AZD5069

P1/2, N=340, Completed, AstraZeneca | Active, not recruiting --> Completed

IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes.

These therapeutic effects were further amplified when combined with the CXCR2 inhibitor AZD5069. Our findings identify Trem2 as a central regulator of the NASH-driven HCC immunosuppressive niche, and suggest a combinatorial therapeutic strategy that targets both myeloid reprogramming and NETosis to overcome immunotherapy resistance in metabolic liver cancer progression.

We chemically modified a small-molecule CXCR2 inhibitor AZD5069 by conjugating it with polyethylene glycol (PEG) to enhance aqueous solubility. Treatment of orthotopic tumor-bearing KPC mice with CXCR2-NPRuxo reduced tumor burden compared with vehicle, free Ruxolitinib, or non-drug-loaded CXCR2-NP treatments, without causing appreciable neutropenia. Taken together, cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.

It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions.

P1/2, N=340, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2025 --> Aug 2025

Single-cell RNA sequencing (scRNA-seq) were performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a Phase II clinical trial cohort...This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist...The association between myeloid IL-8 and ICB therapeutic outcome also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response, but also provides a proof-of-concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.

Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer.

Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.

We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo . Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.

P1/2, N=340, Active, not recruiting, AstraZeneca | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2023 --> Mar 2025

Our findings reveal that blocking GCMSCs-derived IL-8/CXCR2 pathway decreasing PD-L1 expression and lactate production, improving antitumor efficacy of anti-PD-1 immunotherapy, may be of value for the treatment of advanced gastric carcinoma.