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Limitations of adenovirus‐mediated interleukin‐2 gene therapy for oral cancer
Author(s) -
O'Malley Bert W.,
Li Daqing,
Buckner Alyson,
Duan Ling,
Woo Savio L.C.,
Pardoll Drew M.
Publication year - 1999
Publication title -
the laryngoscope
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.181
H-Index - 148
eISSN - 1531-4995
pISSN - 0023-852X
DOI - 10.1097/00005537-199903000-00009
Subject(s) - genetic enhancement , ctl* , cancer research , cd8 , immunotherapy , cancer , in vivo , viral vector , cytotoxic t cell , adenoviridae , immunology , titer , microbiology and biotechnology , biology , in vitro , medicine , immune system , recombinant dna , gene , virus , biochemistry
Objective/Hypothesis : Adenoviral interleukin‐2 (AdV‐IL‐2) gene therapy has previously not proven effective in treating established murine oral cancer. We hypothesize that the intratumoral level of IL‐2 expression is a major limiting factor in treatment outcome. Methods : A microscopic disease and established oral cancer murine model was used to test this hypothesis. IL‐2 gene transfer was performed with a recombinant adenovirus vector. Results : Tumor cells were transduced in vitro with AdV‐IL‐2 and subsequently implanted into the floor of the mouth in C3H/ HeJ mice. IL‐2 expression in vitro ranged from 990 to 1,050 pg/10 6 tumor cells. This microscopic disease treatment resulted in either complete tumor regression or a dramatic decrease in tumor progression. Cytolytic T‐cell (CTL) assays demonstrated a predominance of CD8‐specific, T‐cell–mediated tumor killing. Reducing IL‐2 expression by half with a mixture of 1:1 transduced to nontransduced tumor cells eliminated the antitumor effect and decreased the CTL response. These findings support the presence of a critical “threshold” of IL‐2 expression. Adenovirus repurification and amplification allowed isolation of a twofoldhigher‐titer AdV‐IL‐2 vector. Treatment of established tumors with the higher‐titer AdV‐IL‐2 at a new maximal dose of 1.4 × 10 9 plaque‐forming units (pfu) increased in vivo IL‐2 expression to 1,127 pg/10 6 cells and generated a significant antitumor response. Complete regression of established tumors, however, could not be achieved, and we noted a decrease in IL‐2 expression well below the threshold at 1 week after treatment. Upon repeat maximal AdV‐IL‐2 injection in vivo, a greater antitumor effect and increased CTL response was seen, but also, 28% of the animals died of IL‐2 toxicity. Conclusion : Although limited by expression and toxicity as a single‐treatment strategy for established tumors, AdV‐IL‐2 gene therapy should be considered a potential component of combination therapy strategies.