SU2C-Lustgarten Foundation Pancreatic Cancer Dream Team Shows that Treating CRC and PDA Patients with CXCR4 Inhibitor Effectively Elicits an Integrated Immune Response
Although immune checkpoint inhibitors (ICI) have infused hope in light of profound responses from a subset of patients in a variety of cancer types, it is now accepted that ICI alone may not be sufficient to treat many patients. Stand Up to Cancer-Lustgarten Foundation (SU2C-LF) Pancreatic Cancer Dream Team members report in PNAS results of their correlative analyses on samples from their Phase I clinical trial (NCT02179970) on the CXCR4 inhibitor AMD3100. They showed that blocking the chemokine receptor CXCR4 not only induced T-cell intratumoral accumulation but also elicited an integrated immune response (INTIRE) in pancreatic and microsatellite-stable colorectal cancer.
The SU2C-LF Pancreatic Cancer Dream Team set out in 2014 to develop immune-based therapeutic strategies for pancreatic ductal adenocarcinoma (PDA). Their efforts were spurred by the underlying hypothesis that the immunosuppressive PDA milieu could be reprogrammed into an immuno-stimulatory one capable of tumor rejection, thus converting PDA into a treatable disease.
CXCR4 is the receptor for the chemokine CXCL12 – a chemokine that is produced by cancer-associated fibroblasts (CAF). One of the Team Principals, Douglas Fearon, MD and his group had reported in 20131 that administering a CXCR4 inhibitor (AMD3100) in a pancreatic cancer mouse model induced intratumoral T-cell accumulation. In this current work, they report the effects of CXCR4 inhibitor administration in patients with microsatellite stable PDA (n=10) or microsatellite stable colorectal cancer (n=15). AMD3100 was delivered continuously for 7 days via intravenous infusion to achieve continuous CXCR4 inhibition. Pharmacokinetic, pharmacodynamic, and intratumoral immunological analyses were performed on samples collected during treatment and on paired biopsies taken before and after AMD3100 treatment.
Intravenous infusion at a dose rate of 80 µg/kg/h was sufficient to achieve the target plasma level of ~ 2 µg/ml (4 µM). As an indicator of effective CXCR4 inhibition, CD34+ levels were elevated during AMD3100 infusion. It was also reported that circulating DNA levels were significantly reduced in response to AMD3100 treatment (n=15, p=0.033). Enrichment analyses of RNAseq data on metastatic lesions showed that CXCR4 inhibition induced intratumoral T and NK cell accumulation and activation and also induced an activated B cell response.
The observed immune reaction in response to CXCR4 inhibition was similar to that of noninfected, immunogenic tissues (e.g. microsatellite instable colorectal cancer, and rejecting kidney allografts). The authors developed the INTIRE gene signature – defined by 194 genes that identify 9 components of innate and adaptive immunity; namely, antigen presentation, T and NK cell accumulation, T and NK effector cells, chemokines and chemokine receptors, activated B cells and plasma cells, tertiary lymphoid structures, type I/III interferon response, and endothelial cells. This gene signature was not only seen in the tumor tissues from patients treated with AMD3100 but also in tumor tissues from melanoma patients who responded to ICI treatment.
The results of Dr. Fearon’s group, therefore, confirm that pharmacological inhibition of CXCR4 in patients can induce an integrated immune response. The observation of rapid intratumoral accumulation of B and T cells (i.e. only after 7 days of CXCR4 inhibition) suggests that immune suppression rather than immune ignorance may be a major barrier to clinically effective immunotherapy. The SU2C-LF Pancreatic Cancer Dream Team is continuing to pursue the clinical potential of CXCR4 inhibition, at least in part, by conducting a Phase II clinical trial (NCT04177810) on the combination of AMD3100 with anti-PD-L1.
1Feig C et al., 2013. PNAS 110:20212-20217