Dr Qian on Preclinical Data for a CXCR4 Partial Agonist Plus Anti–PD-1 Therapy in Gastric Cancer.

Jin Qian, PhD, associate research scientist, Department of Medicine, Digestive & Liver Diseases, Herbert Irving Comprehensive Cancer Center, Columbia University, discusses preclinical findings for a secreted CXCR4 partial agonist called trefoil factor family 2 (TFF2) in combination with anti–PD-1 therapy in advanced gastric cancer refractory to PD-1 blockade.

The study utilized a novel TFF2-MSA peptide with extended half-life, generated by fusing mouse TFF2 with murine serum albumin. Therapeutic effects were evaluated both in vitro and in vivo, utilizing HDC-GFP transgenic mice to track polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which highly express CXCR4.

Results presented at the 2024 AACR Annual Meeting demonstrated that the combination of TFF2-MSA and anti–PD-1 antibody exhibited synergy, significantly boosting intratumoral cytotoxic CD8-positive T cells, leading to tumor regression or eradication, reduction of distant metastases, and extension of mouse survival. Importantly, TFF2-MSA treatment systematically reduced HDC-GFP–positive PMN-MDSCs in various components, including tumor, blood, spleen, and bone marrow myeloid progenitors.

Qian notes that further analyses revealed that TFF2-MSA plus anti–PD-1 therapy induced a shift in the composition of tumor HDC-GFP–positive PMN-MDSCs toward less immature subsets expressing interferon-stimulated genes, thereby reducing immunosuppression and enhancing antigen presentation functions. This shift was driven by an IRF1-mediated interferon response in splenic HDC-GFP–positive PMN-MDSCs. In contrast, the CXCR4 antagonist AMD3100, in combination with anti–PD-1, failed to restrict tumor growth or PMN-MDSCs.

Overall, these findings suggest that TFF2-MSA synergizes with PD-1 blockade by selectively targeting PMN-MDSCs with high CXCR4 expression, providing a rationale for further investigation of this novel combination therapy approach in advanced gastric cancer, Qian concludes.