an innovative multi-dimensional ngs approach to ... · an innovative multi-dimensional ngs approach...

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An innovative multi-dimensional NGS approach to understanding the tumor microenvironment and evolutionJames H. Godsey, Ph.D.

Vice President, Research & Development

Clinical Sequencing Division (CSD)

Life Science Solutions

2 For Research Use Only. Not for use in diagnostic procedures.

Lead in oncology Targeted research Expand to applied

Leading the democratization of NGS to accelerate research and clinical applications

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Playing to win in

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CSD Vision and Strategy


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Routine research TranslationalDiagnostics

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Tumor-Immune Interactions are Complex and Warrant a Multi-Dimensional Approach

Immune Repertoire

Source: http://www.sciencedirect.com/science/article/pii/S1074761313002963

License: https://creativecommons.org/licenses/by/4.0/

Labels were removed.

Immune Response

Tumor Mutation Load

http://www.sciencedirect.com/science/article/pii/S1074761313002963

https://creativecommons.org/licenses/by/4.0/


Growing Assay Menu Across All Key Applications

Solid tumor

solutions

Liquid biopsy

solutions

Immuno-oncology

solutions+ +

Oncomine™ Focus

Assay

Oncomine™

Comprehensive

Assay

Oncomine™ BRCA

Research Assay

Oncomine™ Pan-

Cancer Cell-Free

Assay

Oncomine™ cfDNA

Assays

for Lung, Breast,

Colon

Oncomine™ Tumor

Mutation Load Assay

Oncomine TCR Beta-

LR Assay

Oncomine™ Immune

Response Research

Assay

Oncomine™ Lung

cfTNA Research

Assay

Oncomine™ Breast

cfDNA Research

Assay v2

Heme-oncology

solutions+

Oncomine™ Myeloid

Research Assay

Oncomine™

Childhood Cancer

Research Assay


Test

NSCLC

solutions +



Oncomine TCR Beta-

SR Assay

Full

characterization

of oncology

samples

Ion AmpliSeq HD


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Key Questions in Immuno-oncology Translational Research

NGS

Can characterizing the tumor

microenvironment (TME) predict

immune response?

Can we improve a selection

strategy for immune therapy

clinical research trials?

Can we identify the population

predisposed to immune-mediated

adverse events?

Biomarkers

Can we design superior therapeutic

T cells by influencing design and

development through TCR sequencing?

Can we design effective cancer

vaccines using the information

derived from TCR sequencing?

CAR-T

Cancer Vaccines


Interrogating the Tumor Microenvironment – A multi-dimensional approach

Oncomine™ Immune

Response Research Assay

(Targeted RNA-Seq)

Oncomine TCR Beta-SR

Assay

(Immune repertoire

TCR-Seq)

Oncomine Tumor Mutation

Load Assay

(Tumor mutation burden)

• Profile 395 key genes

associated with immune

response

• Accurately measure

gene expression over

wide dynamic range

• Capture low expressing

genes (IFNG) with

greater sensitivity

• Interrogates CDR3 of the

T-Cell Receptor beta

chain, for

characterization of

immune status

• Enables TCR monitoring

of minimal residual

disease in the peripheral

blood

• Quantifies somatic

mutations from 1.7mb

across 409 cancer genes

for accurate assessment

of tumor mutation burden

(TMB)

• Correlates with response

to immune checkpoint

inhibitors


Constant Leader FR1 FR2

Diversity(D) Joining (J)Variable (V)

CDR3

FR3

CDR1 CDR2

Sequencing Beta

Chain of T Cell

Receptors to

Characterize

Immune Status

AmpliSeq Primers ~325-400 bp

Non-FFPE RNA

Long Read NGS assay capturing all 3

CDRs (1,2 &3). Uniquely captures

germline TRBV polymorphism from

blood/tissue to investigate

predisposition to adverse events.

Flexible input/sequencing depth

requirements covering samples with

low, medium, and high clonal

diversity.

Superior informatics for accurate

clonality and β chain sequence

assessment without interference from

primer bias.

10ng-

1mg

Ion Torrent™ Oncomine™ TCR Beta–LR Assay | Makes the PBLs in Peripheral Blood an Additional Rich Source of Predictive Dx Information

Allelic variants alter interaction of CDR1 and 2 with HLA

V-gene polymorphism Clonality / TCR convergence

TCRComplex.png used under creative commons license:

https://creativecommons.org/licenses/by-sa/3.0

https://creativecommons.org/licenses/by-sa/3.0


TCR Convergence May Be a Hallmark of Chronic Antigen Stimulation

Priming and

proliferation of tumor

antigen specific T cells.

T cells do not destroy

tumor.

Tumor antigen continues

to prime naive T cells with

shared antigen specificity.

This distinguishes T cell

responses to cancer from

those following short-term

acute antigen challenge

typical of responses to

infectious disease.

Over time, convergent

TCR groups become

detectable in peripheral

blood.

Tumor Ag


TCR Profiling from Peripheral Blood May Provide the Most Direct Measurement of Tumor Immunogenicity

Tumor acquires non-

synonymous mutation

Non-synonymous

mutation is translated

Translated protein is

broken into peptides

Peptide is presented

by HLA

T cells recognize

peptide and proliferate

Anti-tumor T cell responses

Tumor mutation burden

profiling (TMB) [indirect

measure]

HLA typing

TCRβ sequencing of

peripheral blood [direct

measure]

Sequence of Events to Elicit

Anti-Tumor T Cell Response• Convergent TCRs are the result of T cell responses

to antigen, and thus may serve as a metric for

quantifying tumor immunogenicity.

• We propose that TCR convergence is a T cell

repertoire feature which preferentially arises

following chronic antigen stimulation rather than the

acute but transient antigen challenges elicited by

infectious disease.

• Given that tumor antigens may prime T cells over

months or years time, measurements of TCR

convergence may provide an accurate pre-

treatment estimate of tumor immunogenicity.


Improving Liquid Biopsy Through Sequencing of Peripheral Blood T Cells

• Liquid biopsy is traditionally

defined as the analysis of tumor

cells, or the products of tumor

cells, from peripheral blood.

• cfDNA has been the standard input

material for liquid biopsy.

• However, signatures of T cell

responses to tumor may be

evaluated by T cell repertoire

analysis of peripheral blood

leukocytes.

Oncomine™ cfDNA Assays

Oncomine™ TCR Beta – LR Assay

Image via Wikipedia


Expanding Liquid Biopsy with Custom Panels

Solid tumor

solutions

Liquid biopsy

solutions

Immuno-oncology

solutions+ +

Oncomine™ Focus

Assay

Oncomine™

Comprehensive

Assay

Oncomine™ BRCA

Research Assay

Oncomine™ Pan-

Cancer Cell-Free

Assay

Oncomine™ cfDNA

Assays

for Lung, Breast,

Colon

Oncomine™ Tumor

Mutation Load Assay

Oncomine TCR Beta-

LR Assay

Oncomine™ Immune

Response Research

Assay

Oncomine™ Lung

cfTNA Research

Assay

Oncomine™ Breast

cfDNA Research

Assay v2

Heme-oncology

solutions+

Oncomine™ Myeloid

Research Assay

Oncomine™

Childhood Cancer

Research Assay


Test

NSCLC

solutions +



Oncomine TCR Beta-

SR Assay

Full

characterization

of oncology

samples

Ion AmpliSeq HD


NEW


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• Low limit of detection—variant detection down to

0.1%* enabled by unique molecular tags and dual

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• Customization in your hands—flexible panel

design customization available at an accessible

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• Complete 2-day workflow—fast targeted NGS

workflow from sample to data

New amplicon-based NGS library preparation technology that enables you to

design custom ultra high-sensitivity panels for your targets of interest

Introducing Ion AmpliSeq HD technology:

*For cell-free DNA samples


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an innovative multi-dimensional ngs approach to ... · an innovative multi-dimensional ngs approach...

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