Immuno-Oncology Solutions
Confidential
•
Our I-O Service Portfolio
•
Highlighted Services: • • •
I-O Biomarker Discovery & Clinical Applications Neoantigen Identification & Clinical Applications Regulatable CAR-T Development
Confidential
• • • • • • • •
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 • • • • • •
Transcriptome Seq Exome Seq Epigenetic Analysis Immune Repertoire MHC Binding scRNA-seq
• • • •
Tumor Mutational Burden Microbiome dMMR, MSI-H Checkpoint Inhibitor Expression
Cancer Vaccine
• • • •
Neoantigen Immune Repertoire MHC Binding/Prediction Epigenetic Analysis
Stem cell Transplantation
• HLA Matching • Transcriptome Seq
Neoantigen Identification
Biomarker Discovery
Tumor Microenvironment
Clinical Translation
Discovery
Immuno-Oncology Solutions
ICI Efficacy Prediction
Minimal Residual Disease
Immune Repertoire
• Transcriptome Seq • Exome Seq
Therapeutics
Legend Checkpoint Inhibitor & drug targeting
Solution Regulatable CAR-T Technology
AptaNxTM
RegCAR-TTM Confidential
Confidential
Growth of Cumulative Mentions of Top 30 Immuno-Oncology Biomarkers; 2014 – ’17 https://www.decibio.com
Distribution and Growth of Cumulative Immuno-Oncology Biomarker Mentions by Test Purpose 2014 – 17 Confidential
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
J Yuan et al. Journal for ImmunoTherapy of Cancer20164:3 Confidential
IDO iDC
M1
pDC MDSC
M2
CD4+
CD8+
M-CSF
Putative I-O Biomarkers in the TME
IFNγ Treg
Treg
TIL
TIL
IDO TIL
TIL MDSC Mutational load
CD8+
MDSC
CD8+
Tumor cell
PD-L1
Dead tumor cell
PD-1
MHC I
MDSC
CTLA-4
CD8+
CD8+ T cells
TIM-3
LAG-3
M2
iDC
CD4+ T cells
Tumor antigens
Immature dendritic cell
Neoantigens
Primed dendritic cell
IDO
IFNγ
M1 macrophage
M-CSF
•
PD-L1 expression
•
Tumor-infiltrating lymphocytes (TILs)
•
Mutational load and neoantigens
•
Immunosuppressive cell types
•
Macrophage and DC polarization
•
Immunosuppressive molecules
•
Cytokine signatures
M2 macrophage
T-regulatory cell
© 2017 American Association for Cancer Research
Confidential
Clinical Application Examples
Efficacy Biomarkers of ICI (Immunotherapy Checkpoint Inhibitors)
Confidential
PD-1 inhibitors: • •
Pembrolizumab (Keytruda) Nivolumab (Opdivo)
PD-L1 inhibitors: • • •
Atezolizumab (Tecentriq) Avelumab (Bavencio) Durvalumab (Imfinzi)
CTLA-4 inhibitors: •
Barnhart C. J Adv Pract Oncol. 2015 May-Jun;6(3):234-8.
Ipilimumab (Yervoy)
Confidential
Response rate (Nivolumab) 28%
Response rate (Pembrolizumab) 27%
33% 27%
18% 13%
Melanoma Melanoma
NSCLC
Renal-cell cancer
NSCLC
PD-L1–positive endometrial cancer
Response Rate (Ipilimumab) 10.90%
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.
Melanoma
Confidential
•
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. Confidential
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. Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).
Our Solution: TMB analysis by WES (Whole Exome Sequencing) or our OncoGx gene panel Confidential
Identification of transcriptomic features (IPRES: innate anti-PD-1 resistance) associated with antiPD-1 resistance
Our Solution: RNA expression signature analysis by RNA-Seq
Hugo W. et al. Cell. 2017;168:542. doi: 10.1016/j.cell.2017.01.010.
Confidential
Association of PD-L1 expression in pretreatment 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
Sunshine, J. & Taube, J. M. 23, 32–38, doi:10.1016/j.coph.2015.05.011 (2015). Confidential
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.
Le DT, et al. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.
Confidential
Metagenomics of cancer patient stools revealed correlations between clinical responses to ICI. Our Solution: Gut microbiome analysis by metagenomics or our FloraCheck™ assay.
Routy B. et al. Science. 2017 Nov 2. pii: eaan3706. doi: 10.1126/science.aan3706. Confidential
Snyder, A. et al. N. Engl. J. Med. 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).
A peptide signature from the candidate neoepitopes is generated. This set of neoepitopes defines a signature linked to a benefit from CTLA-4 blockade.
Our Solution: Neoantigen signature analysis by WES (whole exome sequencing), RNA seq, MHC binding prediction and bioinformatics analysis
Confidential
Highlighted Service II
Neoantigen Identification & Clinical Applications
Confidential
Ton N. Schumacher, Robert D. Schreiber Science 03 Apr 2015: Vol. 348, Issue 6230, pp. 69-74 Confidential
H. Hackl, et al. Nature Reviews Genetics 17, 441–458 (2016) Confidential
Clinical Application
• 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.. Confidential
Clinical Application
Tumor Normal Tissue
HLA Typing
MHC Binding
WES
Expression Confirm
Neoantigen
T-cell Activation
Reintroduce to Patient
Hinrichs CS. et al. Immunol Rev. 2014 Jan; 257(1): 56–71
Non-synonymous Mutation
RNA Seq
TCR Clone/Construct
Transfect to T-cell
T-cell Expression
Confidential
Confidential
CAR generation Chronology
1st 1989
2nd 2002
3rd 2009 Li H et al,2017, PMID: 28434147 Confidential
24
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 Confidential
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 Confidential
ON-switch
OFF-switch Tumor cell
Y Tagged Ab
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). Confidential
• 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
Confidential
Aptazyme = Aptamer + Ribozyme ↑ Ligand Aptazyme-ligand as a switch ON-Switch ( Turn on CAR by a ligand)
CAR
AAA
CAR
AAA
OFF-Switch ( Turn off CAR by a ligand) CAR
AAA
CAR
AAA
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. Confidential
• 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
Confidential
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]
Confidential
