In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes
| Autor: | P, Hwu, J C, Yang, R, Cowherd, J, Treisman, G E, Shafer, Z, Eshhar, S A, Rosenberg |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
Ovarian Neoplasms
Lung Neoplasms Recombinant Fusion Proteins Immunoglobulin Variable Region Receptors Antigen T-Cell Antibodies Monoclonal Mice Nude Transfection Immunotherapy Adoptive Mice Inbred C57BL Interferon-gamma Mice Lymphocytes Tumor-Infiltrating Tumor Cells Cultured Animals Humans Interleukin-2 Female Sarcoma Experimental Methylcholanthrene |
| Zdroj: | Cancer research. 55(15) |
| ISSN: | 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|