Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects

Abstract

BackgroundImmunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition.MethodsHere, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred.ResultsThe treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14+CD15+promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses.ConclusionsWe demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.

CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target

“…NOX-A12 is a novel RNA aptamer that binds CXCL12 in two key positions, blocking binding of the chemokine to its receptors and dislodging bound CXCL12 from cell surfaces [ 79 ]. NOX-A12 has synergized with PD-1 blockade by enhancing T-cell infiltration in preclinical models [ 87 ], leading to an exploratory phase 1B study with a small cohort of 11 colorectal and 9 pancreatic cancer patients, where a combination of NOX-A12 with the PD-1 inhibitor pembrolizumab induced T helper type 1 (Th1) immune responses and prolonged disease stabilization in a minority of patients, supporting previous findings that the CXCL12/CXCR4 axis is important in immune evasion in pancreatic cancer [ 88 ].…”

“…Indeed, CAFs appear to limit the access of CD8 + cells to juxtatumoral stromal areas in PDAC [ 93 ]. Intriguingly, a recent clinical study of NOX-A12 revealed that drug treatment significantly reduced the average distance between T cells and tumor cells in PDAC biopsies [ 88 ]. The stroma can thus function as a physical and a dynamic chemical barrier working actively to keep antitumor immune cell types (e.g., CD8 + T cells) out while permitting the migration of immunosuppressive cells such as MDSCs and mast cells.…”

Current Advances in RNA Therapeutics for Human Diseases

“…NOX-A12 is an RNA aptamer that is in clinical trials for the treatment of various types of cancers, for example, pancreatic cancer, colorectal cancer, and multiple myeloma [ 50 , 183 , 184 ]. This drug works by neutralizing CXCL12, which leads to an increase in circulating tumor-infiltrating T-cells [ 185 ].…”

“…This drug works by neutralizing CXCL12, which leads to an increase in circulating tumor-infiltrating T-cells [ 185 ]. To date, clinical trials have demonstrated the potential of NOX-A12 in the treatment of various types of cancer [ 50 , 183 , 184 ].…”

Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies

“…Responses were attributable to the increased CD3 + T cell infiltration and interferon production. However, the authors did not biopsy tumor samples that received the combination treatment, leaving the post-treatment characterization of the TME left much to be desired ( Suarez-Carmona et al, 2021 ). Currently, NOX-A12 is undergoing additional phase II clinical trials in combination with pembrolizumab to evaluate both its safety and toxicity of the therapy in the context of microsatellite-stable metastatic pancreatic cancer (NCT04901741 ( NOXXON Pharma AG, 2021 )) Table 1 .…”