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Inducible T Infiltrating Lymphocyte (iTIL) Cell Therapy

Wilber Huang, MD Abnova Corporation

免責聲明

本簡報及同時發佈之相關訊息包含財務、市場暨產品業務等預測性資訊。本公司未來實際發生的營運結果及財務狀況可能與這些預測性資訊所明示或暗示的預估有所差異，其原因可能來自於各種本公司所不能掌控的風險。這些預估及展望的訊息，反應本公司截至目前為止對於未來的看法，本公司並不負責隨時提醒或更新。

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“……think about the potential breakthrough that it could be. You could be looking at a transformation of the treatment of cancer over the ” next 20 to 30 years. - Joseph Jimenez, CEO of Novartis Forbes, 2014 May

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Almasbak H, et al., J Immuno Res 2016; 2016:5474602

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Prof. Tasuku Honjo
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US FDA recommended the approval of the first CAR-T cell therapy for B cell acute leukemia. (Novartis, 2017)

Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune system. (Honjo, 2002)

IL-2 based immunotherapy shown to reduce tumors in patients with melanoma and renal cell cancer.(Rosenburg, 1985)

2017

2002 2000 Dr. James Allison

1985

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Dr. Steven
Rosenberg
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Dr. Carl H. June
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1995 CTLA-4 is found to inhibit the activity of T cells as a brake" of immune response. (Alison, 1995)

2012

First child with leukemia treated with CAR-T cell therapy. (June, 2012)

1Immunotherapy timeline and progress https://www.cancerresearch.org/immunotherapy/timeline-of-progress 2FASEB: Cancer Immunotherapies: From Magic Bullets to Super T Cells http://faseb.org/Resources-for-the-Public/Breakthroughsand-Horizons-in-Bioscience.aspx

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Novartis – ALL (FDA Approved 8/2017)

� NCI & Kite (acquired by Gileads) – DLBCL (FDA Approved 10/2017)

UPenn, MSKCC, FHCRC & Juno (Invested by Celgene)

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Chimeric Antigen Receptor (CAR) T cell Therapy

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Four Generations of CAR T Cells

Increase CAR T Cell Proliferation, Survival, & Cytokine Production

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Wang M, et al., Immunotherapy 2014; 6(12): 1265-1278

Company	Pipeline	Core Tech	Indication	Stage	Reference
Novartis	Kymirah (Tisagenlecle ucel)	CAR	Lymphoma	FDA Approval	https://www.us.kymri ah.com
Kite/Gilead	Yescarta (Axicabtagen e ciloleucel)	CAR	Lymphoma	FDA Approval	https://www.yescarta .com
Juno/Celgene	JCAR	CAR	Lymphoma	Phase I	https://www.junothe rapeutics.com/our- pipeline/
Tessa Therapeutics	TT10	CTL	Solid Tumor	Phase III	https://www.tessathe rapeutics.com/pipeli ne/
Iovance	LN-144 LN-146	TIL	Solid Tumor	Phase II	http://www.iovance.c om/clinical/c-144- 01-metastatic- melanoma/
Atara Bio	Tab-cel (tabelecleuce l)	Alloge neic T Cell	EBV associated hematologic and solid tumors	Phase III	http://www.atarabio. com/pipeline/
Cell Medica	CMD-003	TIL	Lymphoma	Phase II	https://cellmedica.co m/products/

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Complexities in Solid Tumor Cell Therapy

Specificity Safety Enhance activity Microenvironment T-cell survival Trafficking Proliferation

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Problems #1 –

Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity

Problems #1 – Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity	Problems #1 – Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity	Problems #1 – Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity
Tmor-Associated Antiens
	Tmor-Associated Antiens
	ug
	Cancer	Antigens targeted by CARs
	Breast cancer	ERBB2 and MUC1
	Cervical carcinoma	CD44v6, CD44v7 and CD44v8
	Gastrointestinalcancer	CEA, EPCAM(also known as EGP2 and EGP40), TAG72 and KIT
	Glioblastoma	IL-13Rα2 and EGFR
	Hepatocarcinoma	─
	Lymphomas & Leukemia	CD19, CD20, CD22, CD30, CD33,ҡ-LC, ROR1, CD38 and NKG2D ligands
	Melanoma	CD3, HMW-MAA, MAGE1 and MAGEA3
	Neuroblastoma	CD2, CD171(L1CAM)and NCAM
	Osteoscarcoma	IL-11Rα
	Ovarian cancer	αFR and MUC1
	Pancreatic cancer	CEA
	Prostate cancer	PSCA, PSMA and TARP
	Rhabdomyosarcoma	Fetal acetylcholine receptor
	Renal cancer	CAIX

Tumor vasculature VEGFR2 and PSMA Universal BBIR and FITC Various tumors TAG72, mesothelin, LeY, 5T4 oncofetal antigen, ERBB3, ERBB4 and GP58	Tumor vasculature	VEGFR2 and PSMA
	Universal	BBIR and FITC
	Various tumors	TAG72, mesothelin, LeY, 5T4 oncofetal antigen, ERBB3, ERBB4 and GP58

Keershaw M, et al., Nature Review 2013; August 13: 525-541

Problem #2

Immunosuppressive Tumor Environment Prevents T cell Penetration & Killing of Heterogeneous Tumor Cells

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Scarfo I, et al., Journal for ImmunoTherapy of Cancer 2017 ; 5(28):1-8

Problem #3

Anti-CD19 CAR T Therapy Related Toxicities

Cytokine Release Syndrom (CRS) (On Tumor On Target Toxicity)
Correlates with T cell proliferation and efficacy - Severity related to disease burden
Observed in 88%; 27% required hemodynamic and/or respiratory support
Reversed with IL-6 receptor blockade, Tocilizumab
Neurotoxicity (overlaps with CRS)
Seen in several CD19 immunotherapy trials; NCI, CHOP/UPenn, MSKCC, Blinatumomab
Generally untreated, fully resolves
Chronic B cell Aplasia requiring Ig replacement (Off Tumor On Target Toxicity)
Correlates with T cell proliferation and efficacy

Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events

Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events	Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events	Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events
Institution TAA Gene transfer Positive-receptor (scFv or TCR) Patient populations Lympho depleting Infused cell doses Time Cause & number of
	Institution TAA Gene transfer Positive-receptor (scFv or TCR) Patient populations Lympho depleting Infused cell doses Time Cause & number of
	regimens (total) deaths
	Juno Therapeutics CD19 Retrovirus scFv: 19z1-28ζ(2nd) Relapsed or refractory B-ALL Cy + Flu Unknown Unknown Neurologic toxicity (3) Chinese PLA General Hospital CD20 Lentivirus scFv: CAR.20-CD137ζ (2nd) Diffuse large B- cell lymphoma COD 107/kg 3 weeks Massive hemorrhage of alimentary tract (1)*
	National Cancer Institute HER2 Retrovirus scFv: 4D5-CD8-28BBζ (3rd) Colon cancer metastatic to the lungs and liver Cy 60 mg/kg for 2 days followed by Flu 25 mg/m2 for 5 days 1010cells 5 days CRS; Speculate that off tumor, targeting lung epithelial Cells (1)
	National Cancer Institute MAGE-A3 /A12 Retrovirus TCR: HLA-A0201- restricted MAGE-A3 peptide: KMAELVHFL Patient 5: Melanoma 8: esophageal cancer Cy 60 mg/kg for 2 days followed by Flu 25 mg/m2 for 5 days Patient 5: 7.9 ×1010 cells Patient 8: 6.1×1010 cells Patient 5: 167 days; Patient 8: 94 days Neurologic toxicity (2) Washington Patient 1: Patient 1 :Cy 60 mg/kg for 2 9 Patient 1: 4
University; University of Pennsylvania MAGE-A3 Retrovirus TCR: HLA-A01- restricted MAGE-A3 peptide: EVDPIGHLY Melanoma Patient 2: Myeloma days; Patient 2: Melphalan at 200 mg/m2 followed HSCT 5.3×10 cells 2.4×109 cells. days; Patient 2: 5 days Cardiovascular toxicity (2)	University; University of Pennsylvania MAGE-A3 Retrovirus TCR: HLA-A01- restricted MAGE-A3 peptide: EVDPIGHLY Melanoma Patient 2: Myeloma days; Patient 2: Melphalan at 200 mg/m2 followed HSCT 5.3×10 cells 2.4×109 cells. days; Patient 2: 5 days Cardiovascular toxicity (2)

Mo Z, et al., J Cancer 2017; 8(9):1690-1703

Problem #4

Traditional TIL Therapy Requires Harvesting T cells from Tissue, Instead of Peripheral PBMC in CAR T cell Therapy

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Incomplete Solutions of CAR T Cells against Solid Tumors

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Jackson HJ, et al., Nat Rev Clin Oncol 2016; 13(6): 370-383

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Solution #1 – Pan Tumor Antigen

Use Low-Dose Proprietary Chemotherapy and IL-12 to Increase NKG2D in CD8+ T cells and NKG2D Ligand in All Tumors

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Inducible
Constitutive
NKG2D
NKG2D
Expression
Expression
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CD8+ T cell NKG2D Induction, Localization, and Solid Tumor Inhibition

NKG2D is specifically induced on CD8+ T cells by Doxorubicin + IL-12 but Not Other Types of Immune Cells
CD8+ T cells NKG2D Induction by Doxorubicin + IL-12 Enhances Immune Cell Localization in Solid Tumor
CD8+ T cells Inhibition of Solid Tumor Growth and Metastasis by Doxorubicin + IL-12 is dependent on NKG2D

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Hu J, et al., Molecular Cancer 2014; 13(34): 1-13

Solid Tumor NKG2D Ligand Induction & Expression

• As Tumor Malignancy Increases, the NKG2D Ligand in Tumors Decreases

Chemotherapeutic Agents Can Induce NKG2D Ligand on Tumor Cells in Vitro , Not In Vivo
Combination of a Few Specific Chemotherapeutic Agents and IL-12 Can Increase NKG2D Ligand in Solid Tumors, ie Doxorubicin, Cyclophosphamide, Cisplatin
Doxorubicin + IL-12 Induces Tumor-Specific and Long Lasting NKG2D Ligand Expression
No NKG2D Ligand Induction in Normal Tissues after Doxorubicin + IL-12 Treatment

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Hu J, et al., Cancer Immunol Res 2017; 5(4): 1-12

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Solution #2 – Cell Membrane Anchored IL-12 Use Doxorubicin + attIL-12 Gene Modified T Cells to Induce T Cells to Penetrate Deep into the Tumor and Overcome Tumor Immunosuppressive Environment

Inducible T Infilitrating Lymphocytes (iTIL)

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attIL-12
(Membrane
Secreted IL-12 Anchored IL-12)
IL-
IL-12 IL-12
12
Receptor Receptor
T Cells T Cells
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CD8+ T cells Deep Penetration & Tumor Killing

• Doxorubicin or IL-12 Alone Attracts CD8+ T cells to Tumor Margins. Only Doxorubicin plus IL-12 Recruit CD8+ T cells to Centers of the Tumors (10mm in diameter)

Doxorubicin + IL-12 promotes IFN-gamma which boosted CXCL9 and CXCL10 Expression

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Hu J, et al., Clin Cancer Res 2018; 24(2): 1-16

IL-12, a Critical and Successful Anticancer Agent in Preclinical but not in Clinical Studies (so far)

Recombinant IL-12 Protein
Systematic especially hematologic toxicity
Toxic effects related to secondary production of IFN-gamma and TNF-alpha
IL-12 Gene Therapy
Intratumoral IL-12 plasmid injection has low gene transfer efficiency
Intralesional IL-12 plasmid + electroporation was more effective but not applicable for systemic tumors
Intramuscular IL-12 plasmid + electroporation failed to localize IL-12 product
Tissue TIL + Inducible IL-12 (Dr. Steve Rosenberg, NCI)
Short responses without IL-12 producing TIL persistence in melanoma
High serum IL-12 levels and IFN-g associated clinically toxicities
Peripheral Blood TCR + Inducible IL-12 (Dr. Steve Rosenberg, NCI)
T-cell receptor specific for NY-ESO-1 tumor antigen in sarcoma and melanoma - Study suspended several weeks after start of the trial which was then terminated.
4[th] Generation CAR T cell with Inducible IL-12 (Dr. Brentgens, MSKCC) - MUC-16 CAR T cell with secreting IL-12 against recurrent ovarian cancer

Solution #3 – Localize Cytokine Cytotoxicity Doxorubicin Directs Accumulation of IL-12 Induced IFN-g Secreting Immune Cells in Tumors Only, Negating Systemic IFN-g Effects and Cytokine Release Syndrome

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Zhu S W, et al., Clin Cancer Res 2007; 13(14): 4525-4260

Doxorubicin Localizes the Powerful Intratumoral Biological Effects of IL-12 without Systemic Effects

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Lasek W, et al., Cancer Immunol Immunother 2014; 419-435

Solution #4

attIL-12 Gene Modified Inducible T Infiltrating Lymphocytes (iTIL) Generated from Peripheral PBMC, not Tissue

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Abnova & MD Anderson Collaboration Worldwide Exclusive License iTIL Technology

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AI assistant

Abnova Investor Presentation 2019

52384_rns_2019-12-12_74266237-c8ec-40e1-a5b6-9abe978a689a.pdf

Inducible T Infiltrating Lymphocyte (iTIL) Cell Therapy

免責聲明

Chimeric Antigen Receptor (CAR) T cell Therapy

Four Generations of CAR T Cells

Increase CAR T Cell Proliferation, Survival, & Cytokine Production

Complexities in Solid Tumor Cell Therapy

Problems #1 –

Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity

Problem #2

Immunosuppressive Tumor Environment Prevents T cell Penetration & Killing of Heterogeneous Tumor Cells

Problem #3

Anti-CD19 CAR T Therapy Related Toxicities

Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events

Problem #4

Incomplete Solutions of CAR T Cells against Solid Tumors

Solution #1 – Pan Tumor Antigen

Use Low-Dose Proprietary Chemotherapy and IL-12 to Increase NKG2D in CD8+ T cells and NKG2D Ligand in All Tumors

CD8+ T cell NKG2D Induction, Localization, and Solid Tumor Inhibition

Solid Tumor NKG2D Ligand Induction & Expression

Solution #2 – Cell Membrane Anchored IL-12 Use Doxorubicin + attIL-12 Gene Modified T Cells to Induce T Cells to Penetrate Deep into the Tumor and Overcome Tumor Immunosuppressive Environment

CD8+ T cells Deep Penetration & Tumor Killing

• Doxorubicin or IL-12 Alone Attracts CD8+ T cells to Tumor Margins. Only Doxorubicin plus IL-12 Recruit CD8+ T cells to Centers of the Tumors (10mm in diameter)

IL-12, a Critical and Successful Anticancer Agent in Preclinical but not in Clinical Studies (so far)

Solution #3 – Localize Cytokine Cytotoxicity Doxorubicin Directs Accumulation of IL-12 Induced IFN-g Secreting Immune Cells in Tumors Only, Negating Systemic IFN-g Effects and Cytokine Release Syndrome

Doxorubicin Localizes the Powerful Intratumoral Biological Effects of IL-12 without Systemic Effects

Solution #4

attIL-12 Gene Modified Inducible T Infiltrating Lymphocytes (iTIL) Generated from Peripheral PBMC, not Tissue

Abnova & MD Anderson Collaboration Worldwide Exclusive License iTIL Technology

AI assistant

Abnova — Investor Presentation 2019

52384_rns_2019-12-12_74266237-c8ec-40e1-a5b6-9abe978a689a.pdf

Inducible T Infiltrating Lymphocyte (iTIL) Cell Therapy

免責聲明

Chimeric Antigen Receptor (CAR) T cell Therapy

Four Generations of CAR T Cells

Increase CAR T Cell Proliferation, Survival, & Cytokine Production

Complexities in Solid Tumor Cell Therapy

Problems #1 –

Lack of Tumor-Specific Antigens in Solid Tumors, Tumor Antigen Downregulation, & Tumor Heterogeneity

Problem #2

Immunosuppressive Tumor Environment Prevents T cell Penetration & Killing of Heterogeneous Tumor Cells

Problem #3

Anti-CD19 CAR T Therapy Related Toxicities

Adoptive Gene-Engineered T cell Immunotherapy with Fatal Serious Adverse Events

Problem #4

Incomplete Solutions of CAR T Cells against Solid Tumors

Solution #1 – Pan Tumor Antigen

Use Low-Dose Proprietary Chemotherapy and IL-12 to Increase NKG2D in CD8+ T cells and NKG2D Ligand in All Tumors

CD8+ T cell NKG2D Induction, Localization, and Solid Tumor Inhibition

Solid Tumor NKG2D Ligand Induction & Expression

Solution #2 – Cell Membrane Anchored IL-12 Use Doxorubicin + attIL-12 Gene Modified T Cells to Induce T Cells to Penetrate Deep into the Tumor and Overcome Tumor Immunosuppressive Environment

CD8+ T cells Deep Penetration & Tumor Killing

• Doxorubicin or IL-12 Alone Attracts CD8+ T cells to Tumor Margins. Only Doxorubicin plus IL-12 Recruit CD8+ T cells to Centers of the Tumors (10mm in diameter)

IL-12, a Critical and Successful Anticancer Agent in Preclinical but not in Clinical Studies (so far)

Solution #3 – Localize Cytokine Cytotoxicity Doxorubicin Directs Accumulation of IL-12 Induced IFN-g Secreting Immune Cells in Tumors Only, Negating Systemic IFN-g Effects and Cytokine Release Syndrome

Doxorubicin Localizes the Powerful Intratumoral Biological Effects of IL-12 without Systemic Effects

Solution #4

attIL-12 Gene Modified Inducible T Infiltrating Lymphocytes (iTIL) Generated from Peripheral PBMC, not Tissue

Abnova & MD Anderson Collaboration Worldwide Exclusive License iTIL Technology

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Abnova Investor Presentation 2019