Fattori predittivi di risposta ai farmaci
immunoterapici:
dal PDL-1 al Tumor Mutational Burden
Romano Danesi
Farmacologia -
Università di Pisa
Tumor clonal composition changes during treatment with checkpoint inhibitors:
correlation with outcome?
2
Copy-number alterations on cfDNA can be used for monitoring response to immunotherapy
Jensen et al. Mol Cancer Ther; 18(2), 2019
GIN: genome instability number
Changes in melanoma clonal composition after treatment with nivolumab
Riaz et al., 2017, Cell 171, 934–949 4
Waterfall plot of net change between fraction of mutations representing genomic contraction and genomic persistence
Riaz et al., 2017, Cell 171, 934–949
CR/PR SD PD
OS and PFS by genomic contraction and genomic persistence
Riaz et al., 2017, Cell 171, 934–949 6
Riaz et al., 2017, Cell 171, 934–949 7
Mutation burden decreases with successful
checkpoint blockade therapy
in patients with melanoma,
suggesting that selection against mutant
neoepitopes may be a critical mechanism of action of
nivolumab.
PD-L1 shedding: a simple approach to monitor outcome?
8
Effect tumor microenvironment and sPD-L1 on tumor PD-L1 occupancy by anti-PD-L1 antibodies
Kumar et al. J Clin Invest 2019;129(2):616–630 9
Correlation between plasma level of sPD-L1 at baseline and outcome of nivolumab therapy
10
Baseline sPD-L1 level < 3.357 ng/mL or baseline sPD-L1 Level ‡ 3.357 ng/mL
Okuma et al. Clinical Lung Cancer 2018;19:410-417
Conclusions
• In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral
heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against
neoantigenic mutations on-therapy.
• The use of low-coverage, genome-wide sequencing of cfDNA may detect tumor-specific copy-number alterations to monitor response to checkpoint inhibitors.
• Plasma sPD-L1 levels might represent a novel biomarker for the prediction of the efficacy of nivolumab therapy against NSCLC.
• Pharmacologic treatment dynamically modulates tumor heterogeneity
