Alaunos Therapeutics, Inc. · NASDAQ:TCRT
Alaunos Therapeutics — Ziopharm Oncology — ASH workshop (July 2016)
33 slides from Alaunos Therapeutics's conference presentation, Jul 14, 2016
Slide 1: The "ins" and "outs" of Genetic Engineering of T cells for Human Applications
The "ins" and "outs" of Genetic Engineering of T cells for Human Applications Laurence Cooper M.D., Ph.D. ljncooper@ziopharm.com ASH workshop 3:55 to 4:15 pm July 14, 2016 Exhibit 99.1
Slide 2: Forward-looking statements
This presentation contains certain forward-looking information about ZIOPHARM Oncology, Inc. that is intended to be covered by the safe harbor for "forward-looking statements" provided by the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that
Slide 3: Objectives
Objectives NK cells ab T cells TH17 cells NKT cells Treg cells gd T cells T cells can be genetically modified to introduce desired transgenes and edited to remove undesired endogenous genes. The combination of insertion and elimination can be harnessed to develop T cells with desired specificity, im
Slide 4: T cells genetically engineered for human applications
T cells genetically engineered for human applications Oncology examples T-cell receptor (TCR) Chimeric antigen receptor (CAR) Non-oncology examples CCR5 gene knockout for HIV+ patients ADA-SCID, other primary immune-deficiencies Virus specific T-cells (often after HSCT) Tregs for autoimmunity (e.g.,
Slide 5: Exemplary mechanisms of gene insertion
Exemplary mechanisms of gene insertion Viral Retrovirus Lentivirus Non-integrating lentivirus (“episomal”), S/MAR attachment element Adenovirus (non-integrating) Adeno-associated virus (integration into AAVS1 safe harbor site) Non viral DNA Sleeping Beauty transposon piggyBac transposon mRNA
Slide 6: Targeted integration
Targeted integration Examples: Meganucleases Zinc Finger Nucleases TAL Effector Nucleases CRISPR/Cas9 nucleases Homologous recombination (and selection) Note: “Nucleases” are often used as paired nickases
Slide 7: Mechanisms of gene elimination
Mechanisms of gene elimination Examples Zinc Finger Nucleases TAL Effector Nucleases CRISPR/Cas9 nucleases RNAi On June 21, 2016, NIH RAC approved first-in-human CRISPR gene editing at UPENN CRISPR Knockout: TCRα constant, TCRβ constant, PD-1 Integrate (lentivirus): NY-ESO-1 TCR NIH RAC videocast ht
Slide 8: Exemplary CAR targets
Exemplary CAR targets Oncology Hematologic malignancies Solid tumors Non-oncology Infectious disease Auto-immunity Infectious diseases Autoimmunity HCV E2 glycoprotein Dsg3 (PV autoantigen) HIV (using bnAbs) HIV (using CD4) Hematological Solid tumors CD19 B7H6 (using NKp30) CD22 CD133 CD30 CD171 (L1
Slide 9: Sleeping Beauty (SB) system transposon/transposase
IR/DR IR/DR hEF1a CAR CMVIE SB11 Transposase Co-delivery into cells by nucleofection Transposon DNA plasmid Transposase DNA plasmid (or in vitro transcribed mRNA) Sleeping Beauty (SB) system transposon/transposase for non-random integration CAR Transposon Nucleus Transposase Cytoplasm
Slide 10: First-in-human application of SB system
First-in-human application of SB system CAR+ T cells infused after hematopoietic stem-cell transplantation (HSCT) Methods available at: Huls MH, et al. Clinical application of Sleeping Beauty and artificial antigen presenting cells to genetically modify T cells from peripheral and umbilical cord blo
Slide 11: Non-viral delivery: SB CAR+ T-cell platform (first-in-human studies)
Non-viral delivery: SB CAR+ T-cell platform (first-in-human studies) Long term follow-up data from 1st generation Sleeping Beauty platform in two trials infusing CAR+ T cells after hematopoietic stem-cell transplantation (HSCT) Showed favorable PFS and OS trends in both autologous and allogeneic coh
Slide 12: Reprogram T cells to target carbohydrate antigens
Reprogram T cells to target carbohydrate antigens Redirect T-cell specificity to target Aspergillus Combine binding of pattern-recognition receptor from Dectin-1 with T-cell activation domains (CD28 & CD3-z) Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5 No T cells CD19-specific T cells D-CAR
Slide 13: Genetic engineering of next-generation off-the-shelf (OTS) CAR+ cells
Genetic engineering of next-generation off-the-shelf (OTS) CAR+ cells Mol Ther. 2016 Jun 14. doi: 10.1038/mt.2016.106.
Slide 14: Challenges and opportunities
Challenges and opportunities Serial and specific killing of tumor cells within tumor microenvironment CD19 + malignancies CD19 neg hematologic malignancies Solid tumors
Slide 15: Exemplary Switches
Exemplary Switches iMyD88/CD40 (AP1903 dimerizer); Split CAR (AP21967 dimerizer); “Tandem”, e.g., CD19-OR-CD20 bispecific CAR (Zah 2016); “Switchable” (Ma 2016, Rodgers 2016); SynNOTCH (Roybal 2016); TetOn + tetracycline promoter è CAR (Sakemura 2015 ASH 4424); RheoSwitchÒ + veledimex è CAR (Intrexo
Slide 16: Oral ligand to conditionally express CARs using RTS
Oral ligand to conditionally express CARs using RTS®
Slide 17: Human experience with conditional expression using RheoSwitch System
Human experience with conditional expression using RheoSwitch® System (RTS®)
Slide 18: RTS switch responds to the dose of veledimex in GBM patients
RTS® switch responds to the dose of veledimex in GBM patients
Slide 19: Early data suggests benefit with favorable trend in overall survival in recurrent GBM
Early data suggests benefit with a favorable trend in overall survival for patients with recurrent GBM Median OS has not been reached; 11 patients out of 14 alive In Cohort 1 (N=7), the median follow up is 8.0 months with 6 patients out of 7 alive. 1 patient in Cohort 1 (20 mg) died due to disease p
Slide 20: Conditional expression of CAR under RTS
Conditional expression of CAR under RTS® CD3 Veledimex added to culture for ON; withdrawal is OFF CAR RTS® Conditions ON OFF ON
Slide 21: Safety: Exemplary Suicide Genes
Safety: Exemplary Suicide Genes Gene Kill mechanism Mechanism Immunogenicity iCasp9 AP1903 (dimerizer) Apoptosis No tEGFR Cetuximab ADCC? ADCP? CDC? No (very rare) CD20R RQR8 Rituximab Rituximab, anti-CD34 ADCC? ADCP? CDC? αCD34 Magnetic beads in vitro No HSV-tk Ganciclovir prodrug Block DNA synthes
Slide 22: Improving therapeutic potential of CAR+ T cells
Improving therapeutic potential of CAR+ T cells
Slide 23: Improving CAR+ T cells by co-signaling through IL-15 receptor
Improving CAR+ T cells by co-signaling through IL-15 receptor T-cell survival Tumor only CAR CAR & mIL15
Slide 24: Improving therapeutic potential by co-signaling through homing receptors
Improving therapeutic potential of CAR+ and TCR+ T cells by co-signaling through homing receptors Tissue specific homing involves sequential molecular interactions, concurrent with activation Rolling Activation Arrest Transmigration Perivascular exit Interstitial migration (often chemotaxis).
Slide 25: Targeting intracellular antigens: key to T-cell therapy for solid tumors
Targeting intracellular antigens: The key to implementing T-cell therapy for solid tumors Minority of tumor antigens are on the surface. These can be targeted by CAR Majority of tumor antigens are in the cell. These can be targeted by TCR
Slide 26: TCR targets (using genetically modified T cells)
TCR targets (using genetically modified T cells) Shared antigens Cancer-testis antigens (NY-ESO-1) Oncogenic drivers (Her-2, K-RasG12D) Onco-enzyme products (PhosImmune, Tn) Patient specific neoantigens Mutanome Alexandrov et al 2013 Nature 500: 415-421
Slide 27: Inter- & intra-tumor heterogeneity of tumor-associated antigens
Inter- & intra-tumor heterogeneity of tumor-associated antigens Infuse T cells with one or more specificity Personalized for the patient “N=1” trial paradigm
Slide 28: Neoantigen-specific TCRs expressed using SB system to target solid tumors
Neoantigen-specific TCRs expressed using SB system to target solid tumors Molecular Therapy 05 March 2016
Slide 29: Targeting neo-antigens
Targeting neo-antigens Patient (recipient) Infusion product
Slide 30: Targeting neo-antigens
Targeting neo-antigens
Slide 31: Targeting neo-antigens
Targeting neo-antigens Patient (recipient) Infusion product
Slide 32: The new industrialization of TCR+ T cells
Power-law curve The new industrialization of TCR+ T cells Cost of distribution Number of trials Number of patients Traditional Bio-pharma Next-generation Bio-pharma 1
Slide 33: Thank you
Thank you