Increased immunogenicity of tumors bearing mutant p53 and P1A epitopes after transduction of B7-1 via recombinant adenovirus.
The majority of human solid tumors are likely to express protein epitopes which can act as targets for cytotoxic T cells, but these are frequently not effectively recognized. We tested whether the introduction of the costimulatory molecule B7-1 using a recombinant adenovirus (Ad-B7) can result in effective induction of epitope-specific immunity in two tumor models that express defined endogenous protein epitopes: D459, a fibroblast-derived cell line transfected with a human missense mutant p53 (C to Y at position 135), and P815, a mastocytoma expressing the endogenous tumor epitope P1A. Under the conditions studied, both of these tumors grow and kill their hosts without evidence of significant immune rejection. However, after transduction with the adenovirus containing B7-1, both of these tumors lose tumorigenicity and elicit specific cellular immunity to the mutant p53 epitope in D459 and P1A in P815. In addition, animals exposed to B7-transduced tumor cells were protected from subsequent challenge with nontransduced tumor. Adenovirus has distinct advantages for this approach, as it has high infectivity not requiring in vitro culture, low lytic potential, and transient expression of sufficient duration for immunologic effectiveness but without significant concern over permanent genetic modification. We conclude that transduction of tumor cells with Ad-B7 can increase the immunogenicity of endogenous protein epitopes and may represent a practical therapeutic approach to system human cancers.
Lee
C T
CT
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
Ciernik
I F
IF
Wu
S
S
Tang
D C
DC
Chen
H L
HL
Truelson
J M
JM
Carbone
D P
DP
D000256:Adenoviridae / Q000235:genetics*; D018122:B7-1 Antigen / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology*; D002469:Cell Separation; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000276:immunology*; D011995:Recombination, Genetic; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D018122:B7-1 Antigen; D000939:Epitopes; D016159:Tumor Suppressor Protein p53