen-binding properties was isolated from a human T-cell clone specific for the tumor antigen MUC1. This TCR binds its epitope on the MUC1 protein without the requirement of processing and presentation. A single-chain Valpha/Vbeta/Cbeta (scTCR) was fused to a CD3 zeta (zeta) chain to allow expression on the surface of cells of the innate (granulocytes, macrophages, natural killer [NK] cells) as well as the adaptive (T and B cells) immune system. To test the ability of the cells of the innate immune system to reject a tumor when provided with a tumor antigen-specific TCR, we reconstituted severe combined immunodeficiency (SCID) mice with bone marrow cells transduced with a retroviral vector encoding this receptor and challenged them with a MUC1-positive human tumor. These mice controlled the growth of the tumor significantly better than the control mice. We performed a similar experiment in immunocompetent mice transgenic for human MUC1. Expression of the TCR on large percentages of cells did not result in infiltration or destruction of tissues expressing MUC1. Reconstituted mice controlled the outgrowth of a MUC1-transfected but not the parental control tumor. scTCR expression appears lifelong, suggesting a successful transduction of the self-renewing stem cells.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
authors.forename: Jan
authors.initials: J
authors.lastname: Schmielau
authors.forename: Mark D
authors.initials: MD
authors.lastname: Alter
authors.forename: Michael
authors.initials: M
authors.lastname: Cascio
authors.forename: Olivera J
authors.initials: OJ
authors.lastname: Finn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology*; D017252:CD3 Complex / Q000737:chemistry; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007107:Immune System; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000627:therapeutic use; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012984:Software; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D000939:Epitopes; D007376:Interleukin-2; D018396:Mucin-1; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins
references.citation: Nat Med. 1999 Apr;5(4):405-11
references.pmid: 10202929
references.citation: Nat Med. 1996 Aug;2(8):876-82
references.pmid: 8705856
references.citation: Bone Marrow Transplant. 1998 Oct;22(7):651-9
references.pmid: 9818692
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
references.pmid: 12427970
references.citation: J Immunol. 2001 Nov 15;167(10):5583-93
references.pmid: 11698429
references.citation: Proc Natl Acad Sci U S A. 1989 Sep;86(18):7159-63
references.pmid: 2674949
references.citation: Cancer Res. 1993 Nov 15;53(22):5386-94
references.pmid: 8221676
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6204-9
references.pmid: 11983911
references.citation: J Exp Med. 1993 Feb 1;177(2):265-72
references.pmid: 8426105
references.citation: CA Cancer J Clin. 2003 Jan-Feb;53(1):5-26
references.pmid: 12568441
references.citation: Bone Marrow Transplant. 2000 Jun;25(12):1233-41
references.pmid: 10871727
references.citation: Bone Marrow Transplant. 1997 Jan;19(2):149-56
references.pmid: 9116612
references.citation: Annu Rev Immunol. 2003;21:759-806
references.pmid: 12615892
references.citation: Oncol Rep. 2003 Nov-Dec;10(6):2005-8
references.pmid: 14534734
references.citation: Science. 1992 May 29;256(5061):1318-21
references.pmid: 1598575
references.citation: Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
references.pmid: 2025413
references.citation: Int J Cancer. 1989 Oct 15;44(4):691-6
references.pmid: 2477336
references.citation: J Biomol Struct Dyn. 1995 Oct;13(2):245-60
references.pmid: 8579785
references.citation: Eur J Immunol. 1995 Jun;25(6):1529-34
references.pmid: 7614978
references.citation: Ann N Y Acad Sci. 1993 Aug 12;690:231-43
references.pmid: 7690213
references.citation: J Exp Med. 2002 Dec 2;196(11):1435-46
references.pmid: 12461079
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12654-8
references.pmid: 7809095
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: Blood. 2000 Aug 1;96(3):894-901
references.pmid: 10910902
references.citation: Nature. 2001 Sep 13;413(6852):165-71
references.pmid: 11557981
references.citation: Lancet. 1993 Nov 6;342(8880):1134-7
references.pmid: 7901474
references.citation: Nature. 1985 Aug 15-21;316(6029):606-9
references.pmid: 4033759
references.citation: Bone Marrow Transplant. 1997 Jun;19(12):1183-9
references.pmid: 9208111
references.citation: J Immunol. 2003 Sep 15;171(6):3287-95
references.pmid: 12960359
references.citation: Bone Marrow Transplant. 2000 Jul;26(2):169-76
references.pmid: 10918427
references.citation: N Engl J Med. 2001 Mar 15;344(11):783-92
references.pmid: 11248153
references.citation: Int Immunol. 1994 Mar;6(3):369-76
references.pmid: 8186188
references.citation: Methods Enzymol. 1997;277:505-24
references.pmid: 18488322
references.citation: Cell. 1997 Oct 31;91(3):295-8
references.pmid: 9363937
references.citation: J Immunol. 1998 Apr 1;160(7):3111-20
references.pmid: 9531265
references.citation: Blood. 1998 Aug 15;92(4):1184-90
references.pmid: 9694706
references.citation: Nat Med. 1998 Feb;4(2):168-72
references.pmid: 9461189
references.citation: Cancer Res. 2003 May 15;63(10):2470-6
references.pmid: 12750268
references.citation: Hum Immunol. 2003 Jan;64(1):56-68
references.pmid: 12507815
references.citation: Nat Immunol. 2001 Oct;2(10):962-70
references.pmid: 11577350
references.citation: Science. 1996 Oct 11;274(5285):209-19
references.pmid: 8824178
references.citation: Cancer Res. 2001 Jun 15;61(12):4750-5
references.pmid: 11406547