Analytic and Clinical Validation of a 7-plex MIF Assay for Predictive Response of Advanced NSCLC to Anti-PD-1 based Therapy

7 重 MIF 检测对晚期 NSCLC 对抗 PD-1 治疗的预测反应的分析和临床验证

• 批准号: 10705736
• 负责人: Janis M Taube
• 金额: $ 19.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705736
• 关键词: Advanced Development; Age; Algorithmic Analysis; Algorithms; Antibodies; Antigens; Applications Grants; Biological Assay; Biological Markers; Biological Sciences; Biopsy; CD8B1 gene; Cancer Center; Cd68; Cell surface; Cells; Clinical; Collaborations; Cytokeratin; Disease; Evaluation; FOXP3 gene; Formalin; Gender; Geography; Goals; Image Analysis; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Immunooncology; Individual; Institution; Label; Link; Malignant - descriptor; Malignant Epithelial Cell; Medical center; Membrane; Merkel cell carcinoma; Modality; Morphologic artifacts; Non-Small-Cell Lung Carcinoma; Outcome; PD-1 pathway; PD-1/PD-L1; PD-L1 blockade; Paraffin Embedding; Participant; Pathologist; Patient-Focused Outcomes; Patients; Pigments; Positioning Attribute; Reagent; Receiver Operating Characteristics; Reproducibility; Research Personnel; Resistance; Resolution; Sensitivity and Specificity; Site; Slide; Solid Neoplasm; Specific qualifier value; Specimen; Stains; Standardization; Surgical Pathology; Testing; Therapeutic Agents; Tissue Embedding; Tissues; Tonsil; Tumor Markers; Tumor stage; Universities; Update; Validation; Work; age related; anti-PD-1; anti-PD-L1; anti-PD1 therapy; biomarker development; biomarker identification; cell type; clinic ready; clinical care; clinical implementation; cohort; combinatorial; companion diagnostics; density; design; imaging approach; imaging platform; immunotherapy clinical trials; improved; indexing; light microscopy; liquid crystal polymer; melanoma; multiparametric imaging; multiplex assay; neoplastic cell; next generation; phenotypic data; predicting response; predictive test; prognostic; programmed cell death ligand 1; programmed cell death protein 1; research clinical testing; response; spectrograph; tumor; tumor microenvironment; whole slide imaging

PROJECT SUMMARY PD-L1 membranous (cell surface) expression in pretreatment biopsies is the most commonly used correlate of the likelihood of response to anti-PD-1 therapy. The general finding of an association of PD-L1 expression with tumor response to anti-PD-1 therapy has been substantiated across tens of thousands of patients with numerous tumor types treated with anti- PD-(L)1. However, while PD-L1 expression enriches for response to anti-PD-(L)1, it is not sufficient. Additionally, while pathologists demonstrate good reproducibility for scoring tumor cell (TC) PD-L1 expression by chromogenic IHC and light microscopy, they have poor reproducibility for scoring PD-L1 expression on immune cells (IC). Other related features which have been shown to improve on the PD-L1 biomarker include the proximity of PD-1 to PD-L1, the density of CD8+FoxP3+ cells, and CD68 and tumor marker immunostains, the latter of which help identify co-expression of PD-L1 on ICs and TCs, respectively. A quantitative multiplex immunofluorescence assay which captures all of these features has been developed and includes PD-L1, PD-1, CD8, FoxP3, CD68, a tumor marker (cytokeratin AE1/3 for non-small cell lung carcinoma, NSCLC), a pan-membrane marker and DAPI. Through this assay, it is possible to enumerate key cellular subsets and their co-expression profiles. It is also possible to include spatial parameters, including the distance between PD-1 and PD-L1, which have not previously been included in predictive or prognostic surgical pathology specimen-based assays. This mIF assay has increased sensitivity and specificity for response to anti-PD1 therapy when compared to the assessment of PD-L1 expression alone in multiple tumor types, including melanoma, NSCLC, and Merkel cell carcinoma, amongst others. The purpose of this proposal is to perform inter-site validation of the mIF staining assay and associated lock-down algorithm amongst four major academic sites (Johns Hopkins, MD Anderson, Yale University, and Providence Portland Medical Center). Following analytical validation, discovery and validation cohorts from 250 patients with advanced NSCLC will be used to establish final assay parameters (including thresholds), linked to clinical outcomes following anti-PD-1-based therapy. The deliverable of the study is a refined, multiplex biomarker assay for response/resistance to anti-PD-1 that has been validated across multiple academic sites. The result will be a multiplex IF assay that is suitably staged for advanced development aimed at clinical implementation. While NSCLC is the focus of the current grant proposal, preliminary results suggest that this assay will also have great value in numerous other solid tumor types.

项目总结

项目成果

Comparing and Correcting Spectral Sensitivities between Multispectral Microscopes: A Prerequisite to Clinical Implementation.

• DOI: 10.3390/cancers15123109
• 发表时间: 2023-06-08
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Eminizer, Margaret;Nagy, Melinda;Engle, Elizabeth L.;Soto-Diaz, Sigfredo;Jorquera, Andrew;Roskes, Jeffrey S.;Green, Benjamin F.;Wilton, Richard;Taube, Janis M.;Szalay, Alexander S.
• 通讯作者: Szalay, Alexander S.