Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects: https://jitc.bmj.com/content/10/7/e004863 (review-artikkel, 20. juli 2022)
This review outlines the key mechanisms of CPI resistance, including the role of the immunosuppressive TME, and discusses the rationale for targeting TAM receptors as a novel, promising therapeutic strategy to overcome CPI resistance in NSCLC.
New therapeutic approaches to address CPI resistance using TAM receptor inhibitors
There is a strong biological rationale for combining a TAM tyrosine kinase inhibitor (TKI) with a CPI to overcome resistance and improve clinical responses of patients with NSCLC.80 88–92 Despite inducing an inflammatory TME, TAM inhibition leads to an adaptive resistance to immune cell killing by upregulating molecules of the PD-1/PD-L1 axis, therefore combining TAM inhibition with anti-PD-1 blockade seems necessary and has proven efficacious in both preclinical models and early clinical data.72 In a breast cancer model, Axl inhibition induced an antitumor response including tumor-associated efferocytosis with a synergistic response in combination with PD-1 blockade.92 In another preclinical study, Axl inhibition was shown to induce antitumor responses in murine ovarian and breast cancer models by reprogramming the TME, and enhancing the activation and function of tumor-infiltrating CD4+ and CD8+ T cells, an effect which was further potentiated by PD-1 blockade.90 Moreover, a recent study using leukemia models, demonstrated that Axl inhibition (specifically in macrophages) triggers durable anti-leukemic immunity and elicits susceptibility to PD-1 blockade; interestingly this efficacy was also observed in Axl negative tumors, which has the potential to extend the clinical benefit of Axl inhibition to a wider population of cancer patients.93
Other TAM receptor inhibitors
Bemcentinib (BGB324) is a selective, small-molecule inhibitor that targets the intracellular catalytic kinase domain of Axl.85 In a preclinical lung cancer model, the combination of bemcentinib and anti-PD-L1 therapy significantly reduced tumor growth versus anti-PD-L1 therapy alone; tumors treated with the combination showed altered cytokine signaling, enhanced infiltration by effector cells, and a reduction in MDSCs.105 A single-arm, two-stage, multicohort phase 2 study of bemcentinib plus pembrolizumab in refractory patients with advanced NSCLC (NCT03184571) showed that this combination was well tolerated and clinically active in both the chemotherapy-failed CPI-naive patients (cohort A) and the CPI-refractory patients (cohort B) with cAxl-positive tumors. In cAxl-positive postchemotherapy and post-CPI patients, the clinical benefit rate was 73% and 86%, respectively.106 Bemcentinib in combination with a PD-L1 inhibitor recently received a fast track designation from the FDA for the treatment of patients with serine/threonine kinase 11 (STK11)-altered advanced/metastatic NSCLC without actionable mutations.107
