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Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892 [P. H., J. C. Y., R. C., J. T., G. E. S., S. A. R.]; and Department of Chemical Immunology, Weizmann Institute of Science, Rehovot 76100, Israel [Z. E.]
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 antibodydefined 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-
) 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--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.
1 To whom requests for reprints should be addressed, at National Cancer Institute, Surgery Branch, Building 10, Room 2B42, 9000 Rockville Pike, Bethesda, MD 20892.
Received 1/23/95. Accepted 5/30/95.
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