Abstract 2441: An innovative treatment modality of antibody therapy against intracellular tumor antigens

Abstract

Abstract Therapy with mAb directed against cell surface antigens of cancer is now a well-established treatment modality for human cancer. However, many tumor antigens of great interest have an intracellular location, and therefore not considered suitable targets for antibody therapy. On the other hand, it has been reported that mAbs targeted against specific tumor antigens induce cellular immune response including CD8+ T cells. This raises the possibility that the anti-tumor effects of mAb therapy may partially depend on enhanced cross-priming mediated by APCs following the uptake of antigen released from tumors complexed with Ab (immune-complex). Here, we investigated whether mAb therapy could be applicable to intracellular antigens using a transplantable colon carcinoma CT-26 expressing NY-ESO-1 (a well-studied human cancer/testis antigen), an intracellular antigen lacking cell surface expression. Immune responses to NY-ESO-1 in the murine model closely parallel NY-ESO-1 humoral and cellular immune responses in humans. To accentuate the natural release of intracellular NY-ESO-1 from dying tumor cells to facilitate immune-complex formation, we employed the effect the anti-cancer drug on the response to NY-ESO-1 mAb. The combination of NY-ESO-1 mAb and 5-fluorouracil exhibited a strong and long-lasting anti-tumor effect that could not be achieved by treatment with either 5-fluorouracil or mAb alone. The anti-tumor effect induced by combination therapy was no longer observed when Fc-depleted Fab antibodies were used, indicating a Fc-dependent action on APCs. Furthermore, augmented anti-tumor effects observed by the combination therapy was associated with strong NY-ESO-1-specific CD8+ T cells in draining lymph nodes and tumor sites, and upregulation of maturation markers on dendritic cells. The opsoniziation of released intracellular tumor antigens with injected mAb facilitates uptake by APC and presentation to CD8+ T cells, leading to accelerated and augmented active immunization. The data indicate that mAb to intracellular molecules of cancer represents a promising approach to cancer immunotherapy. 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 2441.