LAUSR

Pancreatic adenocarcinoma (PDAC) is extremely lethal and resistant to checkpoint immunotherapy, characterized by an immunosuppressive tumor microenvironment consisting of stromal and myeloid cells. Prior studies have demonstrated the utility of targeting the chemokine signaling axis CXCR4-CXCL12 (SDF-1), a highlighted feature in PDACs, to overcome the CXCL12-driven immobilization of T cells and thus facilitate their antitumor role within the tumor. Based on these findings, we have conducted a phase 2 trial evaluating the effects of plerixafor, a CXCR4 antagonist, and cemiplimab, a PD1 inhibitor antibody, in patients with metastatic PDAC who have progressed after one line of systemic chemotherapy (NCT04177810). To determine the immunological responses to therapy, blood samples and tissue biopsies were obtained at baseline and during treatment. Hematological assessment confirmed the activity of CXCR4 antagonist in mobilizing hematopoietic precursors (CD34+), immature myeloid cells, and lymphoid cells, as well as monocytic and granulocytic cell populations. Suspension mass cytometry analysis of peripheral blood mononuclear cells revealed that mobilized monocytic subpopulations had high expressions of chemokine receptors CCR2, CCR5, and CXCR2. Histopathologic evaluation of the serial tissue biopsies from the liver metastatic PDAC revealed increased levels of inflammation upon treatment. To further characterize the cellular constituents of the observed inflammation, multiplexed immunohistochemistry by imaging mass cytometry was performed, demonstrating strong trends toward increased infiltration of not only effector T cells but also macrophages and granulocytic cells into the tumor microenvironment. Taken together, these findings suggest that mobilization of myeloid cells by CXCR4 antagonism results in the recruitment of additional myeloid cells from circulation and that alternative chemokine signaling pathways are sufficient for doing so. This implicates a potential mode of resistance against CXCR4-targeted therapies. Furthermore, these observations reinforce the value of ongoing research efforts in the field to subvert the recruitment or immunosuppressive function of myeloid cells, which would be particularly relevant in the setting of CXCR4 antagonism. Citation Format: Sarah M. Shin, Alexei Hernandez, Erin Coyne, Zhehao Zhang, Sarah Mitchell, Jennifer Durham, Xuan Yuan, Hongqui Yang, Elana J. Fertig, Elizabeth M. Jaffee, Katherine M. Bever, Dung T. Le, Won Jin Ho. Combination of CXCR4 antagonist and anti-PD1 therapy results in significant mobilization and increased infiltration of myeloid cells into the metastatic liver microenvironment of PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2270.