Abstract LB-325: Antitumor effect of resveratrol combined with immunocytokine immunotherapy
Authors: Soto Brenda L. , Hank Jacquelyn A. , Polans Arthur S. , van de Voort Tyler , Rakhmilevich Alexander L. , Seo Songwon , Kuyungmann Kim , Gillies Stephen D. , Sondel Paul M. 
Published: February 2011

Abstract
Resveratrol (RV) is a natural compound which is currently being investigated for many possible health promoting activities. It has anti-tumor activity on cancer cells in vitro and in vivo in some animal models of cancer. We are currently examining the ability of RV to be combined with immunotherapy to treat cancer. Our immunotherapy is the hu14.18-IL2 immunocytokine (IC), consisting of the hu14.18 mAb (that targets GD2 on the surface of some tumor cells) linked to interleukin-2 (IL2). The IL2 component attracts and activates immune effector cells expressing IL2 receptors and induces localized destruction of the tumor via antibody dependent cell-mediated cytotoxicity (ADCC) by NK cells. Prior studies have found RV to be immunosuppressive in vitro but not in vivo. RV at a daily intragastric (i.g.) dose of 50mg/kg (1mg per mouse) slowed tumor growth in mice bearing neuroblastoma and was not immunosuppressive. At this dose the peak serum RV level was ∼ 1mcM. Using proliferative and cytotoxicity assays we were defining a dose in vitro and a regimen in vivo that does not suppress the immune system and is additive or synergistic in mediating anti-tumor effects when combined with immunotherapy. In our in vitro studies high concentrations of RV (≥ 25mcM) were found to inhibit both tumor cell proliferation and the ability of PHA and IL2 to stimulate proliferation of human and murine effector cells (measured by 3H-thymidine incorporation and by dilution of CFSE in daughter cells). These cells were arrested in their G1 phase. In addition, these high RV concentrations prevented effector cells from mediating ADCC in vitro. In contrast, 1mcM (as found in serum after i.g. treatment) was not tumoristatic or immunosuppressive in vitro. Systemic RV regimens, although inhibiting tumor growth in vivo, did not induce tumor regression in these models, probably because of the limited amount of RV reaching the tumor. In order to increase the amount of RV in the tumor, studies on the anti-tumor effect of peritumoral (p.t.) injections of 20mg RV in vivo in NXS2 neuroblastoma-bearing mice were performed. The results of these studies showed that peritumoral RV had a robust but transient anti-tumor effect. Primary subcutaneous tumors initially regressed; however, most mice then developed metastatic tumors, and in some cases re-growth of the primary tumor, after cessation of RV therapy. In order to circumvent tumor recurrence and metastasis, intravenous (i.v) immunotherapy was combined with the p.t. injections of 20mg RV. Peritumoral injection with resveratrol enhanced the subsequent efficacy of immunotherapy. Further, most mice receiving p.t. RV in combination with IC not only resolved their primary tumors, but also survived without development of metastatic tumors. Sixty-one % of the mice receiving the combined therapy showed no detectable tumors by day 100 compared to 15-13% of the mice in the RV-alone or the IC-alone groups, respectively (p=0.001 and p=0.0003). These studies indicate the potential for a combined regimen of RV and hu14.18-IL2.
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 LB-325.