Effective Targeting Of Her2-Amplified Cancers With Trastuzumab In Combination With T Cells Expressing A Novel Antibody-Coupled T-Cell Receptor (Actr)

HER2 gene amplification occurs in 20-30% of aggressive breast and gastric cancers, and is associated with poor prognosis. The standard of care for HER2-positive early breast cancer includes the HER2-targeting antibody, trastuzumab, administered with chemotherapy. In patients with advanced HER2-positive disease, the standard of care as first-line therapy includes dual blockade of HER2 with trastuzumab and pertuzumab, an antibody that binds to an alternative epitope of HER2. Despite the clinical success of targeting HER2, many patients are intrinsically resistant or develop resistance during treatment regardless of continued expression of HER2, highlighting the need for novel therapeutic paradigms. Engineered cell therapies, including chimeric antigen receptor (CAR) T cells, have demonstrated promising clinical activity in advanced cancers. Despite success, CAR-T cells have shown substantial toxicity, and in initial clinical trials of HER2-amplified cancer CAR-T cells demonstrated acute toxicities, presumably due to target/off activity. The Antibody-Coupled T-cell Receptor (ACTR) platform is a universal, engineered T-cell therapy developed to mediate antitumor activity when administered with tumor-targeting antibodies. The ACTR construct is composed of the extracellular domain of the high-affinity CD16 (FCGR3A) V158 variant fused with costimulatory and CD3ζ intracellular signaling domains. ACTR is engineered to engage the Fc domain of human IgG1 antibodies when opsonized to target cells, which delivers an activation signal to the engineered T cells. Two distinct ACTR variants, ACTR087 and ACTR707, are currently being evaluated clinically in combination with rituximab in patients with B cell lymphoma (NCT02776813, NCT03189836). The ACTR707 variant was selected from a panel of constructs based on its strong performance in preclinical tests to assess activity not only in hematologic cancers, but also in solid tumors. When combined with trastuzumab, ACTR707 mediated potent cytotoxicity against HER2-amplified tumor cell lines in vitro. Cytokine response and proliferation of ACTR707 was also observed in the presence of trastuzumab and target cells. ACTR707 activity was specific to trastuzumab-treated HER2-positive cells as no cytotoxicity was observed in the absence of trastuzumab, or with a nontargeting antibody. In HER2-amplified xenograft models, such as the N87 gastric cancer model, ACTR707 and trastuzumab combination treatment mediated tumor regressions, demonstrating significantly enhanced activity compared to trastuzumab alone. Finally, the activity of ACTR707 on a panel of normal cells representing normal tissue expression of HER2 was tested in the presence of trastuzumab. ACTR707 in combination with trastuzumab demonstrated marginal cytotoxicity on these cells. In contrast, trastuzumab-based CAR-T cells mediated potent cytotoxicity against these cells. Taken together, our data demonstrate that ACTR707 in combination with trastuzumab has robust antitumor activity in vitro and in vivo. Furthermore, this combination has differential cytotoxicity on HER2-amplified tumor cells compared to HER2-expressing nonmalignant cells, suggesting that a favorable therapeutic index may be established in the clinical treatment of HER2-amplified cancers. Citation Format: Katie M. O9Callaghan, John Shin, Eugene Choi, Greg Motz, Casey B. Judge, Heather A. Huet, Birgit C. Schultes, Seth A. Ettenberg. Effective targeting of HER2-amplified cancers with trastuzumab in combination with T cells expressing a novel Antibody-Coupled T-cell Receptor (ACTR) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A163.