Targeted delivery of tumor necrosis factor-alpha to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin.

Abstract

PURPOSE:

We sought to demonstrate that a single systemic administration of L19mTNFalpha (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor alpha, TNFalpha) in combination with melphalan induced complete and long-lasting tumor eradication in tumor-bearing mice and triggered the generation of a specific T cell-based immune response that protects the animals from a second tumor challenge, as well as from challenges with syngeneic tumor cells of different histologic origin.

EXPERIMENTAL DESIGN AND RESULTS:

Treatment with L19mTNFalpha, in combination with melphalan, induced complete tumor regression in 83% of BALB/c mice with WEHI-164 fibrosarcoma and 33% of animals with C51 colon carcinoma. All cured mice rejected challenges with the same tumor cells and, in a very high percentage of animals, also rejected challenges with syngeneic tumor cells of different histologic origin. In adoptive immunity transfer experiments, the splenocytes from tumor-cured mice protected naive mice both from C51 colon carcinoma and from WEHI-164 fibrosarcoma. Similar results were also obtained in adoptive immunity transfer experiments using severely immunodepressed mice. Experiments using depleted splenocytes showed that T cells play a major role in tumor rejection.

CONCLUSIONS:

The results show that the selective targeting of mTNFalpha to the tumor enhances its immunostimulatory properties to the point of generating a therapeutic immune response against different histologically unrelated syngeneic tumors. These findings predicate treatment approaches for cancer patients based on the targeted delivery of TNFalpha to the tumor vasculature.

• Authors: Enrica Balza, Lorenzo Mortara, Francesca Sassi, Stefano Monteghirfo, Barbara Carnemolla, Patrizia Castellani, Dario Neri, Roberto S Accolla, Luciano Zardi, Laura Borsi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 8 Pg. 2575-82 (Apr 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16638868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibronectins
• Immunoglobulin Fragments
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• Melphalan

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytotoxicity, Immunologic (immunology)
• Dose-Response Relationship, Drug
• Fibronectins (genetics, immunology)
• Immunity, Cellular (drug effects, immunology)
• Immunoglobulin Fragments (genetics)
• Immunotherapy, Adoptive (methods)
• Melphalan (administration & dosage)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neoplasms, Experimental (immunology, prevention & control, therapy)
• Recombinant Fusion Proteins (pharmacology, therapeutic use)
• Spleen (cytology, immunology, transplantation)
• Survival Analysis
• T-Lymphocytes (cytology, immunology)
• T-Lymphocytes, Cytotoxic (cytology, immunology)
• Time Factors
• Tumor Necrosis Factor-alpha (genetics, pharmacology, therapeutic use)