Abstract POSTER-THER-1433: Overcoming resistance to antibody targeted therapy in ovarian cancer

Targeted therapies utilizing monoclonal antibodies (mAbs) are now the major class of successful therapeutics for treating a variety of malignancies. Mechanistically, mAbs can have direct antitumoral activity but often their effectiveness relies upon antibody-dependent cellular cytotoxicity (ADCC). For instance, Trastuzumab is a therapeutic monoclonal antibody directed against HER2 that is well-tolerated and useful in the treatment of HER2-positive breast cancer, where efficacy is mediated in part by ADCC. In contrast, Trastuzumab is relatively ineffective in the treatment of epithelial ovarian cancer (EOC) where virtually all cancer cells express detectable levels of HER2. Poor response to mAb therapy in EOC and other types of cancers may be explained in part by diminished numbers and cytotoxic potential of NK cells in cancer patients, compared to healthy individuals. Therefore, reports of poor antitumor effect of Ab-therapy in cancer led us to hypothesize that the development of potent effector cells with the capacity to bind tumor-bound mAb and mediate strong antibody-directed cellular cytotoxicity would markedly improve the efficacy of mAb-targeted therapy for EOC. In order to expand applications for T cell-based immunotherapy and to enhance ADCC, we developed novel effector T cells engineered to express Fc binding immune receptors (FcIR) containing human Fc receptor of low FcγRIIIA (CD16), intermediate FcγRIIA (CD32) or high affinity FcγRI (CD64) molecules fused to intracellular TCR and co-stimulatory signaling domains in order to enable cytotoxic T cells to mediate strong mAb-directed cytotoxicity against antigen-expressing tumor cells. Following FcIR gene transduction, all forms of FcγRs were efficiently expressed on the surface of primary human T cells which allowed these cells to be armed with mAb. Trastuzumab-armed FcIR T cells specifically recognized HER2+ cancer cells, as did unarmed FcIRs but only when the cancer cells were first pre-bound with Trastuzumab. Addition of a CD28 cytoplasmic domain juxtaposed to the TCR CD3z signaling moiety increased IFN-g secretion by FcIR-28z transduced T cells following encounter with antigen-bound mAb on the cancer cell surface. Notably, T cells expressing a high affinity FcIRI (CD64) demonstrated the greatest specific anti-tumor reactivity in comparison to cells expressing FcγRIIA (CD32) or FcγRIIIA (CD16) FcIRs. In addition, FcIRI (CD64) T cells exhibited stronger specific lytic activity than NK cells, even at low antibody concentrations. Further, co-administration of FcIRI (CD64) FcIR-28z T cells with immunotherapeutic mAb, Trastuzumab, exerted strong antitumor activity in vivo, completely eliminating HER2+ tumor. In summary, our results show that ADCC can be enhanced by human T cells engineered to express an FcIR and that this novel approach may overcome issues of resistance to mAb-targeted therapies including those utilizing Trastuzumab. Citation Format: Katarzyna Urbanska, Mathilde Poussin, Caitlin Stashwick, Jenessa B. Smith, Daniel J. Powell Jr. Overcoming resistance to antibody targeted therapy in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1433.