Abstract
Oxidative signaling involving the glutathione system of redox control has been implicated in the regulation of T cell function. NOV‐002, a glutathione disulfide mimetic, added to standard chemotherapy increased anti‐tumor activity and survival in advanced non‐small cell lung cancer patients compared to chemotherapy alone. Similarly, NOV‐002 treatment significantly increased circulating T cell levels [CD4+, CD8+] in these patients. Here, we investigated whether the addition of NOV‐002 to our previously established murine adoptive therapy (AT) regimen could enhance the anti‐tumor activity of the transferred T cells. Adoptive transfer of early effector Pmel CD8+ cells activated in the presence of IL‐12 (PmelIL12) into lymphopenic hosts is effective in regressing previously established B16 tumors. Daily administration of NOV‐002 (25 mg/kg, i.p.) for 7 days following AT in C57BL/6 mice resulted in a significant delay in tumor progression when compared to mice subjected to AT alone, consistent with a marked enhancement of PmelIL12 anti‐tumor immune activity. This enhanced anti‐tumor effect was accompanied by a significantly longer median overall survival in mice treated with AT + NOV‐002 compared to those treated with AT + saline [45 vs 28 days; 95% CI 34–56 days vs 23–32 days, respectively; p=0.02]. We then investigated, whether NOV‐002 creates a more favorable micro‐environment for expansion of transferred Pmel cells in a lymphopenic host. To this end, non‐tumor bearing mice were treated with cyclophosphamide (CTX, 200mg/kg; to induce lymphopenia) or saline, and 7 days later 5×106 Pmel cells were adoptively transferred into all mice. In addition, mice were treated with either NOV‐002 (25 mg/kg, i.p.) or saline daily for 7 days following AT. All mice were vaccinated with gp100 (the melanoma tumor antigen towards which the Pmel T cells are specifically reactive) 24 hours after AT to elicit in vivo activation and proliferation of transferred Pmel cells. On day 3 after vaccination, peripheral blood was collected, and analyzed by flow cytometry for the presence of donor Pmel cells (= Ly5.1+ cells) which represents T cell priming in response to vaccination. A significantly lower frequency of donor Pmel cells were seen in the animals treated with CTX relative to saline controls (9% vs. 20%; p=0.01). The addition of NOV‐002 to CTX treatment, however, resulted in significantly higher frequencies of activated Pmel cells than CTX alone (18% vs 9%; p=0.03). Taken together, these results indicate that NOV‐002 enhances the effect of AT thereby generating a significantly greater antitumor T cell response, resulting in decreased tumor growth, and improved survival. Moreover, NOV‐002 enhances the expansion of CD8+ T cells in a lymphopenic host. These findings are consistent with the hypothesis that enhanced immune responsiveness may contribute to the clinical profile of NOV‐002 in oncology trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C238.
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