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Limitations of adenovirus-mediated interleukin-2 gene therapy for oral cancer
B W O'Malley1, D Li, A Buckner
1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
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 twofold-higher-titer AdV-IL-2 vector. Treatment of established tumors with the higher-titer AdV-IL-2 at a new maximal dose of 1.4 x 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.
Insights
Adenoviral interleukin-2 (AdV-IL-2) gene therapy shows promise for oral cancer, but expression levels and toxicity are key factors. Higher IL-2 expression improved antitumor effects, suggesting AdV-IL-2 could be part of combination therapies.
Area of Science:
- Oncology
- Gene Therapy
- Immunotherapy
Background:
- Adenoviral interleukin-2 (AdV-IL-2) gene therapy has shown limited efficacy for established murine oral cancer.
- Intratumoral interleukin-2 (IL-2) expression levels are hypothesized to be a critical determinant of treatment success.
Purpose of the Study:
- To investigate the role of IL-2 expression levels in AdV-IL-2 gene therapy for oral cancer.
- To determine if increasing IL-2 expression can enhance antitumor responses in a murine model.
Main Methods:
- Utilized a murine model of microscopic and established oral cancer.
- Administered IL-2 gene transfer using a recombinant adenovirus vector (AdV-IL-2).
- Assessed tumor regression, IL-2 expression levels, and T-cell mediated cytotoxicity (CTL).
Main Results:
- Microscopic disease treatment with AdV-IL-2 resulted in complete tumor regression or decreased progression, linked to CD8+ T-cell killing.
- A critical threshold of IL-2 expression was identified; reducing it halved the antitumor effect.
- Higher AdV-IL-2 titers increased in vivo IL-2 expression and antitumor response in established tumors, but complete regression was not achieved.
- Repeat injections showed increased efficacy but also 28% mortality due to IL-2 toxicity.
Conclusions:
- AdV-IL-2 gene therapy's effectiveness for established oral tumors is limited by expression levels and toxicity.
- Despite limitations, AdV-IL-2 holds potential as a component in combination therapy strategies for oral cancer.