Modulation of the tumor microenvironment by the CXCR4 antagonist AMD3100 in pancreatic and colorectal adenocarcinoma
Immunotherapy with checkpoint inhibitors has not been effective thus far in patients with micro-satellite stable pancreatic ductal adenocarcinoma (PDAC), which suggests an immunosuppressive mechanism operates within the tumour microenvironment (TME) of PDAC. In the KRasG12D; p53R172H; Pdx1-Cre (KPC) genetically engineered mouse model of PDAC, T cells are excluded from tumour nests and this effect is related to the chemokine CXCL12 produced by FAP+ stromal cells. Targeting the CXCL12/CXCR4 pathway with AMD3100, a CXCR4 antagonist, resulted T cell infiltration and tumor regression with anti-PD-L1 therapy in the KPC model. The CAMPLEX clinical trial was initiated to assess the safety of a 7-day AMD3100 infusion and provide proof-of-concept that AMD3100 reverses CXCL12 mediated immune-suppression in the TME.
The safety and pharmacokinetic results from the CAMPLEX dose escalation phase are presented. A dose-rate of AMD3100 80ug/kg/hr was safe, reasonably well tolerated, and achieved relevant plasma concentrations at steady state. However, pharmacodynamic makers of CXCR4 inhibition, including peripheral white blood cell and CD34+ cell mobilization, were maximal at the lowest dose-rate of 20ug/kg/hr, with little drug-related adverse events. An increase in T cell infiltration was observed in paired pre/post infusion tumour biopsies in a subset of patients, consistent with the pre-clinical KPC data.
To further characterize the pharmacodynamic effects of AMD3100 on the TME, additional pre-clinical experiments in the KPC model were performed. Increased CXCR4 protein expression within the TME is a robust effect of AMD3100, which was also observed in the CAMPLEX biopsies. Furthermore, there was a large increase in the infiltration of F4/80+ macrophages at 6 days in KPC mice receiving a high dose of AMD3100. Further studies are warranted to determine their source, polarization, and whether they are related to the anti-tumour effects of AMD3100.