Fluorescent Multiplex Immunohistochemistry Coupled With Other State-Of-The-Art Techniques to Systematically Characterize the Tumor Immune Microenvironment

Boisson, Anaïs; Noel, G. R.; Saiselet, Manuel; Vitória, Joel Rodrigues; Thomas, Noémie; Fontsa, Mireille Langouo; Sofronii, Doïna; Naveaux, Céline; Duvillier, Hugues; Craciun, Ligia; Larsimont, Denis; Awada, Ahmad; Detours, Vincent; Willard-Gallo, Karen; Garaud, Soizic

doi:10.3389/fmolb.2021.673042

Cited by 22 publications

(16 citation statements)

References 42 publications

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“…Fluorescent multiplex immunohistochemistry (mIHC) is rapidly becoming a routine tool to simultaneously assess and profile multiple markers of the tumor immune microenvironment (TME), including the tumor-infiltrating lymphocyte (TIL) phenotype [ 40 ]. Multimodality biomarker assessment and mIHC, were associated with improved performance in predicting response to anti-PD-1/PD-L1 therapy over IHC-based PD-L1 expression status, tumor mutational burden (TMB), or gene expression profiling (GEP) alone [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Sintilimab plus docetaxel as second-line therapy of advanced non-small cell lung cancer without targetable mutations: a phase II efficacy and biomarker study

et al. 2022

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Background Single-agent immunotherapy is currently the recommended second-line therapy for patients with advanced non–small cell lung cancer (NSCLC) without targetable mutations; however, the objective response rate (ORR) remains low. This phase II study evaluated the efficacy of the combination therapy of sintilimab plus docetaxel and explored potential biomarkers for efficacy prediction. Methods Thirty patients with NSCLC without targetable mutations whose disease progressed from first-line platinum-based chemotherapy from October 2019 to December 2020 were enrolled in this single-arm, single-center, phase II trial. Sintilimab (200 mg) and docetaxel (75 mg/m2) were administered every 3 weeks until progression. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarker analyses of blood and tissue samples were also performed. Results Among 30 patients, 11 patients had partial response, resulting in an ORR of 36.7%. The median PFS was 5.0 months (95%CI: 3.9–6.1) and OS was 13.4 months (95%CI: 5.6–21.2). The most common immune-related adverse event of any grade was hepatitis, observed in 23.3% (7/30) of patients. Treatment-emergent adverse events were manageable. Patients detected with high PD-L1 expression in circulating tumor cells (cutoff value ≥32.5% based on the median CTC-PD-L1 expression) achieved significantly higher ORR (60% versus 13.3%, p = 0.021) and significantly longer median PFS (6.0 versus 3.5 months, p = 0.011) and median OS (15.8 versus 9.0 months, p = 0.038) than those with low CTC-PD-L1 level. Patients detected with PD-L1 < 1% and CD8 ≥ 1% expression from their baseline tissue samples had significantly higher ORR (83.3% versus 12.5%, p = 0.026) but similar PFS (p = 0.62) and OS (p = 0.15). Conclusion This study demonstrated the effectiveness and safety of sintilimab plus docetaxel as a second-line treatment of NSCLC without targetable mutations after progression from first-line platinum-based chemotherapy. Trial registration This study was registered in the Clinical trials registry with ClinicalTrials.gov Identifier NCT03798743 (SUCCESS).

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Section: Discussionmentioning

confidence: 99%

Sintilimab plus docetaxel as second-line therapy of advanced non-small cell lung cancer without targetable mutations: a phase II efficacy and biomarker study

et al. 2022

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“…Moreover, results from proximity studies between cancer cells and immune cells may be affected by difference in cell densities. Towards this end, performing proximity analysis between compartments with similar levels of cellular infiltration has been suggested [121]. Other challenges could be posed within the image analysis pipeline, such as the development of good-quality data, existence of inter-center and inter-vendor variability, as well as intra-and inter-observer variability either during tissue sample preparation or during image acquisition.…”

Section: Discussionmentioning

confidence: 99%

Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution

Tzoras

Zerdes

Tsiknakis

et al. 2022

Cancers

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The tumor immune microenvironment (TIME) is an important player in breast cancer pathophysiology. Surrogates for antitumor immune response have been explored as predictive biomarkers to immunotherapy, though with several limitations. Immunohistochemistry for programmed death ligand 1 suffers from analytical problems, immune signatures are devoid of spatial information and histopathological evaluation of tumor infiltrating lymphocytes exhibits interobserver variability. Towards improved understanding of the complex interactions in TIME, several emerging multiplex in situ methods are being developed and gaining much attention for protein detection. They enable the simultaneous evaluation of multiple targets in situ, detection of cell densities/subpopulations as well as estimations of functional states of immune infiltrate. Furthermore, they can characterize spatial organization of TIME—by cell-to-cell interaction analyses and the evaluation of distribution within different regions of interest and tissue compartments—while digital imaging and image analysis software allow for reproducibility of the various assays. In this review, we aim to provide an overview of the different multiplex in situ methods used in cancer research with special focus on breast cancer TIME at the neoadjuvant, adjuvant and metastatic setting. Spatial heterogeneity of TIME and importance of longitudinal evaluation of TIME changes under the pressure of therapy and metastatic progression are also addressed.

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“…The workflow utilizes tyramide signal amplification (TSA) to intensify and stabilize fluorescent signals (e.g., Stack et al, 2014 ; Surace et al, 2019 ; Francisco-Cruz et al, 2020 ; Parra et al, 2020 ; Boisson et al, 2021 ). Different TSA-linked fluorophores are available under the Opal trademark.…”

Section: Multiplexing—phenoimagermentioning

confidence: 99%

Companion diagnostic requirements for spatial biology using multiplex immunofluorescence and multispectral imaging

Locke

Hoyt

2023

Front. Mol. Biosci.

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Immunohistochemistry has long been held as the gold standard for understanding the expression patterns of therapeutically relevant proteins to identify prognostic and predictive biomarkers. Patient selection for targeted therapy in oncology has successfully relied upon standard microscopy-based methodologies, such as single-marker brightfield chromogenic immunohistochemistry. As promising as these results are, the analysis of one protein, with few exceptions, no longer provides enough information to draw effective conclusions about the probability of treatment response. More multifaceted scientific queries have driven the development of high-throughput and high-order technologies to interrogate biomarker expression patterns and spatial interactions between cell phenotypes in the tumor microenvironment. Such multi-parameter data analysis has been historically reserved for technologies that lack the spatial context that is provided by immunohistochemistry. Over the past decade, technical developments in multiplex fluorescence immunohistochemistry and discoveries made with improving image data analysis platforms have highlighted the importance of spatial relationships between certain biomarkers in understanding a patient’s likelihood to respond to, typically, immune checkpoint inhibitors. At the same time, personalized medicine has instigated changes in both clinical trial design and its conduct in a push to make drug development and cancer treatment more efficient, precise, and economical. Precision medicine in immuno-oncology is being steered by data-driven approaches to gain insight into the tumor and its dynamic interaction with the immune system. This is particularly necessary given the rapid growth in the number of trials involving more than one immune checkpoint drug, and/or using those in combination with conventional cancer treatments. As multiplex methods, like immunofluorescence, push the boundaries of immunohistochemistry, it becomes critical to understand the foundation of this technology and how it can be deployed for use as a regulated test to identify the prospect of response from mono- and combination therapies. To that end, this work will focus on: 1) the scientific, clinical, and economic requirements for developing clinical multiplex immunofluorescence assays; 2) the attributes of the Akoya Phenoptics workflow to support predictive tests, including design principles, verification, and validation needs; 3) regulatory, safety and quality considerations; 4) application of multiplex immunohistochemistry through lab-developed-tests and regulated in vitro diagnostic devices.

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Fluorescent Multiplex Immunohistochemistry Coupled With Other State-Of-The-Art Techniques to Systematically Characterize the Tumor Immune Microenvironment

Cited by 22 publications

References 42 publications

Sintilimab plus docetaxel as second-line therapy of advanced non-small cell lung cancer without targetable mutations: a phase II efficacy and biomarker study

Sintilimab plus docetaxel as second-line therapy of advanced non-small cell lung cancer without targetable mutations: a phase II efficacy and biomarker study

Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution

Companion diagnostic requirements for spatial biology using multiplex immunofluorescence and multispectral imaging

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