Background Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are potential therapeutic targets in immune checkpoint cancer therapy, particularly for cancers that are unresponsive to anti-PD-1 therapy. It has previously been demonstrated that trefoil factor family 2 (TFF2), a secreted anti-inflammatory peptide, can partially suppress MDSC expansion and partially activate tumor immunity through agonism of the CXCR4 receptor.1–3 We investigated whether a novel fusion protein, murine TFF2-murine serum albumin (mTFF2-MSA), designated mTNX-1700, has single agent activity and can improve on the therapeutic effects of anti-PD-1 in the Pan02 syngeneic mouse model of advanced pancreatic cancer.
Methods A syngeneic pancreatic mouse model was developed using the Pan02 pancreatic cell line grafted subcutaneously into C57BL/6 mice. We generated a recombinant fusion protein, designated mTFF2-MSA, which contains murine TFF2 fused to murine serum albumin (MSA), for the purpose of increasing half-life and reducing the frequency of dosing. Mice subsequently received mTFF2-MSA, anti-PD-1 antibody (clone RMP1–14) or combination of mTFF2-MSA and anti-PD-1, and tumor volume was measured. At the endpoint, flow cytometry was performed on the tumor, axillary lymph node, blood, and bone marrow, to examine treatment-induced effects on cellular immune profiles.
Results In the Pan02 model, on Day 19 of treatment, tumor growth was suppressed (TGI) by mTFF2-MSA alone, anti-PD-1 alone, and by the combination mTFF2-MSA and anti-PD-1 by 23%, 28% and 36% TGI, respectively. In the blood, as measured by flow cytometry, there was a significant increase in total macrophages and M2 macrophages between the control and all treatment groups, and a decrease in monocytes and neutrophils in the groups dosed with anti-PD-1. In the axillary lymph node, there was a significant decrease in VISTA+ cells in both the CD4+ and CD8+ T-cells, and an increase in T regulatory cells in all treatment groups as compared to the control. In addition, an increase in PD-1+ and Lag3+ in both the CD4+ and CD8+ T-cells in the anti-PD-1 and combination treated groups was observed.
Conclusions mTFF2-MSA exhibits single agent activity and is additive to anti-PD-1 antibody checkpoint inhibition in treating the Pan02 syngeneic mouse model of advanced pancreatic cancer.
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