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.
OBJECTIVE
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.


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.
Balza
Enrica
E
Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Unit of Innovative Therapies, Istituto Giannina Gaslini, Centro Biotecnologie Avanzate, Genoa, Italy.
Mortara
Lorenzo
L
Sassi
Francesca
F
Monteghirfo
Stefano
S
Carnemolla
Barbara
B
Castellani
Patrizia
P
Neri
Dario
D
Accolla
Roberto S
RS
Zardi
Luciano
L
Borsi
Laura
L
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*
D005353:Fibronectins; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan