Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance
By Whijae Roh, Pei-Ling Chen, A. Reuben, C. Spencer, P. Prieto, John P Miller, V. Gopalakrishnan, Feng Wang, Z. Cooper, S. Reddy and 30 more. Science Translational Medicine, 2017
775 citations recorded by the source corpus.
Profiling of melanoma patients treated with checkpoint blockade reveals TCR clonality and copy number loss as correlates of therapeutic response. Checking on checkpoint inhibitors Immune checkpoint blockade has greatly improved the success of treatment in melanoma and other tumor types, but it is expensive and does not work for all patients. To optimize the likelihood of therapeutic success and reduce the risks and expense of unnecessary treatment, it would be helpful to find biomarkers that can predict treatment response. Roh et al. studied patients treated with sequential checkpoint inhibitors targeting CTLA-4 and then PD-1. In these patients, the authors discovered that a more clonal T cell population specifically correlates with response to PD-1 blockade, but not CTLA-4, which may help identify the best candidates for this treatment. In addition, increased frequency of gene copy number loss was correlated with decreased responsiveness to either therapy. Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen–4 (CTLA-4) followed by programmed death receptor–1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
Subfields: Cancer Research, Oncology
View Paper: https://www.semanticscholar.org/paper/632fae5bc2f9afe087fc116c410468cd3e876ecd
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Citations in the corpus
- Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features (2017, neutral): “5 g/L 26 (12) 13 (11) 42 (31) Platelet count, 41 (18) 17 (13) N/A AFP, >100 mg/dL (%) 51 (23) 38 (31) 43 (33) Events (%) Recurrence 150 (67) 78 (60) 88 (59) Death 133 (59) 46 (35) 84 (44) Median follow-up, months 49 51 N/A”
- Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “Aneuploidy was shown recently to reduce response to immunotherapy in patients with melanoma.(29,30) These reports largely focused on patients treated with CTLA-4”
- Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. (2019, positive): “While non-responding patient numbers in the combined immunotherapy cohort are small, other published studies (Ho et al., 2012; Roh et al., 2017) have demonstrated that oxidative phosphorylation resulting in resistance to T cell-mediated killing is a central point for tumor progression and melanogene”
- Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures (2019, background): “However, these responses occur only in a minority of patients, and several studies have found that PD-1 expression, PD-L1 expression, MSI status, and mutation load are not efficient biomarkers for predicting the benefits of immune-checkpoint blockade (15, 69, 70).”
- Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy (2018, background): “Somatic mutation clonality and copy number variation (CNV) have previously been reported to positively and negatively associate, respectively, with response to PD-1 checkpoint blockade (23, 24).”