Immune monitoring of blood in advanced gastroesophageal adenocarcinoma patients treated with an anti-MMP9 monoclonal antibody in combination with nivolumab.

Abstract

13 Background: A phase 1b study was conducted in Japanese patients with >2nd line advanced gastroesophageal adenocarcinoma (GEA) to evaluate the safety, tolerability and explore efficacy and biomarkers, of andecaliximab (ADX), an anti-MMP9 monoclonal antibody, in combination with nivolumab (nivo). In this study, 5 of the 10 enrolled patients had a partial response and the remaining 5 had progressive disease. A larger parallel study in western patients showed no improvement in response or survival for the addition of ADX to nivo. A biomarker study is reported here which explored the hypothesis that baseline levels or early changes in the frequency of peripheral immune cells might identify responders to immunotherapy. Methods: Blood samples were collected at screen, C1D1, C1D8, C1D15, C2D1, C2D15 and then at CXD1 until end of treatment and processed to viably-frozen PBMCs. Immune cell analysis was conducted by flow cytometry (FCM), and included evaluation of T cells, B cells, myeloid derived suppressor cells, NK cells, monocytes, and dendritic cells (DCs). Baseline status and on treatment changes were explored. Results: FCM analysis of peripheral blood showed that the 5 responders had higher frequency of LAG3+CD8+ T cells and myeloid DCs, and lower frequency of plasmacytoid DC than non-responders at baseline. The number of CD8+ T cells decreased at C1D8 and then recovered in responders. In contrast, no CD8+ T cell changes were observed in non-responders. CTLA-4+ CD4+ T cells also increased after treatment in responders but not in non-responders. Changes in other evaluated cell populations were not observed. Conclusions: The observation that baseline levels of LAG3+CD8+ T cells and DCs were higher in responders is consistent with a prior anti-tumor immune response. Transient decreased peripheral CD8+ T cells might reflect T-cell trafficking into tumor in response to immunotherapy, and increased peripheral CTLA-4+ CD4+ T cells may also relate to tumor-localized response. Although in a very small number of patients, the observations are consistent with early changes in peripheral immune cells that may relate to response to immunotherapy. Clinical trial information: NCT02862535.