Multiplexed Evaluation of Microdosed Antineoplastic Agents <i>In Situ</i> in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma

Gundle, Kenneth R.; Deutsch, Gary B.; Goodman, Howard J.; Pollack, Seth M.; Thompson, Marc; Davis, Jessica L.; Lee, Mee Young; Ramirez, Daniel C.; Kerwin, William S.; Bertout, Jessica A.; Grenley, Marc; Sottero, Kimberly H.W.; Beirne, Emily; Frazier, Jason P.; Dey, Joyoti; Ellison, Micah; Klinghoffer, Richard A.; Maki, Robert G.

doi:10.1158/1078-0432.ccr-20-0614

Cited by 11 publications

(19 citation statements)

References 37 publications

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“…Sathe et al integrated scRNAseq with mIHC to demonstrate dramatic increases in exhausted and regulatory T lymphocytes in gastic carcinoma compared to normal mucosa (Sathe et al, 2020). Gundle et al, in reporting microdosing of drug combinations in soft tissue sarcoma (STS), used mIHC and GeoMx Digital Spatial Profiling (Nanostring) to reveal putative mechanisms of tumor resistance to drug treatment (Gundle et al, 2020). These studies highlight the power of multiplex analysis to reveal a variety of immune cell phenotypes and their spatial arrangements in the TME from a single cancer biopsy, and based on these reports we anticipate growing use of multiplex technologies to probe patient tumor biopsies.…”

Section: Immunotherapy the Tumor Microenvironment And Multiplex Stainingmentioning

confidence: 99%

Tissue Multiplex Analyte Detection in Anatomic Pathology – Pathways to Clinical Implementation

Wharton¹,

Wood²,

Manesse³

et al. 2021

Front. Mol. Biosci.

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Background: Multiplex tissue analysis has revolutionized our understanding of the tumor microenvironment (TME) with implications for biomarker development and diagnostic testing. Multiplex labeling is used for specific clinical situations, but there remain barriers to expanded use in anatomic pathology practice.Methods: We review immunohistochemistry (IHC) and related assays used to localize molecules in tissues, with reference to United States regulatory and practice landscapes. We review multiplex methods and strategies used in clinical diagnosis and in research, particularly in immuno-oncology. Within the framework of assay design and testing phases, we examine the suitability of multiplex immunofluorescence (mIF) for clinical diagnostic workflows, considering its advantages and challenges to implementation.Results: Multiplex labeling is poised to radically transform pathologic diagnosis because it can answer questions about tissue-level biology and single-cell phenotypes that cannot be addressed with traditional IHC biomarker panels. Widespread implementation will require improved detection chemistry, illustrated by InSituPlex technology (Ultivue, Inc., Cambridge, MA) that allows coregistration of hematoxylin and eosin (H&E) and mIF images, greater standardization and interoperability of workflow and data pipelines to facilitate consistent interpretation by pathologists, and integration of multichannel images into digital pathology whole slide imaging (WSI) systems, including interpretation aided by artificial intelligence (AI). Adoption will also be facilitated by evidence that justifies incorporation into clinical practice, an ability to navigate regulatory pathways, and adequate health care budgets and reimbursement. We expand the brightfield WSI system “pixel pathway” concept to multiplex workflows, suggesting that adoption might be accelerated by data standardization centered on cell phenotypes defined by coexpression of multiple molecules.Conclusion: Multiplex labeling has the potential to complement next generation sequencing in cancer diagnosis by allowing pathologists to visualize and understand every cell in a tissue biopsy slide. Until mIF reagents, digital pathology systems including fluorescence scanners, and data pipelines are standardized, we propose that diagnostic labs will play a crucial role in driving adoption of multiplex tissue diagnostics by using retrospective data from tissue collections as a foundation for laboratory-developed test (LDT) implementation and use in prospective trials as companion diagnostics (CDx).

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Section: Immunotherapy the Tumor Microenvironment And Multiplex Stainingmentioning

confidence: 99%

Tissue Multiplex Analyte Detection in Anatomic Pathology – Pathways to Clinical Implementation

Wharton¹,

Wood²,

Manesse³

et al. 2021

Front. Mol. Biosci.

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“…The study also demonstrated the utility of control and simultaneous contralateral systemic microdose-level measurements in modelling the microdose versus therapeutic-level dose range. Recent reports applied ITM principles in the development of TRPV1 antagonists for pain management by using microdose amounts to elicit pain sensations and behaviour in skin noci ceptors in a limited area of skin 17 , and or simultaneously testing multiple candidates (cassette microdosing) for chemoresis tance by administering them directly into tumours 15,16,18 . Advanced modelling techniques using physiologically based pharmacokinetics and pharmacodynamic principles, including, where appropriate, in vivo/in vitro modelling of molecular (for example, receptor binding) and tissue (for example, tissue concentrations and transporters) markers of test compound engagement, are being…”

Section: Intratarget Microdosingmentioning

confidence: 99%

“…Phase 0 approaches also have the potential to provide data that is not readily available with traditional approaches. These include first-in-human testing in patients, simultaneous testing of multiple drug candidates (known as cassette microdosing), intravenous administration of oral drugs and intratarget microdosing (ITM; the administration of microdoses locally to generate momentarily therapeutic level exposures in targets of interest) [9][10][11][12][13][14][15][16][17][18] . These advantages allow triaging of preclinical candidates for entry into clinical Adoption of phase 0/microdosing approaches by drug developers has been limited by uncertainty about the impact of non-linearity on extrapolation from subtherapeutic to therapeutic-level exposures, the perception that only pharmacokinetic data can be obtained with these approaches and the concern that application of phase 0 approaches will lead to delays in developmental timelines 26,27 .…”

mentioning

confidence: 99%

“…In addition, greater insight into non-linear mechanisms, their impact on extrapolation of subtherapeutic to therapeutic-level exposures and their management through modelling further increased the reliability and validity of extrapolation 29,33,[37][38][39][40] (discussed further later). In parallel, academic and commercial entities continued research into methods and applications 18, (Supplementary information A) to expand the effectiveness of these approaches, and sponsors have increasingly used phase 0 approaches in developmental scenarios not effectively addressed by traditional approaches [9][10][11][12][13][14]16,35,37,38,41, (Table 3; Supplementary information A).…”

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confidence: 99%

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Phase 0/microdosing approaches: time for mainstream application in drug development?

Burt¹,

Young

Lee

et al. 2020

Nat Rev Drug Discov

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Phase 0 approaches-which include microdosing-evaluate subtherapeutic exposures of new drugs in first-inhuman studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

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“…Lastly, Digital Spatial Profiling enables multiplexed measurement of proteins or RNAs within microscopically-identified regions of interest, at the resolution of a single cell type, by utilizing UV-cleavable oligonucleotide conjugated antibodies or RNA probes. Analysing immune cells in this sarcoma microenvironment using this technology has already been used to characterize mechanisms of doxorubicin resistance [97]. Going forward, these new technologies will increasingly be used to characterize the complex sarcoma tumor microenvironment to guide development of immuno-oncology strategies.…”

Section: New Technologiesmentioning

confidence: 99%

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Zhu

Shenasa

Nielsen

2020

Cancer Treatment Reviews

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Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an "immune cold" tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.

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Multiplexed Evaluation of Microdosed Antineoplastic Agents In Situ in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma

Abstract: Frazier has ownership interest (including patents) in Presage Biosciences, Inc. R. Klinghoffer has ownership interest (including patents) in Presage Biosciences.

Cited by 11 publications

References 37 publications

Tissue Multiplex Analyte Detection in Anatomic Pathology – Pathways to Clinical Implementation

Tissue Multiplex Analyte Detection in Anatomic Pathology – Pathways to Clinical Implementation

Phase 0/microdosing approaches: time for mainstream application in drug development?

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

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