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Targeted Delivery of Tumor Necrosis Factor- to Tumor Vessels Induces a Therapeutic T Cell–Mediated Immune Response that Protects the Host Against Syngeneic Tumors of Different Histologic Origin

Authors' Affiliations: ¹ Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, ² Unit of Innovative Therapies, Istituto Giannina Gaslini, Centro Biotecnologie Avanzate, Genoa, Italy, ³ Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy, and ⁴ Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland

Requests for reprints: Luciano Zardi, Unit of Innovative Therapies, Istituto Giannina Gaslini, Centro Biotecnologie Avanzate, L.go Rosanna Benzi 10, 16132 Genoa, Italy. Phone: 39-10-573-7509; Fax: 39-10-529-9074; E-mail: luciano.zardi{at}poste.it.

Purpose: We sought to demonstrate that a single systemic administration of L19mTNF (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor , TNF) 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 L19mTNF, 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 mTNF 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 TNF to the tumor vasculature.

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