Modulation of the tumor microenvironment by the CXCR4 antagonist AMD3100 in pancreatic and colorectal adenocarcinoma

Change log
Smoragiewicz, Martin 

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.

Jodrell, Duncan
pancreatic cancer, immunotherapy, CXCR4, AMD3100
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge