Author: Nakao, Aki ; Diehn, Maximilian ; Aliminati, Manjula ; Ashutosh, Ashutosh ; Newman, Aaron M. ; Ghosh, Jayati ; Stephenson, Kristi ; Alizadeh, Ash A. ; Ghosh, Mistuni

AbstractBackground: Cell profiling methods such as flow/mass cytometry and single-cell RNA-sequencing are powerful tools for quantifying immune composition from healthy and neoplastic tissues. However, only a modest number of markers can be interrogated by the former and the latter remains cost prohibitive for large-scale analysis. Here we demonstrate robust, accurate, and reproducible enumeration of immune cell subsets from 36 whole blood samples using SureSelect XT HS2 RNA sequencing combined with CiberMed’s iSortTM digital cytometry solution. Enrichment of genes in the LM22 signature matrix, a well-established collection of reference profiles for deconvolving 22 human immune subsets, was achieved with two new targeted sequencing panels—Agilent SureSelect CD CiberMed Heme and Agilent SureSelect CD CiberMed Heme + HiRes. Both panels were assessed for their ability to profile leukocyte subsets with CiberMed’s iSortTM Fractions software, an optimized and standardized version of CIBERSORTx with novel enhancements.Methods: Whole blood samples were freshly collected from 36 healthy donors and split into two fractions—one was immediately processed for complete blood count (CBC) and flow cytometric enumeration of major leukocyte populations; the other was stored in PAXgene Blood RNA tubes for subsequent RNA sequencing. A Sysmex system was employed for CBC quantification and a Becton Dickinson 6-color TBNK MultiTest in vitro diagnostic (IVD) assay was employed for enumerating B cells, CD8 T cells, CD4 T cells, NK cells. These data were used as ground truth to assess iSortTM deconvolution performance from targeted and whole-transcriptome bulk RNA sequencing data. RNA-seq expression values were used as input to iSortTM Fractions to deconvolve 22 immune subsets in each sample.Results: Across 7 major populations, cell type fractions determined by iSortTM Fractions were highly concordant with ground truth fractions determined by clinical grade standards (r≥0.96) and exhibited strong reproducibility across technical replicates (r≥0.98). Furthermore, targeted enrichment using the SureSelect CD CiberMed Heme panel reduced the sequencing requirement by nearly 50-fold compared to whole-transcriptome sequencing, while also improving accuracy.Conclusion: These new panels for digital cytometry are being released through the Agilent Community Design program to enable focused, reliable, and high-throughput analysis of cell type composition from peripheral blood samples.Citation Format: Aki Nakao, Aaron M. Newman, Ash A. Alizadeh, Maximilian Diehn, Mistuni Ghosh, Manjula Aliminati, Jayati Ghosh, Kristi Stephenson, Ashutosh Ashutosh. Highly accurate profiling of leukocyte composition from bulk peripheral blood with targeted digital cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4898.

01 Dec 2020·Clinical Cancer ResearchQ1 · MEDICINE

Molecular and Immunologic Signatures are Related to Clinical Benefit from Treatment with Vocimagene Amiretrorepvec (Toca 511) and 5-Fluorocytosine (Toca FC) in Patients with Glioma

Q1 · MEDICINE

Article

Author: Nakao, Aki ; Diehn, Maximilian ; Accomando, William P. ; Diago, Oscar R. ; Newman, Aaron M. ; Rao, Aliz R. ; Gruber, Harry E. ; Haghighi, Ali ; Gammon, Dawn ; Ostertag, Derek ; Jolly, Douglas J. ; Hogan, Daniel J. ; Alizadeh, Ash A.

AbstractPurpose:High-grade gliomas (HGGs) are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell–mediated antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy.Patients and Methods:In a phase I clinical trial (NCT01470794), patients with recurrent HGG treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As a part of this trial, we performed whole-exome DNA sequencing, RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood samples.Results:Genetic analyses suggest mutations, copy-number variations, and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response.Conclusions:These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are related to clinical benefit from treatment.

20 May 2020·Journal of Clinical Oncology

Analytical validation of iSort digital cytometry for leukocyte enumeration in clinical tumor specimens.

Author: Alizadeh, Ash A. ; Diehn, Maximilian ; Li, Kathy ; Liu, Chih-Long ; Newman, Aaron M. ; Nakao, Aki ; Wilson, Douglas Collins

e15243 Background: Tumor infiltrating leukocytes (TILs) are major determinants of anti-tumor immune responses and mediate effector functions for diverse immunotherapies. Techniques relying on intact cells such as flow cytometry (FACS), immunohistochemistry (IHC), and scRNA-Seq can be powerful for measuring TIL heterogeneity. However, such methods are often impractical on large patient cohorts, can be poorly quantitative, and some cannot be applied to formalin-fixed paraffin embedded (FFPE) specimens. We developed iSort, a transcriptome deconvolution method based on CIBERSORTx for TIL enumeration. We evaluated iSort by comparing its performance in FFPE and fresh frozen (FF) human tumor tissues to established methods. Methods: We profiled human tumors for diverse TIL subsets, as quantified by iSort, FACS, and IHC. iSort was performed on RNA-Seq libraries derived from bulk human tumors, including FF tumor tissue samples, tumor cell suspensions obtained after dissociation, and FFPE specimens. We assessed the influence of tissue fixation on common TIL subsets enumerated by iSort, by comparing matched pairs of FF and FFPE lung tumor specimens (NSCLC). Finally, we compared iSort with automated microscopic enumeration of CD8 TILs by IHC on primary human lung tumors (FFPE/NSCLC). Results: iSort TIL enumeration was highly correlated with FACS across primary human tumors (CRC = 3, HNSCC = 1) for common TIL subsets (B cells, CD8 T, CD4 T, monocytes/macrophages, dendritic cells, PMNs/MDSCs) and total immune content (median r = 0.91 [0.71 - 0.99]). Tissue dissociation caused significant depletion of monocytes/macrophages (p < 0.01), when comparing bulk tumor specimens with cell suspensions after sample digestion. iSort showed high correlation across 12 TIL subsets when comparing 9 pairs of FF and FFPE specimens (r = 0.90). Finally, we observed high linearity between iSort and microscopic enumeration of CD8 TILs from IHC (r = 0.87, n = 5). Conclusions: iSort digital cytometry achieves accurate and robust TIL enumeration as compared with FACS and IHC, showing comparable performance in fixed and frozen primary human tumors. Importantly, iSort is directly applicable to bulk tumors and is unaffected by tissue dissociation artifacts, unlike methods requiring cell suspensions for TIL enumeration (FACS, scRNA-seq). Therefore, iSort is a promising approach for development and measurement of immunotherapy biomarkers.

News (Medical) associated with Cibermed, Inc.

03 Apr 2024

·www.biospace.com

Agilent at AACR 2024: Empowering Breakthroughs in Cancer Research and Diagnostics

SANTA CLARA, Calif.--(BUSINESS WIRE)-- Agilent Technologies Inc. (NYSE: A), a global leader in life sciences and diagnostics, announced today its participation in the American Association for Cancer Research Annual Meeting (AACR). At the meeting, which will take place from April 5 to 10, 2024, in San Diego, CA, Agilent will highlight new cell analysis, genomics, digital pathology, and companion diagnostics solutions. Featured products and solutions that play a crucial role in advancing cancer research and diagnostics, will include: Agilent NovoCyte Opteon Spectral Flow Cytometer - The Agilent NovoCyte Opteon Spectral Flow Cytometer, is an advanced solution in spectral flow cytometry. This user-friendly system allows simultaneous analysis of multiple markers and offers flexibility in designing multiple marker panels. With configurations ranging from 3 to 5 lasers and support for up to 70 high-quality detectors, the NovoCyte Opteon promises enhanced research capabilities for scientists and researchers. Agilent Avida - Agilent Avida’s new cutting-edge target enrichment solutions enable simultaneous DNA and methylation profiling from a single sample. The proprietary Avida technology maintains original sample quality and quantity, supporting advanced applications such as liquid biopsy and multiomics capabilities for targeted next-generation sequencing (NGS). Researchers gain accelerated access to genetic and epigenetic data from limited samples, propelling cancer biology and clinical insights. The high-performance and streamlined workflows offer outstanding fidelity, turnaround time, and ease of use. Agilent SureSelect Cancer Custom panels - Agilent SureSelect Cancer Custom panels offer the ability to add new and emerging biomarkers, including tumor mutational burden (TMB) and microsatellite instability (MSI), to custom tumor genomic profiling assays. These custom NGS cancer panels are designed quickly and easily using Agilent SureDesign 8.0, an intuitive probe design software powered by machine learning. These custom cancer panels extend the SureSelect Cancer product portfolio and underscore Agilent’s commitment to advancing precision oncology. Agilent SureSelect CD CiberMed Tissue and SureSelect CD CiberMed Heme panels - Agilent announces a new partnership with CiberMed. This company aims to simplify cellular profiling and biomarker discovery with its digital cytometry software, iSort. The new Agilent SureSelect CD CiberMed Tissue and SureSelect CD CiberMed Heme panels enable a combined SureSelect and iSort workflow to offer a cellular profiling solution from bulk RNA-Seq data with enhanced sensitivity, accuracy, and robustness. “Agilent continues to direct strategic focus toward the battle against cancer. Our comprehensive portfolio encompasses groundbreaking technologies, from cell analysis to genomics, digital pathology, and companion diagnostics,” stated Bob McMahon, interim president of Agilent’s Diagnostics and Genomics Group. “These innovations empower scientists, clinicians, and researchers worldwide to ignite discoveries and enhance patient outcomes.” Agilent will also host two joint events with key collaborators. The first with SomaLogic®, now part of StandardBioTools™ on Sunday, April 7 at 1:30 pm. The focus of this symposium is cancer understanding and care. Presenters Marc Gunter from Imperial College London and Karl Smith-Byrne from Oxford University will discuss their utilization of SomaLogic’s SomaScan® Platform. They will delve into discovering novel causes and biomarkers of cancer within a large-scale prospective cohort. The second symposium on Sunday, April 7 at 3:30 pm will focus on novel technologies for precision medicine. Caroline Germa, CMO from Transcenta Therapeutics will present on how the use of Claudin 18.2 IHC assay informed Transcenta Therapeutics’ Osemitamab program, and Bellal Moghis from Agilent will discuss Agilent’s new Avida targeted sequencing. In addition, Agilent will feature partnerships with BostonGene and CiberMed at the Agilent booth (#1531). AACR attendees can also explore multiple Agilent research posters and over 50 additional customer posters highlighting Agilent instruments and solutions. For more details about these events, visit the Agilent booth. About Agilent Technologies Agilent Technologies Inc. (NYSE: A) is a global leader in analytical and clinical laboratory technologies, delivering insights and innovation that help our customers bring great science to life. Agilent’s full range of solutions includes instruments, software, services, and expertise that provide trusted answers to our customers’ most challenging questions. The company generated revenue of $6.83 billion in fiscal 2023 and employs approximately 18,000 people worldwide. Information about Agilent is available at . To receive the latest Agilent news, please subscribe to the Agilent Newsroom. Follow Agilent on LinkedIn and Facebook.

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