Abstract 5620: Immunomodulatory activity of NOV-002 potentiates the anti-tumor efficacy of cyclophosphamide in the CT26 murine colon cancer model
Authors: Diaz-Montero C. Marcela , Perez Antonio , Zidane Sherif , Pazoles Chris J. , Montero Alberto J. 
Published: February 2011

Clinical trials in a number of solid tumor indications have shown that the addition of NOV-002 (a formulation of disodium glutathione disulfide) to a range of cytotoxic chemotherapeutic regimens potentiates their anti-tumor efficacy. However, the specific mechanisms involved remain unclear. Previous in vitro studies demonstrated that NOV-002 generates oxidative signals in human tumor cell lines resulting in apoptosis and decreased proliferation. In addition, NOV-002 has been reported to display in vivo immunomodulatory properties in oncology settings. Hence, NOV-002: (i) significantly increases circulating T-lymphocyte subsets [CD4+, CD8+, NK-T lymphocytes] in non-small lung cancer patients receiving chemotherapy plus NOV-002 vs. chemotherapy alone; (ii) reverses T-cell suppressive effect of myeloid suppressor cells in mice; (iii) potentiates anti-tumor effect of adoptive immunotherapy in a mouse melanoma model; (iv) increases intra-tumoral memory T-cells and anti-tumor immune responsiveness in a mouse model of ovarian cancer. Here, we sought to test the hypothesis that NOV-002 potentiates the anti-tumor effect of chemotherapy through immune-mediated mechanisms. To this end in the CT26 murine colon cancer model, tumor-bearing mice were treated with NOV-002 (25 mg/kg, i.p.) or saline (daily on days 1-14, then Monday-Friday, beginning 5 days post-tumor injection until tumor progression), followed by 200mg/kg cyclophosphamide (CTX) on days 6 and 9. In three independent experiments we found that while NOV-002 alone had only a modest effect on tumor growth rate, the addition of NOV-002 to CTX resulted in significantly slower tumor growth compared to CTX alone. Mean overall survival was significantly longer in CTX/NOV mice [90 vs 47 days; P=0.005]. Interestingly, all mice receiving CTX alone developed tumors, while approximately 40% of CTX/NOV-002 mice showed no tumor development. To further investigate whether failure of tumor development in these mice was due to an immune mechanism, they underwent tumor rechallenge. In two independent experiments only 1/7 mice (14%) developed tumors after rechallenge. To test the contribution of memory T-cells, which are known to home to the bone marrow, CTX/NOV-002 mice with tumor failure were sacrificed and marrows adoptively transferred to mice bearing 7 day old CT26 tumors. A significant delay in tumor progression was observed in mice receiving adoptively transferred marrow suggesting that the immunologic memory generated after CTX/NOV-002 treatment was sufficient to effectively prevent or regress tumor formation. Taken together, these data provide further support to the hypothesis that, when combined with chemotherapy, NOV-002's anti-tumor efficacy may be due at least in part to enhancement of anti-tumor cellular immune responsiveness.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5620.