PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application

Mastracci, Luca; Grillo, Federica; Parente, Paola; Gullo, Irene; Campora, Michela; Angerilli, Valentina; Rossi, Chiara; Sacramento, Maria Luisa; Pennelli, Gianmaria; Vanoli, Alessandro; Fassan, Matteo

doi:10.32074/1591-951x-803

Cited by 25 publications

(13 citation statements)

References 100 publications

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“…In our study, we observed that the combination of MSI status and PD-L1 expression could distinguish the prognosis of immunotherapy for both OS and PFS. We found patients with PD-L1 CPS ≥ 5 had a better both OS and PFS than patients with CPS < 5 in multivariate analysis, which is consistent with our previous study [ 61 – 64 ]. However, the significance of PD-L1 expression as a biomarker for BTC immunotherapy remains controversial.…”

Section: Discussionsupporting

confidence: 92%

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Yang,

Lian,

Zhang

et al. 2024

BMC Med

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Background Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. Methods We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. Results Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. Conclusions MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. Trial registration This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

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Section: Discussionsupporting

confidence: 92%

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Yang,

Lian,

Zhang

et al. 2024

BMC Med

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“…The pattern of expression and potential of PD‐L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms (Mastracci et al ., 2022 ) but a comprehensive glycan analysis has not yet been reported. Here, we show that plant‐derived DL variants are able to bind PD‐L1 expressed in gastric and colorectal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Plant‐derived Durvalumab variants show efficient PD‐1/PD‐L1 blockade and therapeutically favourable FcR binding

Izadi,

Gumpelmair,

Coelho

et al. 2023

Plant Biotechnology Journal

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SummaryImmune checkpoint blocking therapy targeting the PD‐1/PD‐L1 inhibitory signalling pathway has produced encouraging results in the treatment of a variety of cancers. Durvalumab (Imfinzi®) targeting PD‐L1 is currently used for immunotherapy of several tumour malignancies. The Fc region of this IgG1 antibody has been engineered to reduce FcγR interactions with the aim of enhancing blockade of PD‐1/PD‐L1 interactions without the depletion of PD‐L1‐expressing immune cells. Here, we used Nicotiana benthamiana to produce four variants of Durvalumab (DL): wild‐type IgG1 and its ‘Fc‐effector‐silent’ variant (LALAPG) carrying further modifications to increase antibody half‐life (YTE); IgG4S228P and its variant (PVA) with Fc mutations to decrease binding to FcγRI. In addition, DL variants were produced with two distinct glycosylation profiles: afucosylated and decorated with α1,6‐core fucose. Plant‐derived DL variants were compared to the therapeutic antibody regarding their ability to (i) bind to PD‐L1, (ii) block PD‐1/PD‐L1 inhibitory signalling and (iii) engage with the neonatal Fc receptor (FcRn) and various Fcγ receptors. It was found that plant‐derived DL variants bind to recombinant PD‐L1 and to PD‐L1 expressed in gastrointestinal cancer cells and are able to effectively block its interaction with PD‐1 on T cells, thereby enhancing their activation. Furthermore, we show a positive impact of Fc amino acid mutations and core fucosylation on DL's therapeutic potential. Compared to Imfinzi®, DL‐IgG1 (LALAPG) and DL‐IgG4 (PVA)S228P show lower affinity to CD32B inhibitory receptor which can be therapeutically favourable. Importantly, DL‐IgG1 (LALAPG) also shows enhanced binding to FcRn, a key determinant of serum half‐life of IgGs.

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“…Preliminary studies on intratumour molecular heterogeneity indicate that TMB is a stable biomarker, and it is relatively independent of the location of acquisition [22], without significant variations between primary and metastatic sites. On the contrary, it is well established that PD-L1 expression rates may vary between primary tumours and different metastatic sites due to the influence of the tumour microenvironment [23]. Therefore, the inclusion of both primary and metastatic lesions in the analysis may represent a limitation for biomarker evaluation, particularly for PD-L1.…”

Section: Discussionmentioning

confidence: 99%

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study.

Prete

Manca

Morano

et al. 2022

JCO

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5 Background: Advanced squamous cell anal cancer (aSCAC) is a rare and aggressive disease, accounting for poor prognosis and high morbidity. No targeted therapies are currently available and, after the first line, no standard treatments are approved. Immune checkpoint inhibitors (ICI) showed signs of activity in previous phase I/II trials, but predictive and prognostic biomarkers are lacking. Anti-EGFR have been tested given the rarity of KRAS mutations in aSCAC, with encouraging results. Earlier preclinical evidence suggests possible synergism between cetuximab (cet) and ICI. Methods: In the phase II randomized trial CARACAS (NCT03944252), we tested avelumab (ave) alone (Arm A) or with cet (Arm B) in pretreated aSCAC; overall response rate (ORR) was the primary endpoint. With one-sided a error set at 0.05 and power of 80%, at least 4 responses out of 27 patients (pts) per arm had to be observed to declare the study positive. On pre-treatment tumor tissue samples, we assessed HPV status, PD-L1 expression, microsatellite status, tumor mutational burden (TMB) and performed next generation sequencing (NGS) via FoundationOne CDx. Primary objective was to describe the clinical outcomes of ICI in SCAC in the CARACAS trial population according to molecular analyses. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular characteristics to individuate new prognostic biomarkers in SCAC. Cox regression was used to investigate the effect of the main variables analysed on survival. Translational analyses were performed on the 100% of the study population since all the pts received ICI. Results: In the clinical trial, the Arm B reached the primary endpoint (ORR 17%, 95% CI 5·6-34·7). High TMB (≥10 mutations per megabase) was related with longer OS (HR=0.09; 95% CI 0.01-0.68; p=0.019), showing the same trend in PFS (HR=0.44; 95%CI=0.15-1.27; p=0.129). As well, tumors with high expression of PD-L1 (>40 measured with combined positive score, CPS) showed significantly longer OS (HR=2.19; 95% CI=0.92-5.19; p=0.075) and PFS (HR=2.35; 95%CI=1.09-5.1; p=0.03). High TILs (>1.2) did not affect significantly OS (HR=0.77; 95% CI=0.42-1.4; p=0.39) nor PFS (HR=1.19; 95%CI=0.57-2.48; p=0.645). When combined together and with high TILs, high TMB and PD-L1identified pts with significantly better prognosis in OS (HR=0.43; 95% CI=0.21-0.87; p=0.019) and PFS (HR=0.48; 95%CI=0.23-1.00; p=0.051). Remarkable responses were also observed in pts with high PD-L1 expression and TMB. Conclusions: TranslaCARACAS study documented prognostic role of high TMB and PD-L1 in mSCAC treated with ICI with or without anti-EGFR. Stratifying per high TMB, PD-L1 and TILs, a subgroup of pts with particularly favorable prognosis and deep responses were detected. Further investigation in larger cohorts is warranted to confirm our findings.

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PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application

Cited by 25 publications

References 100 publications

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Plant‐derived Durvalumab variants show efficient PD‐1/PD‐L1 blockade and therapeutically favourable FcR binding

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study.

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