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Review
. 2021 Jun;6(3):100106.
doi: 10.1016/j.esmoop.2021.100106. Epub 2021 Apr 14.

Combining immunotherapy with an epidrug in squamous cell carcinomas of different locations: rationale and design of the PEVO basket trial

E de Guillebon  1 , M Jimenez  2 , L Mazzarella  3 , F Betsou  4 , P Stadler  5 , I Peták  6 , E Jeannot  7 , L Chanas  8 , N Servant  9 , G Marret  10 , B A Duso  11 , F Legrand  2 , K N Kornerup  4 , S H Bernhart  5 , G Balogh  5 , R Dóczi  12 , P Filotás  12 , G Curigliano  13 , I Bièche  14 , J Guérin  8 , A Dirner  12 , C Neuzillet  15 , N Girard  15 , E Borcoman  10 , L Larbi Chérif  10 , P Tresca  10 , D B Roufai  10 , C Dupain  10 , S Scholl  10 , F André  16 , X Fernandez  8 , T Filleron  17 , M Kamal  18 , C Le Tourneau  19
Affiliations
Review

Combining immunotherapy with an epidrug in squamous cell carcinomas of different locations: rationale and design of the PEVO basket trial

E de Guillebon et al. ESMO Open. 2021 Jun.

Abstract

Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations.

Keywords: HPV; epigenetics; immunotherapy; precision medicine clinical trial; squamous cell carcinoma.

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Conflict of interest statement

Disclosure GC: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, Nanostring, Samsung, Celltrion, Ellipsis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Mylan. CLT: Roche, Seattle Genetics, Rakuten, Nanobiotix, MSD, BMS, Merck Serono, AstraZeneca, GlaxoSmithKline, Novartis, Celgene. XF: Roche, Janssen, BMS, Leo Pharma, Amgen Research. LC: Leo Pharma, Amgen. JG: Roche, Leo Pharma. IP: employee and equity holder in Oncompass Medicine Ltd. RD, PF, and AD are employees of Oncompass Medicine Ltd. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Effects of HDAC inhibition on the tumor microenvironment immune cells. HDAC, histone deacetylase; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-L1, programmed death-ligand 1; T cell, T lymphocyte.
Figure 2
Figure 2
PEVOsq clinical trial design. ATAC-Seq, assay for transposase-accessible chromatin with sequencing; C, cycle; ChIP-Seq, chromatin immunoprecipitation with sequencing; FFPE, formalin fixed paraffin embedded; HPV, human papillomavirus; IHC, immunohistochemistry; pts, patients; RNAseq, RNA sequencing; WES, whole exome sequencing. ∗, duration of each treatment cycles is 3 weeks.
Figure 3
Figure 3
PEVOsq translational data management and integration. #, number; C, cycle of treatment; constit. DNA, constitutional DNA; eCRF, electronic case report form; FFPE, formalin fixed paraffin embedded; HLA, human leucocyte antigen; HPV, human papillomavirus; IBBL, Integrated BioBank of Luxembourg; IC, Institut Curie; ID, identification; IEO, Instituto Europeo di Oncolegia; IHC, immunohistochemistry; IUCT, Institut Universitaire du Cancer de Toulouse; OM, Oncompass Medicine; RNAseq, RNA sequencing; TME, tumor microenvironment; UL, University of Leipzig; WES, whole exome sequencing.
See this image and copyright information in PMC

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