A phase 2 trial of CXCR4 antagonism and PD1 inhibition in metastatic pancreatic adenocarcinoma reveals recruitment of T cells but also immunosuppressive macrophages.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stroma and myeloid-rich microenvironment that confer resistance to immunotherapies. Previous studies demonstrated that disrupting the immune-stroma CXCR4-CXCL12 axis facilitates T cell recruitment and mobility to collaborate with anti-PD1/PD-L1 therapy. We sought to test the clinical viability of this immunotherapeutic strategy. 21 patients with metastatic PDAC were enrolled and treated in a phase 2 trial evaluating the effects of the plerixafor/AMD3100 and cemiplimab. Primary endpoint was objective response rate. Blood and tissue biospecimens were collected for correlative analyses. Parallel mouse studies were used to determine potential mechanisms of resistance. Treatments were well-tolerated, but only two patients demonstrated a best response of stable disease. Correlative analyses confirmed significant mobilization of immune cells into circulation as well as increased immune infiltration into the tumor. High-parameter imaging revealed higher levels of CD8⁺ T cells but also granulocytes and macrophages upon treatment. Spatial analysis showed that treatment resulted in closer proximity between macrophages and T cells but not between granulocytes and T cells. Mouse studies revealed that whereas total granulocyte depletion had no effect on immunotherapeutic efficacy, macrophage-targeting yielded significant benefit. Tumor growth measurements and immune profiling of immunotherapeutic combinations incorporating macrophage-targeting showed that despite the increased T cell infiltration, CXCR4 antagonism was in fact associated with enrichment of CD206^hiIA/IE^lo macrophage subtypes and modestly dampened efficacy. Our findings validate the utility of CXCR4 antagonism as an effective immune-recruiting platform but also underscores the need for strategies that better leverage its effects.