Abstract 3950: Rovalpituzumab tesirine enhances the anti-tumor efficacy of PD-1 blockade in a murine model of small cell lung cancer with endogenous Dll3 expression
Authors: Vitorno Philip M. , Chuang Chen-Hua , Moore Christine , Turan Tolga , Ferrando Ronald , Nichols Aaron , Madhavan Shravanthi , Saunders Laura R. 
Published: August 2019

Abstract
Rovalpituzumab tesirine (Rova-T) is an antibody drug conjugate (ADC) comprised of a DLL3-targeted antibody conjugated to a potent cytotoxic pyrrolobenzodiazepine (PBD) toxin that is currently being investigated clinically in phase 3 trials for small cell lung cancer (SCLC). Cytotoxic DNA damaging agents including PBDs may elicit immunologic cell death (ICD), a form of apoptosis that enhances immune activation (Rios-Doria J 2017). Blockade of PD-1, an immune checkpoint receptor, using Nivolumab in 3L+ SCLC patients, showed an objective response rate (ORR) of 11.9%, with ORR higher in patients with high tumor mutation burden (Hellmann MD 2018). Here we report that sub-efficacious doses of Rova-T in combination with anti-PD-1 mAb resulted in enhanced anti-tumor activity in KP1, a murine SCLC syngeneic tumor model (Park KS 2011) that endogenously expresses Dll3, compared to Rova-T alone or anti-PD-1 mAb alone. In contrast, a single cycle of cisplatin + etoposide (C/E) standard of care chemotherapy alone showed some tumor burden reduction, but no additive activity was seen for combination C/E + anti-PD1 mAb. Rova-T alone, anti-PD1 alone, and the combination increased CD4+ and CD8+ T-cell infiltration in the tumor, as measured by gene expression analysis, flow cytometry and immunostaining of tumors after treatment. A multiplex immunofluorescence panel showed that the increased lymphocytes are restricted to the surrounding stroma in tumors treated with Rova-T or anti-PD1 alone. Unique to the Rova-T + anti-PD1 treated tumors, lymphocytes were found throughout the tumor, and they expressed granzyme B, a marker of activation. CD8 but not CD4 T-cell depletion before and during in vivo treatment with Rova-T + anti-PD1 reduced the anti-tumor efficacy, supporting a role for cytotoxic CD8 T cells in the combination efficacy. In addition to enhancing T-cell infiltration, Rova-T alone and Rova-T + anti-PD1 increased expression of PD-L1, the immune suppressive ligand of PD-1, on tumor cells. Mice treated with a single efficacious dose of Rova-T alone or Rova-T + anti-PD1 showed durable tumor suppression (&gt;50 days) and did not develop tumors when re-injected with 1 million tumor cells on the opposite flank, indicating that treatment conferred immunologic memory and sustained anti-tumor immunity. Together, these data provide pre-clinical rationale for the ongoing combination SCLC clinical trials of Rova-T and Nivolumab (NCT03026166) and Rova-T and ABBV-181 (NCT03000257).
Citation Format: Philip M. Vitorno, Chen-Hua Chuang, Christine Moore, Tolga Turan, Ronald Ferrando, Aaron Nichols, Shravanthi Madhavan, Laura R. Saunders. Rovalpituzumab tesirine enhances the anti-tumor efficacy of PD-1 blockade in a murine model of small cell lung cancer with endogenous Dll3 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3950.