Pancreatic ductal adenocarcinoma (PDAC) is resistant to PD1/PDL1 blocking antibodies. The purpose of this study was to evaluate if immunotherapy with LOAd703, an oncolytic adenovirus armed with trimerized CD40L and 4-1BBL, can sensitize PDAC to mAbs targeting PD1/PDL1. The high content of myeloid-derived suppressor cells (MDCSs) in the tumor microenvironment may in part explain the limited anti-tumor T cell response in PDAC. We have previously shown that gemcitabine can reduce MDSCs in patients with PDAC, with the T cell proliferative capacity remaining intact. Further, LOAd703 has been demonstrated to efficiently and robustly kill PDAC cells and stimulate the maturation of dendritic cells (DCs), which, in turn, induces T cell activation. Patients with advanced PDAC, colorectal, biliary, and ovarian cancer (NCT03225989) were treated with intratumoral injections of LOAd703 combined with appropriate chemotherapy such as gemcitabine ± nab-paclitaxel for PDAC patients, or combined with gemcitabine if there was no standard of care. Blood sampling was performed for immune cell profiling and anti-adenovirus antibodies (flow cytometry, ELISA). Tumor biopsies were also analyzed for mRNA expression (NanoString; PanCancer Immune Profiling Panel). The study was approved by the ethical review board and the Swedish Medical Products Agency. The dose of LOAd703 was escalated (5 × 10e10 VP, 1 × 10e11 VP, 5 × 10e11VP) in separate cohorts of new patients and administered every other week. To date, blood samples from 23 patients have been analyzed by flow cytometry to profile immune cells. The mean percentages of monocytic- and granulocytic MDSCs, Tregs and M2-like myeloid cells were significantly decreased after treatment initiation. The effector memory (EM) and central memory (CM) CD8+ T cells were significantly increased, while naïve and CM cells were increased among CD4 T cells. Both CD4 and CD8 T cells expressing ICOS were present post-treatment but only CD8 T cells showed significant elevation of PD1. The NanoString data were analyzed using published mRNA immune signatures (bioinformatics). LOAd703 in combination with chemotherapy inflamed tumor lesions as shown by increased markers of the T cell inflamed signature (16 genes), T effector cell signature (19 genes), expanded immune signature (25 genes) and IFNg-related gene signature (12 genes) (week 1 versus week 13). Anti-adenovirus antibody titers increased in all patients after treatment initiation. The antibody levels did not correlate with the dose of virus, radiological response to treatment, nor overall survival. The results presented herein show that LOAd703 combined with chemotherapy enhances immune reactivity in patients with immune cold tumors as demonstrated by increases in EM and CM T cells in the peripheral blood, while suppressive immune cells were decreased. Further, the tumor milieu was inflamed post treatment as shown by mRNA profiling. Hence, LOAd703 may sensitize immune cold tumors to mAbs targeting PD1/PDL1.
Citation Format: Jessica Wenthe, Emma Eriksson, Linda Sandin, Tanja Lövgren, Justyna Leja Jarblad, Hanna Dahlstrand, Ulla Olsson-Strömberg, Aglaia Schiza, Anders Sundin, Sandra Irenaeus, Eric Rowinsky, Gustav Ullenhag, Angelica Loskog. Inflaming advanced solid tumors including pancreatic cancer using LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic virus [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-018.