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.
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.
Alajez
Nehad M
NM
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Schmielau
Jan
J
Alter
Mark D
MD
Cascio
Michael
M
Finn
Olivera J
OJ
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
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
Nat Med. 1999 Apr;5(4):405-11
10202929
Nat Med. 1996 Aug;2(8):876-82
8705856
Bone Marrow Transplant. 1998 Oct;22(7):651-9
9818692
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
12427970
J Immunol. 2001 Nov 15;167(10):5583-93
11698429
Proc Natl Acad Sci U S A. 1989 Sep;86(18):7159-63
2674949
Cancer Res. 1993 Nov 15;53(22):5386-94
8221676
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6204-9
11983911
J Exp Med. 1993 Feb 1;177(2):265-72
8426105
CA Cancer J Clin. 2003 Jan-Feb;53(1):5-26
12568441
Bone Marrow Transplant. 2000 Jun;25(12):1233-41
10871727
Bone Marrow Transplant. 1997 Jan;19(2):149-56
9116612
Annu Rev Immunol. 2003;21:759-806
12615892
Oncol Rep. 2003 Nov-Dec;10(6):2005-8
14534734
Science. 1992 May 29;256(5061):1318-21
1598575
Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
2025413
Int J Cancer. 1989 Oct 15;44(4):691-6
2477336
J Biomol Struct Dyn. 1995 Oct;13(2):245-60
8579785
Eur J Immunol. 1995 Jun;25(6):1529-34
7614978
Ann N Y Acad Sci. 1993 Aug 12;690:231-43
7690213
J Exp Med. 2002 Dec 2;196(11):1435-46
12461079
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12654-8
7809095
J Mol Biol. 1990 Oct 5;215(3):403-10
2231712
Blood. 2000 Aug 1;96(3):894-901
10910902
Nature. 2001 Sep 13;413(6852):165-71
11557981
Lancet. 1993 Nov 6;342(8880):1134-7
7901474
Nature. 1985 Aug 15-21;316(6029):606-9
4033759
Bone Marrow Transplant. 1997 Jun;19(12):1183-9
9208111
J Immunol. 2003 Sep 15;171(6):3287-95
12960359
Bone Marrow Transplant. 2000 Jul;26(2):169-76
10918427
N Engl J Med. 2001 Mar 15;344(11):783-92
11248153
Int Immunol. 1994 Mar;6(3):369-76
8186188
Methods Enzymol. 1997;277:505-24
18488322
Cell. 1997 Oct 31;91(3):295-8
9363937
J Immunol. 1998 Apr 1;160(7):3111-20
9531265
Blood. 1998 Aug 15;92(4):1184-90
9694706
Nat Med. 1998 Feb;4(2):168-72
9461189
Cancer Res. 2003 May 15;63(10):2470-6
12750268
Hum Immunol. 2003 Jan;64(1):56-68
12507815
Nat Immunol. 2001 Oct;2(10):962-70
11577350
Science. 1996 Oct 11;274(5285):209-19
8824178
Cancer Res. 2001 Jun 15;61(12):4750-5
11406547