In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes.
In an effort to broaden the applicability of adoptive cellular immunotherapy toward nonmelanoma cancers, we have designed chimeric antibody/T-cell receptor genes composed of the variable domains from mAbs joined to T-cell receptor-signaling chains. We have demonstrated that T cells retrovirally transduced with these genes can recognize antibody-defined antigens and that this recognition leads to T-cell activation, specific lysis, and cytokine release. In this study, we have examined the in vivo activity of murine T cells transduced with a chimeric receptor gene (MOv-gamma) derived from the mAb MOv18, which binds to a folate-binding protein overexpressed on most human ovarian adenocarcinomas. Nude mice that were given i.p. implants of human ovarian cancer (IGROV) cells were treated 3 days later with i.p. murine tumor-infiltrating lymphocytes (TIL) derived from an unrelated tumor. Mice treated with MOv-gamma-transduced TIL (MOv-TIL) had significantly increased survival compared to mice treated with saline only, nontransduced TIL, or TIL transduced with a control anti-trinitrophenyl chimeric receptor gene (TNP-TIL). In another model, C57BL/6 mice were given i.v. injections of a syngeneic methylcholanthrene-induced sarcoma transduced with the folate-binding protein (FBP) gene. Three days later, mice were treated i.v. with various transduced murine TIL (derived from an unrelated tumor), followed by low-dose systemic interleukin 2. Eleven days after tumor injection, mice were sacrificed, and lung metastases were counted. In multiple experiments, mice receiving MOv-TIL had significantly fewer lung metastases than did mice treated with interleukin 2 alone, nontransduced TIL, or TNP-TIL. These studies indicate that T cells can be gene modified to react in vivo against tumor antigens, defined by mAbs. This approach is potentially applicable to a number of neoplastic and infectious diseases and may allow adoptive immunotherapy against types of cancer not previously amenable to cellular immunotherapy.
Hwu
P
P
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Yang
J C
JC
Cowherd
R
R
Treisman
J
J
Shafer
G E
GE
Eshhar
Z
Z
Rosenberg
S A
SA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology / Q000627:therapeutic use*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D008748:Methylcholanthrene; D007371:Interferon-gamma