Immuno-gene therapy with interferon-beta before surgical debulking delays recurrence and improves survival in a murine model of malignant mesothelioma.
OBJECTIVE
Immuno-gene therapy of mesothelioma with an adenovirus encoding interferon-beta mediated strong antitumor responses in murine models with low but not high tumor burden. Our goals were to determine the mechanisms responsible for this loss of efficacy and to test the hypothesis that the combination of preoperative adenovirus encoding interferon-beta and surgical resection would be effective in treating bulky tumors.


METHODS
Flank tumors of a mouse mesothelioma cell line were treated with adenovirus encoding interferon-beta or adenoviral vector encoding the bacterial protein beta-galactosidase. Cytotoxic T lymphocytes and tumor infiltration by T lymphocytes were measured. Tumors were surgically excised 72 hours later and tumor cells were injected in the contralateral flank to create a model of a metastatic focus. Tumor-free survival and distant metastatic disease were assessed.


RESULTS
Immuno-gene therapy effectively treated small tumors (<200 mm(3)) but did not reduce the size of large (>800 mm(3)) flank tumors. Although treatment with adenovirus encoding interferon-beta resulted in the generation of tumor-neutralizing splenocytes in large tumors, the number of T cells visualized within the tumors was minimal. Tumors treated with adenovirus encoding interferon-beta (versus adenoviral vector encoding the bacterial protein beta-galactosidase or phosphate-buffered saline solution) prior to debulking increased long-term tumor-free survival and resulted in two- to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively.


CONCLUSIONS
The use of adenovirus encoding interferon-beta or surgical debulking alone is ineffective in treating large tumors, but combining preoperative adenovirus encoding interferon-beta and surgical debulking significantly reduces tumor recurrence and improves long-term tumor-free survival. We postulate that adenovirus encoding interferon-beta amplifies the cytotoxic T-lymphocyte antitumor response, allowing elimination of residual tumor cells.
Kruklitis
Robert J
RJ
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
Singhal
Sunil
S
Delong
Peter
P
Kapoor
Veena
V
Sterman
Daniel H
DH
Kaiser
Larry R
LR
Albelda
Steven M
SM
D000256:Adenoviridae; D000818:Animals; D001707:Biopsy, Needle; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D016899:Interferon-beta / Q000494:pharmacology*; D008654:Mesothelioma / Q000401:mortality / Q000473:pathology* / Q000601:surgery* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011300:Preoperative Care; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015996:Survival Rate
D016899:Interferon-beta