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Immuno-Oncology Solutions
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• Our I-O Service Portfolio
• Highlighted Services:
• I-O Biomarker Discovery & Clinical Applications
• Neoantigen Identification & Clinical Applications
• Regulatable CAR-T Development
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ICI Efficacy Prediction
Cancer Vaccine
Checkpoint Inhibitor & drug targeting
Regulatable CAR-T
Neoantigen Identification
Immune Repertoire
• Tumor Mutational Burden• Microbiome• dMMR, MSI-H• Checkpoint Inhibitor
Expression
• Neoantigen• Immune Repertoire• MHC Binding/Prediction• Epigenetic Analysis
• Transcriptome Seq• Exome Seq• Epigenetic Analysis• Immune Repertoire• MHC Binding• scRNA-seq
AptaNxTM RegCAR-TTM
Biomarker Discovery
• Exome Seq• Transcriptome Seq• Epigenetic Analysis • HLA Typing
• Exome Seq• Transcriptome Seq• Epigenetic Analysis• AptaNxTM
• Immune Repertoire• MHC Binding• Checkpoint Inhibitor
Discovery• Exome Seq• Transcriptome Seq• scRNA-seq
Solution
Technology
DiscoveryClinical
Translation
Therapeutics
Immuno-OncologySolutions
Legend
Stem cell Transplantation
• HLA Matching• Transcriptome Seq
Minimal Residual Disease • Transcriptome Seq
• Exome Seq
Tumor Micro-environment
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Distribution and Growth of Cumulative Immuno-Oncology Biomarker
Mentions by Test Purpose 2014 – 17Growth of Cumulative Mentions of Top 30 Immuno-Oncology Biomarkers; 2014 – ’17
https://www.decibio.com
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J Yuan et al. Journal for ImmunoTherapy of Cancer20164:3
Technology
Whole Exome Sequencing
Gene signature/RNA Seq
Epigenetic Analysis
Antigen/Neoantigen Identification
B/T-cell receptor repertoire
Flow cytometry/WES/RNA Seq
Multicolor IHC
Therapeutic strategy
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Putative I-O Biomarkers in the TME
• PD-L1 expression
• Tumor-infiltrating lymphocytes (TILs)
• Mutational load and neoantigens
• Immunosuppressive cell types
• Macrophage and DC polarization
• Immunosuppressive molecules
• Cytokine signatures
Tumor cell Dead tumor cell MDSC CD8+ T cells CD4+ T cells Immature
dendritic cell
Primed
dendritic cell
M1
macrophage
M2
macrophage
PD-L1 PD-1 MHC I CTLA-4 TIM-3 LAG-3 Tumor Neoantigens IDO IFNγ M-CSF T-regulatory cell
antigens
© 2017 American Association for Cancer Research
M1
M2
IFNγ
M-CSF
iDC
CD8+
CD8+
CD8+
MDSC
CD8+
MDSC
MDSC
TIL
TIL
TIL
TIL
IDO
M2
IDO
iDC
Mutational
load
pDC
CD4+
Treg Treg
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Clinical Application Examples
Efficacy Biomarkers of ICI (Immunotherapy Checkpoint Inhibitors)
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Barnhart C. J Adv Pract Oncol. 2015 May-Jun;6(3):234-8.
PD-1 inhibitors:• Pembrolizumab (Keytruda)
• Nivolumab (Opdivo)
PD-L1 inhibitors:• Atezolizumab (Tecentriq)
• Avelumab (Bavencio)
• Durvalumab (Imfinzi)
CTLA-4 inhibitors:• Ipilimumab (Yervoy)
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28%
18%
27%
Melanoma NSCLC Renal-cell cancer
Response rate (Nivolumab)
33%
27%
13%
Melanoma NSCLC PD-L1–positive endometrial
cancer
Response rate (Pembrolizumab)
10.90%
Melanoma
Response Rate (Ipilimumab)
SL Topalian, FS Hodi, JR Brahmer , etal N Engl J Med 366: 2443– 2454,2012
A Ribas, et al. JAMA. 2016 Apr 19. doi: 10.1001/jama.2016.4059
R Hui, EB Garon, et al. Ann Oncol. 2017 Apr 1;28(4):874-881. doi: 10.1093/annonc/mdx008.
Ott et al. Journal of Clinical Oncology 35, no. 22 (August 2017) 2535-2541.
F Stephen Hodi et al. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466.
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• TMB (Tumor Mutational Burden)
• RNA signature
• PD-1, PD-L1 expression
• dMMR, MSI-H
• Microbiome
• Neoantigen
Hugo W. et al. Cell. 2017;168:542. doi: 10.1016/j.cell.2017.01.010.
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Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).
There was a significant difference in mutational load between patients with a long-term clinical benefit and those with a minimal benefit or no benefit.
Our Solution:
TMB analysis by WES (Whole Exome Sequencing) or our OncoGx gene panel
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Hugo W. et al. Cell. 2017;168:542. doi: 10.1016/j.cell.2017.01.010.
Identification of transcriptomic features (IPRES:
innate anti-PD-1 resistance) associated with anti-
PD-1 resistance
Our Solution:
RNA expression signature analysis by RNA-Seq
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Sunshine, J. & Taube, J. M. 23, 32–38, doi:10.1016/j.coph.2015.05.011 (2015).
Association of PD-L1 expression in pre-
treatment tumor specimens with
objective response to anti-PD-1/PD-L1
therapy
Our Solution:
Expression analysis of PD-1 and PD-L1
in tumor tissue by IHC
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Le DT, et al. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.
Mismatch repair–deficient tumors are more responsive to
PD-1 blockade than are mismatch repair–proficient tumors
Our Solution:
MSI-H and dMMR status testing by our MSI-H/dMMR or
OncoGx gene panels.
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Metagenomics of cancer
patient stools revealed
correlations between clinical
responses to ICI.
Routy B. et al. Science. 2017 Nov 2. pii: eaan3706. doi: 10.1126/science.aan3706.
Our Solution:
Gut microbiome analysis by metagenomics
or our FloraCheck™ assay.
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A peptide signature from the candidate neoepitopes is generated. This set of neoepitopes
defines a signature linked to a benefit from CTLA-4 blockade.
Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).
Our Solution:
Neoantigen signature analysis by WES (whole exome sequencing),
RNA seq, MHC binding prediction and bioinformatics analysis
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Highlighted Service II
Neoantigen Identification & Clinical Applications
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Ton N. Schumacher, Robert D. Schreiber Science 03 Apr 2015: Vol. 348, Issue 6230, pp. 69-74
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H. Hackl, et al. Nature Reviews Genetics 17, 441–458 (2016)
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• Whole-exome sequencing (WES) - identified neoantigen
• RNA-seq - Validate and assess the expression of neoantigen
• HLA binding - predict
• Vaccine synthesize and administration
At a median of 25 months after vaccination
4 patients: no disease recurrence
2 patients with lung metastases: disease recurrence
ICI treatment
complete responses
Ott PA et al. Nature. 2017 Jul 13;547(7662):217-221..
Clinical Application
ConfidentialHinrichs CS. et al. Immunol Rev. 2014 Jan; 257(1): 56–71
Clinical Application
Tumor
Normal TissueWES
RNA Seq
Non-synonymous Mutation
Expression ConfirmHLA Typing
MHC Binding Neoantigen
T-cell Activation
Reintroduce to Patient
TCR Clone/Construct
T-cell Expression
Transfect to T-cell
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Confidential 24
CAR generation 1st 2nd 3rd
Chronology 1989 2002 2009
Li H et al,2017, PMID: 28434147
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Clinical trial 1
63 r/r B-cell ALL
(3-21 yrs old)
Clinical trial 2
101 NHL
(77 DLBCL + 24 TFL/PMBCL)]
CR: complete remission; ORR: objective response rate; NHL: Non-Hodgkin's Lymphoma;
DLBCL: Diffuse Large B-Cell Lymphoma; TFL: transformed follicular lymphoma;
PMBCL: Primary Mediastinal Large B-Cell Lymphoma
Data from public news release
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Clinical Trial 1
63 patients with r/r B-cell ALL
(3-21 yrs old)
Clinical Trial 2
101 patients with NHL
(77 DLBCL + 24 TFL/PMBCL)
CR: complete remission; ORR: objective response rate; CRS: cytokine release syndrome
ALL: Acute Lymphoblastic Leukemia; NHL: Non-Hodgkin's Lymphoma;
DLBCL: Diffuse Large B-Cell Lymphoma; TFL: transformed follicular lymphoma;
PMBCL: Primary Mediastinal Large B-Cell Lymphoma;
Data from public news release
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ON-switch OFF-switch
Li H et al,2017, PMID: 28434147
Dose tuning to reduce CRS and avoid long-term B-cell aplasia while maintaining CAR-T
efficacy (PMID: 26759369; 26759368).
Tagged Ab
Tumor cell
Y
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• Limited options of the split proteins with the capability of
chemical induced dimerization (CID)
• The function of tagged antibodies may be affected by the
tagging position, tagging efficiency and tissue penetration
• The construct is too large to allow multi-layer T-cell
engineering
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ON-Switch ( Turn on CAR by a ligand)
OFF-Switch ( Turn off CAR by a ligand)
AAACAR
AAACAR
AAACAR
AAACAR
Aptazyme-ligand as a switch Potential Advantages
• Control CAR expression at mRNA level, no cell
stress due to constitutive overexpression of
CAR components.
• Aptazymes may be developed against
intracellular and external ligands, allowing
multiple layers of control.
• Aptazyme is small (~100 nt), allowing multiple
layer engineering of CAR constructs.
Aptazyme = Aptamer + Ribozyme
↑
Ligand
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• Admera Health is an advanced life science company focused on personalized
medicine, non-invasive cancer testing, immuno-oncology solution, and digital
health.
• A CLIA- & CLEP- certified and CAP-accredited lab
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For more information, please contact:
Dr. Jun T. Huang
126 Corporate Blvd.
South Plainfield, NJ 07080
908-222-0533 ext. 3443
844-4ADMERA
Web: www.admerahealth.com
Email: [email protected]