Abstract 2670: Combination of anti-HER2 ADC XMT-1522 and checkpoint inhibitor pembrolizumab for treatment of NSCLC in preclinical models
Authors: Bodyak Natalya , Protopopova Marina , Zhang Qingxiu , Yurkovetskiy Alex , Yin Mao , Qin LiuLiang , Poling Laura L. , Mosher Rebecca , Bergstrom Donald A. , Lowinger Timothy B. 
Published: July 2017

Abstract
The combination of antibody-drug conjugates (ADCs) and immunomodulatory cancer therapies is emerging as a powerful strategy for cancer treatment. Tumor-targeted delivery of a cytotoxic payload capable of inducing immunogenic cell death (ICD) can trigger both an innate and an adaptive immune response, whereby increased recruitment of effector T-cells to the tumor and formation of tumor specific immunological memory can result in a durable treatment response. The ADC XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR of 12 AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. We have characterized the ability of both the free payload AF-HPA and the ADC XMT-1522 to induce ICD in vitro in multiple cell lines (NCI-N87, HT-29, SKBR3), as measured by the cell surface expression of the ICD marker calreticulin (CRT) by microscopy and flow cytometry (FACS). CRT, usually contained in the lumen of the endoplasmic reticulum, translocated to the cell surface within a few hours after treatment with AF-HPA or XMT-1522. XMT-1522 as a single agent induced significant tumor regressions in two patient-derived xenograft (PDX) models of HER2-espressing non-small cell lung cancer (NSCLC) at a dose of 3 mg/kg weekly for 3 doses. The combination of XMT-1522 in combination with the checkpoint inhibitor pembrolizumab was tested in one of these patient-derived HER2-expressing PDX models in a mouse with a humanized immune system. Expression of huPD-L1 in the tumor was confirmed by FACS and immunohistochemistry (IHC). Lymphocyte sub-populations were quantified in whole blood and in tumor by FACS and IHC. XMT-1522 treatment alone induced tumor growth delay after 3 weekly doses of 1 mg/kg. Pembrolizumab as a single agent administered every 5 days for 6 doses (q5dx6) at a dose of 2.5 mg/kg led to less tumor growth delay than XMT-1522 treatment. The combination of these two treatment regimens resulted in a better response than either of the two monotherapies. These data provide a rationale for XMT-1522 to be tested clinically as a single agent in HER2-expressing NSCLC, as well as a rationale for combination of XMT-1522 and immunomodulatory therapies in NSCLC.
Citation Format: Natalya Bodyak, Marina Protopopova, Qingxiu Zhang, Alex Yurkovetskiy, Mao Yin, LiuLiang Qin, Laura L. Poling, Rebecca Mosher, Donald A. Bergstrom, Timothy B. Lowinger. Combination of anti-HER2 ADC XMT-1522 and checkpoint inhibitor pembrolizumab for treatment of NSCLC in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2670. doi:10.1158/1538-7445.AM2017-2670