The folate receptor (FR) which binds the vitamin folic acid with high affinity is overexpressed by a variety of human cancers including ovarian, endometrial, renal, and lung cancers. Consequently, the receptor has been exploited for the delivery of imaging agents and highly potent drugs exclusively to FR expressing tumors while avoiding uptake by the surrounding healthy tissue. This targeting mechanism can also be utilized for immunotherapy by vaccinating mice against a particular hapten in order to induce the production of anti-hapten antibodies and subsequently treating tumor bearing mice with a folate-hapten conjugate. The resulting reduction in tumor burden is achieved by antibody-dependent cellular cytotoxicity (ADCC). However, hapten mediated immunotherapy alone has been ineffective at controlling tumor progression over longer periods of time and requires supplementation with immunomodulatory cytokines for optimum therapeutic results. Several multitargeted receptor tyrosine kinase (RTK) inhibitors have recently shown promising synergy in a variety of different cancers when combined with other immunotherapies. Therefore, we examined the effect of combining the RTK inhibitors sunitinib and axitinib with folate-fluorescein therapy in tumor bearing mice that had previously been immunized against fluorescein. We report here that sunitinib synergizes with folate-fluorescein in both the L1210A lymphoma and the M109 lung cancer models resulting in slowed tumor progression, inhibition of tumor vasculature, and increased levels of circulating CD4+ and CD8+ T cells. The combination of axitinib with folate-fluorescein was only evaluated in mice bearing L1210A tumors and these mice have also demonstrated lower average tumor volumes than mice treated with either drug alone or not treated at all. These results suggest that RTK inhibitors play an important role in modulating the anti-tumor immunity of tumor bearing mice and could be a potent addition to ADCC mediated therapeutic approaches for cancers.

Citation Format: Nimalka A. Bandara, Philip S. Low. Multitargeted receptor tyrosine kinase inhibitors synergize with folate-hapten mediated immunotherapy in folate receptor positive cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2593. doi:10.1158/1538-7445.AM2014-2593