Abstract 1293: AZD0171 (anti-LIF) combines productively with chemotherapy and anti-PD-L1 in mouse models of cancer

Abstract

Leukemic inhibitory factor (LIF) is an IL-6 family member involved in embryonic stem cell maintenance and protection from maternal immune-attack. Emerging evidence indicates that LIF biology is hijacked by some tumors to promote immunosuppressive tumor associated macrophages, cancer initiating cells and epithelial-mesenchymal transition (EMT). In patients treated with anti-PD-1/anti-PD-L1 antibodies (IO), baseline high LIF expression correlated with poor outcome (Loriot et al. 2021). In preclinical models, LIF blockade has separately been reported to sensitize tumors to IO and to chemotherapy (chemo), but the impact of LIF blockade on chemo/IO combination activity is unknown. We therefore evaluated the hypothesis that LIF blockade sensitizes tumors to chemo/IO combinations. AZD0171 is a monoclonal antibody that binds to LIF and prevents signaling through LIF receptor. A murine surrogate of AZD0171 (mAZD0171) was generated and tested in vivo using three syngeneic murine cancer models, and AZD0171 was tested in patient derived xenograft models. Monotherapy mAZD0171 induced tumor gene expression changes consistent with its proposed mechanism of action in the syngeneic CT26 colon tumor model; including elevated CD8 attracting chemokines (CXCL9/10), cDC1 transcription factor (Batf3) and reduced stem cell (CD44), EMT (CY61) and hypoxic/angiogenic signatures, including CXCL12. Flow cytometry analysis highlighted changes consistent with suppressive macrophage re-education (reduced CD206/elevated MHCII). mAZD0171 sensitized mouse tumors to both IO and chemo. mAZD0171 + anti-PD-L1 treatment reversed CD8 T cell exclusion in the D2A1-m2 model; a LIF expressing cancer associated fibroblast rich, anti-PD-L1 resistant mouse mammary tumor syngeneic model (Jungwirth et al. 2018). mAZD0171 + anti-PD-L1 treatment further inhibited D2A1-m2 growth versus (vs) anti-PD-L1 treatment alone. In a non-small cell lung carcinoma patient derived xenograft model, AZD0171 improved the tumor growth inhibitory effect of Carboplatin + Paclitaxel. The triplet combination of mAZD0171 plus chemo and IO had the most marked impact on both tumor microenvironment and tumor growth. mAZD0171 addition to oxaliplatin (OHP) or Docetaxel (DTX) chemotherapy plus anti-PD-L1 significantly elevated CD8 abundance and granzyme B expression in MC38 colon tumors. mAZD0171 + anti-PD-L1 + OHP or DTX improved inhibition of MC38 tumor growth (63% for OHP triplet vs 34% for anti-PD-L1 + OHP; 49% for DTX triplet vs 36% for anti-PD-L1 + DTX) and extended median survival times (P<0.05 vs anti-PD-L1+OHP/DTX). Together these data support the hypothesis that AZD0171 has the potential to sensitize solid tumors to chemotherapy/IO combinations. The safety and activity of AZD0171 is currently being assessed in a Ph2 clinical trial in combination with durvalumab (anti-PD-L1) and chemotherapy in metastatic pancreatic cancer (NCT04999969). Citation Format: Juliana Candido, Gozde Kar, Bairu Zhang, Grace Opoku-Ansah, Amit Grover, Elizabeth A. Kuczynski, Tim Slidel, Doug Palmer, Robert W. Wilkinsom, Nadia Luheshi, Jim Eyles. AZD0171 (anti-LIF) combines productively with chemotherapy and anti-PD-L1 in mouse models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1293.

Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

“…[24][25][26] Combination therapy with MSC-1 and a PD-1 inhibitor induced durable slowing of tumor growth more than PD-1 inhibitor monotherapy in these tumor models, suggesting a synergistic mechanism of action. 26 It is hypothesized that in patients with advanced solid tumors, MSC-1 could effectively block LIF signaling, activate immune-mediated antitumor effects, and inhibit cancer stem cells.…”

“…24,26 MSC-1 monotherapy decreased tumor growth and drove reprogramming of the TME from an immunosuppressive M2-like state to an immunostimulatory M1-like state, while decreasing regulatory T cells and increasing T-effector cells and natural killer cells. [24][25][26] Combination therapy with MSC-1 and a PD-1 inhibitor induced durable slowing of tumor growth more than PD-1 inhibitor monotherapy in these tumor models, suggesting a synergistic mechanism of action. 26 It is hypothesized that in patients with advanced solid tumors, MSC-1 could effectively block LIF signaling, activate immune-mediated antitumor effects, and inhibit cancer stem cells.…”

“…24 It is a potent and specific LIF antagonist, which inhibits LIF signaling by binding to an epitope that overlaps with the gp130 receptor binding site on LIF. 25,26 MSC-1 potently inhibits LIF-induced pSTAT3 signaling in vitro and in vivo. 24 Preclinical evidence suggests that it promotes antitumor inflammation through TAM modulation, which induces CD8þ T-cell activity and improves response to PD-1 inhibitors.…”

“…24 Preclinical evidence suggests that it promotes antitumor inflammation through TAM modulation, which induces CD8þ T-cell activity and improves response to PD-1 inhibitors. 14,24,26 The activity of MSC-1 monotherapy and in combination with a PD-L1 inhibitor has been demonstrated in preclinical studies, using the CT26 and MC38 syngeneic mouse tumor models. 24,26 MSC-1 monotherapy decreased tumor growth and drove reprogramming of the TME from an immunosuppressive M2-like state to an immunostimulatory M1-like state, while decreasing regulatory T cells and increasing T-effector cells and natural killer cells.…”

“…14,24,26 The activity of MSC-1 monotherapy and in combination with a PD-L1 inhibitor has been demonstrated in preclinical studies, using the CT26 and MC38 syngeneic mouse tumor models. 24,26 MSC-1 monotherapy decreased tumor growth and drove reprogramming of the TME from an immunosuppressive M2-like state to an immunostimulatory M1-like state, while decreasing regulatory T cells and increasing T-effector cells and natural killer cells. [24][25][26] Combination therapy with MSC-1 and a PD-1 inhibitor induced durable slowing of tumor growth more than PD-1 inhibitor monotherapy in these tumor models, suggesting a synergistic mechanism of action.…”