Can cancer treatment with immune checkpoint inhibitors be improved?
Austin James Rayford completed October 11, 2024 his PhD degree at the University in Bergen with his thesis "Studies on the effect of AXL inhibition in non-small cell lung cancer".
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Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide and is responsible for most cancer-related deaths in Norway. Non-small cell lung cancer (NSCLC) accounts for around 80% of lung cancer cases. The introduction of targeted therapies and immune checkpoint inhibitors (ICIs) has revolutionized the treatment of NSCLC in recent years, particularly due to the remarkable clinical efficacy of ICIs observed in a subset of patients. However, intrinsic and acquired resistance to ICIs remains a barrier to durable clinical benefit, and the complex molecular mechanisms mediating resistance are still poorly understood.
AXL, a receptor tyrosine kinase, is upregulated by normal and malignant cells in many tissues during chronic inflammation and wound-healing and is also a central negative feedback regulator of innate immunity. Although many studies have implicated AXL in both tumor-intrinsic and immune-mediated mechanisms of ICI resistance, current data on AXL expression in tumor and immune cells in clinical NSCLC specimens is lacking, while its prognostic and predictive role in the context of ICI treatment and the ability of AXL-inhibiting drugs to potentiate ICI efficacy remains elusive.
The main goal of this doctoral work was to map molecular mechanisms of resistance to ICI. A key objective was to map the expression of the membrane receptor AXL on cancer cells and immune cells in NSCLC samples, as well as to investigate whether treatment response could be predicted using the AXL expression. Another aim was to investigate the effect of targeted AXL inhibition on response to treatment with ICI.
In this work, the group first showed that AXL expression in tumor cells was associated with aggressive phenotypic features, an immunosuppressive tumor microenvironment and poor survival in a real-world cohort of NSCLC patients treated with ICI monotherapy. They then demonstrated that the addition of bemcentinib, a selective small-molecule AXL kinase inhibitor, to ICI therapy in a multi-national clinical trial of advanced pretreated NSCLC patients resulted in improved clinical benefit compared to standard-of-care treatments, particularly within subgroups with AXL-positive and STK11-inactivated tumors expected to have the worst prognosis. In murine models, bemcentinib sensitized STK11-mutant NSCLC tumors to ICI treatment via AXL-targeting in dendritic cells, suggesting an additional tumor-cell extrinsic mechanism that supports the efficacy of bemcentinib-ICI treatment observed in patients with STK11-loss.
Overall, the results from Rayford's doctoral work provide increased insight into the complex mechanisms of AXL-mediated resistance development and cell type-specific effects of AXL inhibition in NSCLC. These findings provide a strong scientific rationale for current and future clinical trials incorporating AXL inhibitors with ICI therapy to improve NSCLC patient outcomes, hopefully leading to more patients in the future being able to experience long-term effects of their cancer treatment.
About Austin Rayford
Austin Rayford completed his bachelor's degree at the University of California, Berkeley in 2015. He worked for two years at Roche Molecular Systems in California, before starting his master's degree in 2017 in Professor Jim Loren's research group at the Department of Biomedicine/CCBIO, UiB. Rayford was employed by BerGenBio from 2019. He began his PhD work in 2020 as an industry PhD student. The main supervisor for the work is Professor James B. Lorens and co-supervisors are Agnete Engelsen and David Micklem.
