Novel Targets and T-Cell Receptors for Adoptive Cell Therapy CAR-TCR Summit 2017 Boston, Sep 6

Transcription

1 Novel Targets and T-Cell Receptors for Adoptive Cell Therapy CAR-TCR Summit 2017 Boston, Sep 6 Steffen Walter, Ph.D. Co-founder and CSO Immatics US Inc., Houston/TX

2 1) Introduction 2) XPRESIDENT Guided Target Discovery & Validation 3) XPRESIDENT Guided TCR Discovery & Validation 4) ACTolog and ACTengine Lead ACT Programs

3 Immatics Unlocking the human immunopeptidome to deliver novel targets and TCRs Founded in 2000 as a spin-out from the University of Tuebingen, Germany (Prof. HG Rammensee) Leader in cancer immunotherapy and discovery of novel tumor antigens World-leading proprietary antigen discovery engine XPRESIDENT ACTolog ACTengine Extensive discovery and development capability in cancer immunotherapy including proprietary TCR platform Strong IP protection on all assets and technology Vaccines incl. Neoantigens XPRESIDENT Targets & TCR Engine ACTallo Experienced R&D and management team Raised ~$190m in grants and financings ~130 FTEs in Germany (Tuebingen/ Munich) and US (Houston, TX) TCR-like mabs Soluble TCRs

4 Immatics ACT and bi-specific pipeline Track Indications Stage Partners ACT, TCR and Ab Bispecifics pipeline ACTolog T cells: autologous TCR: endogenous multiple Discovery IMA101 Lead CMC IND Phase I/II ACTengine T cells: autologous TCR: engineered multiple IMA201 IMA202 IMA203 ACTallo T cells: allogeneic TCR: engineered multiple IMA300/301 TCR Bispecifics multiple 3 programs TCR Bispecifics BiTE multiple Multiple programs mab Bispecifics multiple Multiple programs Immunotherapies multiple Multiple programs

5 The Problem: Missing Targets CHECKPOINT INHIBITORS CAR T-CELL THERAPY TCR T-CELL THERAPY MODE OF ACTION TARGET SPACE APPLICATION Non-targeted - Cancer with high mutation rate Targeted <25% Mainly liquid cancers Targeted 100% All cancers including solid cancers Current immunotherapies are limited to liquid cancers and subpopulations of solid cancers with high mutation rate The medical need for all other cancer types is largely unmet

6 1) Introduction 2) XPRESIDENT Guided Target Discovery & Validation 3) XPRESIDENT Guided TCR Discovery & Validation 4) ACTolog and ACTengine Lead ACT Programs

7 XPRESIDENT Target Database Competitive advantages Primary Cancer tissues AML Bladder Cancer Breast Cancer CLL Colorectal Cancer Esophagus Cancer Gallbladder Gastric Cancer Glioma Liver Cancer Melanoma Multiple Myeloma Non-Hodgkin Lymphoma NSCLC Ovary Pancreas Cancer Prostate Cancer Renal Cell Carcinoma SCLC Uterus LC-MS/MS N>700 tumor samples N>500 normal samples XPRESIDENT LC-MS/MS Immatics XPRESIDENT Target Database >60 million MS/MS spectra From >10,000 MS experiments From >1,100 tissue samples >4,000 promising tumor-associated candidates filed in patent applications from HIP >70 prioritized HLA-A*02 targets Largest known target database Only database with both normal and tumor primary tissues Only database with quantitative data (relative and absolute) Normal Control Tissues Adipose Tissue Ovary Adrenal Gland Pancreas Artery Peripheral Nerve Bladder Pituitary Gland Blood Cells Placenta Bone Marrow Pleura Brain Prostate Breast Rectum Cartilage Salivary Gland Cervix Skin Colon Small Intestine Esophagus Spleen Eye Stomach Gall Bladder Testis Heart Thymus Kidney Thyroid Liver Trachea Lung Ureter Lymph Node Uterus Muscle Vein

8 XPRESIDENT Guided Target Characterization Competitive advantages Selection of the relevant targets from the same tumor antigen Reveals which targets are naturally presented on tumor tissue, ranked by their absolute copy numbers Thorough on-target toxicity analysis of pmhc-targeting biologics (e.g. TCRs, mabs) Identifies and flags normal tissues with residual expression of the target peptide Efficient off-target toxicity screening of pmhc-targeting biologics (e.g. TCRs, mabs) Facilitates identification of potentially cross-reactive peptides with amino acid sequences closely related to the target peptide and verified expression in normal tissue

9 Novel Neoantigen-like Target Classes Not supported by RNA normal ligandomes required as included in XPRESIDENT Known peptide from transcription factor with only modest tumor selectivity A tumor-specific variant of this peptide, maybe created by protein splicing, has been discovered by Immatics Tumor specificity is invisible at the mrna level and can only be deduced from large MS data set containing tumors and normal tissues Finding and exploiting such attractive targets requires comprehensive data on normal tissue ligandomes Gene has limited tumor specificity on RNA level Normal tissue Tumor tissue 1) Known peptide (not tumor specific) 2) Novel Immatics neoantigen-like TUMAP Peptide frequently detected on normal tissue Normal tissue Tumor tissue Normal tissue Tumor tissue

10 1) Introduction 2) XPRESIDENT Guided Target Discovery & Validation 3) XPRESIDENT Guided TCR Discovery & Validation 4) ACTolog and ACTengine Lead ACT Programs

11 Immatics Proprietary TCR Discovery Platform Process overview A. Healthy Donors B. T-cell Priming C. TCR Identification D. Affinity + Avidity Determination > 20 HLA-matched + mismatched donors/ run Immatics proprietary targets + artificial APCs Platform allows for discovery of 100+ unique TCRs per target or direct identification from naive repertoire E. Specificity/ Safety Screen F. Efficacy/ Potency Screen

12 XPRESIDENT -guided TCR Discovery and Candidate Selection Screening against XPRESIDENT normal tissue peptide-hla database TCR binding motif identification (Ala-scan) Interrogate XPRESIDENT for homologous peptides presentation in healthy tissues Synthesis of homologous peptides and peptides of highest similarity Functional crossreactivity screen Cross-reactive TCR (excluded) Highly specific TCR (selected) IFN-y release IFN-y release wt a1 a2 a3 a4 a5 a6 a7 a8 a9 c1 c2 c3 XPRESIDENT normal tissue database reveals N=72 peptides from HLA-A*02 with identical TCR binding motif Genome-wide search revealed additional N>100 peptides from HLA-A*02 with identical TCR binding motif TCR reactive against highest similarity peptides TCR excluded from further development wt a1 a2 a3 a4 a5 a6 a7 a8 a9 c1 c2 c3 XPRESIDENT normal tissue database reveals N=0 peptides from HLA-A*02 with identical TCR binding motif Genome-wide search revealed N=0 peptides from HLA-A*02 with identical TCR binding motif TCR not reactive against highest similarity peptides TCR candidate for ACT program

13 TCR Discovery Platform Re-expression and qualification of candidate TCRs Safety and Efficacy screening Tumor cells T cell with transduced TCR Normal cells of various tissues SPR affinity determination 1G4 stcr:pmhc --- K D = 11.3µM Soluble TCR

14 (optional): TCR Engineering Moderate affinity maturation for ACT ACTengine/allo TCR Bispecifics Increasing Affinity Affinity range of highly specific TCR leads for N=3 frontrunner targets Librarybased affinity maturation Library-based stability and affinity maturation Enhanced TCRs for ACT TCR maturation for TCR Bispecifics

15 1) Introduction 2) XPRESIDENT Guided Target Discovery & Validation 3) XPRESIDENT Guided TCR Discovery & Validation 4) ACTolog and ACTengine Lead ACT Programs

16 Adoptive Cell Therapy (ACT) Programs Pursued by Immatics Joint venture with MD Anderson Cancer Center launched in 2015 ACTolog T cells: autologous TCR: endogenous ACTengine T cells: autologous TCR: engineered ACTallo T cells: allogeneic TCR: engineered HLA/ peptidemultimer (fishing rod for T cell) Lentivirus encoding novel T-cell receptor Off-the-shelf Gamma-delta T cell encoding novel T-cell receptor Donors Patrick Hwu Division Head Cancer Medicine Cassian Yee Professor Department of Melanoma Medical Oncology and Immunology Director of Solid Tumor Cell Therapy

17 Endogenous T-cell (ETC) Therapy Clinical proof of concept 1 Tumor target Clinical Proof of Concept 2 T-cell generation process Identification of specific cells Priming using IL-21 Expansion Leukapheresis Prof. Cassian Yee MD Anderson Cancer Center Chapuis et al, JCO (2016) Early promising clinical efficacy results in metastatic melanoma patients with one target 2/10 Patients experienced durable complete remission after infusion of MART1 specific cells generated with the same technology in combination with Ipilimumab Re-infusion 3 Re-Infusion Cancer patient

18 ACTolog IMA101 Overview of technology platform ACTolog overview 2 T-cell generation process Identification of specific cells Priming using IL-21 Expansion 1 Leukapheresis Re-infusion Tumor target Biomarker profiling Pre-defined target warehouse 3 Re-Infusion up to 4 products Cancer patient Multiple products Reduced risk for tumor escape T cells TCR IMA101 Autologous Endogenous Targets Warehouse of 8 proprietary targets Multi-target approach each patient receives up to 4 products accounting for antigen loss & tumor escape Personalization Active tailoring of the products to patient s tumor Process/ IP Targets (Immatics) License for IL-21 priming technology (MD Anderson) Indication Recurrent targets expressed in solid tumor patients (including NSCLC, HNSCC, EC, OV) Patient numbers First in human trial (N=20) After N=6 patients combination with CP inhibitors planned FPI July 2017

19 ACTengine IMA201/ 202/ 203 Overview of technology platform 1 Tumor target 2 TCR ACTengine overview Tumor sample Leukapheresis IMA201/ 202/ Vector encoding novel T-cell receptor T cells TCR Targets Autologous Engineered Undisclosed (one target/ TCR per trial) Autologous T cells Indication Recurrent target expressing solid tumor patients infused with autologous, genetically engineered T cells specific to antigens expressed by their tumor Cancer patient 4 Generation of TCR transgenic T cells pre-activation transduction expansion Patient numbers 3 trials (3 different TCRs) with N=10 per trial in first cohort Expansion cohort upon clinical signal Target TCR LV GMP IMA201 Biomarker CSP pre-ind IND FPI IMA202 IMA203

20 1 st ACTengine Program: IMA201 Target Peptide presentation Exon expression (tumor vs. healthy; in-house data) Exon expression (healthy tissue; GTEx data) Exon expression (tumor tissue; TCGA data)

21 1 st ACTengine Program: IMA201 TCR Affinity, specificity and functionality Affinity and functional avidity TCR-pHLA affinity/ BLI: 29 µm Functional avidity/ peptide titration EC 50 : 3 nm A375 tumor Efficacy cell Data growth Non-transduced Safety Data F o l d T u m o r G r o w t h low TCR% transduction <10% H o u r s C o - C u l t u r e high transduction TCR% >10% target + tumor cells Primary healthy cells

22 1 st ACTengine Program: IMA201 Manufacturing efficacy and robustness PQ1 PQ2 %Dex+ of CD3+CD NT Transduced LV-R73 LV Transduction IFNγ (pg/ml) NT A375 (Target +ve) MCF-7 (Target -ve) Function: IFNγ release Donor 1 NT A375 R73 A375 R73 MCF-7 Fold expansion % Lysis Expansion 0 1:40 1:20 1:10 1:5 Function: Target killing

23 1 st ACTengine Program: IMA201 Preservation of Tn/Tscm-like phenotype Proliferative capacity Effector function Restifo et al., Blood 2014 Restifo et al., Nat Rev Imm 2012 Kaech et al., Nat Rev Imm 2012 Gated on live CD3+CD8+Dex+ Donor #1 Day 0 Day 6 Day 10 Day 14 Days into manufacturing Donor #2 Tn/Tscm Tcm Tem Teff NSCLC #1 Representative examples

24 2 nd ACTengine Program: IMA202 Target Peptide presentation Exon expression (tumor vs. healthy; in-house data) Exon expression (healthy tissue; GTEx data) Exon expression (tumor tissue; TCGA data)

25 2 nd ACTengine Program: IMA202 TCR Affinity, specificity and functionality Affinity and functional avidity TCR-pHLA affinity/ BLI: 8.7 µm Functional avidity/ peptide titration EC 50 : 11 nm Efficacy Data Safety Data 6 Fold tumor cell growth Non-transducedN T Frontrunner R 3 7 TCR Other R 4 3 TCR Frontrunner TCR Other TCR Other TCR Hours Primary healthy cells and ips-derived cells target + tumor cells

26 2 nd ACTengine Program: IMA202 Association of TCR function and absolute peptide copies per tumor cell TCR efficacy (pg/ml IFNg) Target peptide on cell line (copies per cell) 0 U266B1 UACCC257 KMM1 A Target peptide copy number on tumor tissue is 1100 (median copies per cell) TCR recognizes tumor cell lines presenting target peptide at physiological copy numbers

27 Summary XPRESIDENT : >15 years of experience in ultra-high sensitive, quantitative mass spectrometry to discover and validate novel immuno-oncology targets Human Immunopeptidome Program discovered >4000 tumor-associated targets including >70 prioritized targets with high tumor selectivity; HIP 2.0 program started to identify next-generation target classes TCR discovery platform established allowing high-throughput identification of natural TCRs including XPRESIDENT -guided on- and off-target toxicity screening Translation of world-leading target and TCR capabilities into clinical application through adoptive cell therapy and Bispecifics Comprehensive and highly standardized clinical development biomarker, immunomonitoring and PBMC collection platforms established for >10 years Privileged partnership with MD Anderson Cancer Center through co-launching broad joint venture Immatics US based in Houston, TX ACT platforms ACTolog and ACTengine clinically launched in 3Q 2017

28 Acknowledgments Germany Carsten Reinhardt (CMO) Toni Weinschenk (Discovery/ CTO) Jens Fritsche (Bioinformatics) Oliver Schoor (Discovery) Sarah Kutscher (Sc. Coord.) Sabrina Kuttruff (Trans. Dev.) Norbert Hilf (Trans. Dev.) Lea Stevermann (Discovery) Dominik Maurer (Immunology) Sebastian Bunk (Immunology) Claudia Wagner (Immunology) With generous support of the State of Texas Cancer Prevention Research Institute of Texas US Harpreet Singh (CEO) Steffen Walter (CSO) Agathe Bourgogne (Program Mgmt) Chad Stewart (Program Mgmt) Hong Ma (Clinical) Ali Mohamed (CMC) Yanick Bulliard (Product Science) and more than 80 highly dedicated scientists, clinicians and technicians at Immatics Patrick Hwu Cassian Yee Lia Tsimberidou George Blumenschein John Heymach Willem Overwijk Amir Jazaeri Immatics Scientific Advisory Board Hans-Georg Rammensee (Chair) Christoph Huber Kees Melief Pedro Romero Craig Slingluff Patrick Hwu Cassian Yee Willem Overwijk

29 Thank you Immatics Paul-Ehrlich-Str. 15, Tuebingen, Germany Phone Fax W. Holcombe Blvd., Suite , Houston, Texas 77030, USA Phone Fax