A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study.

BACKGROUND: Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. METHODS: In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. FINDINGS: We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57-0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66-0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63-42·1; vs 11·5 months in the low radiomic score group, 7·98-15·6; hazard ratio 0·58, 95% CI 0·39-0·87; p=0·0081) and multivariate analyses (0·52, 0·35-0·79; p=0·0022). INTERPRETATION: The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. FUNDING: Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology.

Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine.

Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine.