Radiotherapy enhances responses of lung cancer to CTLA-4 blockade

• Main Authors: Anna Wilkins, Fiona McDonald, Kevin Harrington, Alan Melcher
• Format: Article
• Language: English
• Published: BMJ Publishing Group 2019-03-01
• Series: Journal for ImmunoTherapy of Cancer
• Subjects: Abscopal effect; CTLA-4 blockade; Ipilimumab; Non-small cell lung cancer
• Online Access: http://link.springer.com/article/10.1186/s40425-019-0542-z

Abstract Formenti et al. have recently reported the clinical outcomes and translational readouts of a trial of the anti-CTLA-4 inhibitor, ipilimumab, in combination with palliative radiotherapy in 39 patients with non-small cell lung cancer. A radiological response was seen in 18% of patients and 31% of patients experienced disease control. These clinical outcomes appear to be superior to historical studies using ipilimumab alone and suggest that radiation may have triggered systemic, so-called abscopal, immune responses in some patients. Induction of interferon-beta (IFN-β) and maximal expansion and contraction of distinct T cell receptor clones were the most significant factors predicting response. Importantly, established predictive biomarkers of response to immunotherapy alone, including the expression of PD-L1 in diagnostic biopsies and tumour mutational burden, did not predict response. The report provides important human qualification of pre-clinical mechanistic insights indicating that abscopal responses can be generated with optimised radiotherapy fractionation schedules and anti-CTLA-4 inhibition. Additionally, an intriguing mechanism by which radiation can be immunogenic is described, namely radiation-induced transcriptional upregulation of neo-antigens.