In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes.

Abstract

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.

• Authors: P Hwu, J C Yang, R Cowherd, J Treisman, G E Shafer, Z Eshhar, S A Rosenberg
• Journal: Cancer research (Cancer Res) Vol. 55 Issue 15 Pg. 3369-73 (Aug 01 1995) ISSN: 0008-5472 [Print] United States
• PMID: 7614473 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin Variable Region
• Interleukin-2
• Receptors, Antigen, T-Cell
• Recombinant Fusion Proteins
• Methylcholanthrene
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Female
• Humans
• Immunoglobulin Variable Region (immunology, therapeutic use)
• Immunotherapy, Adoptive (methods)
• Interferon-gamma (metabolism)
• Interleukin-2 (therapeutic use)
• Lung Neoplasms (secondary, therapy)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Methylcholanthrene
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Ovarian Neoplasms (metabolism, therapy)
• Receptors, Antigen, T-Cell
• Recombinant Fusion Proteins (therapeutic use)
• Sarcoma, Experimental (chemically induced, metabolism, therapy)
• Transfection
• Tumor Cells, Cultured