ESMO Immuno-Oncology 2025 | Mechanisms of resistance to checkpoint inhibitors in head & neck cancer
Amanda Psyrri, MD, PhD, FACP, National Kapodistrian University of Athens, Athens, Greece, discusses the limitations of immune checkpoint inhibition in recurrent metastatic head and neck squamous cell carcinoma. Different patterns of resistance to immune checkpoint inhibition include primary intrinsic resistance, adaptive resistance, clonal resistance, and acquired resistance. Therapeutic strategies to overcome resistance should focus on converting a cold tumor into an inflamed phenotype and increasing T-cell function and infiltration. This interview took place at 2025 European Society for Medical Oncology (ESMO) Immuno-Oncology Congress in London, UK.
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Transcript
Yes. So, as you know, immune checkpoint inhibition has transformed the treatment landscape of recurrent metastatic head and neck squamous cell carcinoma. Anti-PD-1 agents represent the standard of care in recurrent metastatic head and neck cancer, both in the first line and second line setting. However, despite these advances, almost 60% of patients fail to respond. And only about 20% attain durable disease control, highlighting the critical problem of resistance to immunotherapy...
Yes. So, as you know, immune checkpoint inhibition has transformed the treatment landscape of recurrent metastatic head and neck squamous cell carcinoma. Anti-PD-1 agents represent the standard of care in recurrent metastatic head and neck cancer, both in the first line and second line setting. However, despite these advances, almost 60% of patients fail to respond. And only about 20% attain durable disease control, highlighting the critical problem of resistance to immunotherapy. So a very important paper by Sharma and colleagues describes the patterns of resistance to immune checkpoint inhibition. This includes primary intrinsic resistance, where tumors fail to mount an effective immune response from the outset. Adaptive resistance in which an initial immune response is generated but counteracted by a regulation of inhibitory pathways. Clonal resistance where sensitive and resistant clones can coexist, and resistant populations progressively dominate. Acquired resistance, where tumors initially respond, but ultimately escape immune control. These resistance mechanisms can be contextualized within the cancer immunity cycle, which illustrates the sequential steps required for effective anti-tumor immunity, from antigen release and presentation to T-cell priming, trafficking, infiltration, and tumor cell killing. Disruption at any point in this cycle can prevent durable immune-mediated tumor eradication. So, therapeutic strategies to overcome resistance broadly focus on three major areas: converting a cold tumor into an inflamed phenotype. Nevertheless, initial immune inflammation, particularly T cell content and PD-L1 expression, remains strongly associated with outcome in patients with PD-L1 inhibitors. So I will go over the strategies that are being used in clinical trials to improve response to immune checkpoint inhibitors. So to increase T-cell function and infiltration, multiple immunotherapy combinatorial approaches have been explored. Unlike other tumor types, dual checkpoint blockade with anti-PD-1 plus anti-CTLA-4 failed to demonstrate a survival advantage in head and neck squamous cell carcinoma. Similarly, phase two trials combining anti-PD-1 with anti-LAG-3 with or without anti-TIM-3 did not show evidence of additive or synergistic effect.
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