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The concept of exploiting the host’s immune system to fight cancer relies on the concept of tumour immune surveillance, the insight that the immune system should eliminate malignant cells. Immunotherapy is a form of treatment aimed at manipulating the immune system to activate, break, regulate or reinforce immune functions. Cancer immunotherapy is revolutionising cancer treatment through the discovery and development of novel approaches that enhance the body’s antitumour immune functions by ‘releasing the brake’ on the immune system: the so-called immune checkpoints (eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1)) whose physiological functions are to limit autoimmune processes but are also co-opted by tumours allowing cancer immune escape mechanisms. In initial trials, checkpoint blockade showed success in promoting anti-tumour immunity and durable responses in patients with solid tumours. Several antibodies against the PD-1/PD-ligand-1 (PD-L1) checkpoint pathway have recently been approved in diverse indications (melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, Hodgkin lymphoma, bladder cancer, Merkel cell carcinoma and microsatellite instability high or mismatch repair-deficient solid tumour), and the clinical use of these antibodies is rapidly expanding including in some first-line therapy (eg, metastatic non-squamous non-small cell lung cancer). Although the results are impressive for a fraction of patients, most patients do not show complete responses or long-lasting remission, and several cancers, including GI cancers (eg, pancreatic cancer), remain refractory to checkpoint blockade. While anti-PD1 therapy has been approved last year by the Food and Drug Administration for the treatment of advanced hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib, the study (CHECKMATE-040, NCT01658878) showed an overall response rate of only 14.3%.1 A better understanding of why checkpoint inhibitor immunotherapies result in significant clinical benefit in some patients …
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