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Gene Modified T CellsOncology Immunotherapeutics-I
Laurence J.N. [email protected]
10-23-201410:30 am to 12:00 pm
Disclosure. Dr. Laurence J. N. Cooper has been a consultant for American Stem Cells, Inc., GE Healthcare, Ferring Pharmaceuticals, Inc., and Bristol-Myers Squibb. Dr. Cooper has received multiple grants from foundations in the state of Texas, including CPRIT and UT STAR, and Federal to support research. Dr. Cooper has received honoraria and payment for the development of education presentations including service on speakers’ bureaus from Miltenyi Biotec. Dr. Cooper has received travel/accommodations expenses covered/reimbursed by Lonza.
Thanks to Dr. George McNamara
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Broadening the clinical appeal of genetically modified T cells
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Torikai H, Moyes JS, Cooper LJN 2014 engineering T cells to target tumor cells. In W. Cai (ed) Engineering in Translational Medicine, Springer-Verlag London 2014.
Tumor-associated antigens targeted by CARs
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Identify tumor-associated antigens
Collaboration with Immatics and XPRESIDENT® Discovery Platform
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LB Alexandrov et al. Nature, 1-7 (2013) doi:10.1038/nature12477
Requires targeting self antigens? Targeting neoantigens possible?
• Boundaries on this slide are arbitrary• Immunogenic neoantigens may be identified by exome sequencing with sufficient probability only on
mutation-rich tumors• Identifying immunogenic self antigens will require a different technology, e.g. mass spectrometry
applicable to all HLA expressing tumors
Targeting tumor-associated antigens
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Broadening the clinical appeal of genetically modified T cells
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GOF Gain of functionLOF Loss of functionDGF Dominant gain of functionDNF Dominant negative form
Approaches to gene transfer
Viral• Retrovirus • Lentivirus
• Enhancer deleted, self inactivating (SIN) long terminal repeat lentivirus vectors. • Adenovirus• AAV• other
Non-viral • DNA (electroporation or other)• Sleeping Beauty (SB11, SB100X)• piggyBac
mRNA• Transient production• Artificial nucleases, transposases, recombinases
TransposasemRNA
Nucleus
Transposon
CAR
Cytoplasm
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Genetic modification of T cells to redirect specificity
Kershaw, Westwood, Darcy Nature Reviews Cancer 13, 525–541 (2013)
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Personalizing the therapy:Manipulating the T cell by harvesting and re-expressing melanoma-
specific TCR
6 OCTOBER 2006 VOL 314 SCIENCE
TCR gene therapy in patients with metastatic melanoma
J Clin Oncol 2011;29:917-9243 (3, 8, 9+)2 (22+, 20+)511humanNYESO1/A2
Blood. 2009;114:535-5462 (4, 3)1 (14+)316mousegp100/A2
Blood. 2009;114:535-5466 (3, 4, 9, 16+, 17+, 17+)
620human high avidityMART-1/A2
Science 2006; 314:126-129 Blood. 2009;114:535-5464431humanMART-1/A2
ReferencePRCRResponsePatient TCRabTarget Antigen
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Torikai, Moyes, Cooper 2014 Engineering T cells to target tumor cells. In W. Cai (ed) Engineering in Translational Medicine, Springer-Verlag London 2014.
Govers et al 2014 J Immunol
CD3ε (epsilon)
not CD3ζ (zeta)
Avoiding TCR miss-pairing
Zhang, Morgan Adv Drug Delivery Rev 2012 64: 756–762.Provasi et al., Nat Med. 2012 May;18(5):807-15. Torikai et al., Blood. 2012 Jun 14;119(24):5697-705.
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Identification of target antigens and TCRs for CD8+ T cells
Siewert et al., Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides. Nat Med. 2012.
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Outcomes and toxicities infusing CD19-specific CAR+ T cells
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NucleasesCRISPR/Cas9MeganucleasesTALENsZFNs
Recombinases / TransposasesAdenovirusCreSB11, SB100X piggyBac
ActivationsgRNA:dCas9-TFTALEZFP-TF
site specific integration by HR, mutations by NHEJ.clustered regularly interspaced short palindromic repeat (RNA)/ Cas9I-CreI meganucleases derived from self-splicing introns/inteinsTAL Effector NucleasesZinc Finger Nucleases
Adenovirus delivery of TALENs+DNA with protein capped ends (Holkers 2014)Cre recombinaseSleeping Beauty transposase (2 of various versions), random AT sitespiggyBac transposases (various versions), random AATT sites
Synthetic guide RNA:disabled Cas9 nuclease-Transcription FactorTranscription Activator like-EffectorZinc Finger Protein-Transcription Factor
Alternative functional domains include: Paired Nickases (increase selectivity for double stranded breaks), recombinases, repressors, epigenomic modifiers (DNA methyltransferases, histone acetylases or deacetylases, etc), fluorescent proteins (SUNtags, TALEcolor, TALE-Lights).NHEJ: Non-homologous end joining (& micro-homologous recombination).HR: Homologous recombination.Select companies in this field are highlighted later.
Approaches to gene editing, genome engineering
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Artificial nucleases
http://www.toolgen.com/html/eng/technology/engineered_nucleases.php
Hard
Easy
Clinical
Research
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Adenosine
A2AR (drug or delete gene)
BCM: “Rewire”: TGFβRex-TLR4in co-stimulationArginaseand iNOSdeplete Arg, iNOS generatesH2O2
TILs, CAR or Delete
HypoxiaHigh adenosine, H2O2, lactate, PGE2, TGFβArg, Trp depletion
Tumor
Adapted from: Gattinoni, Klebanoff, Restifo 2012 Nat Rev Cancer 12: 671-684
Cellular substrates
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CAR designscFv • affinity • Other binders … ex. D-CAR based on Dectin-1
(Kumarasen et al. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5. )
Stalk• Which stalk … Ig vs. CD8 vs. short• Length of hinge+ stalk for proximal vs. distal
epitopes• Reduce FcR bindingSignaling domains• Signal 1, 2, 3
Jena et al. Curr Hematol Malig Rep. 2014 Mar;9(1):50-6.
CAR designs
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2nd: inhibitory costimulation modulatory ligands-> signal(s) K = kinase docking sites P = phosphorylation sites Other sites possible (ITAMs, ITIMS …)Abate-Daga, et al., Oncoimmunology. 2014 Jun 18;3:e29194.
Combinatorial CARs
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Conditional ablation of T cells
Casucci, Bondanza 2011 J of Cancer
HSV-tk: phosphorylates pro-drug ganciclovir, that is then incorporated into DNA.HSV-tk can be immunogenic
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• CD3 with CD28 beads (Novartis)• CD3 and CD28 beads (TransACT, Miltenyi Biotec)• Activating and propagating cells (AaPC),
• many variations … different outputs
Forget et al. 2014 J Immunother 37: 448-460.
Approaches to propagation of genetically modified T cells
Huls et al., J Vis Exp. 2013 Feb 1;(72):e50070. doi: 10.3791/50070.
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Gattinoni, Klebanoff, Restifo 2012 Nat Rev Cancer 12: 671-684.
T-cell subpopulations for genetic engineering
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Lymphocyte populations for engineering
* mbIL-21 AaPC
CD16 T cells Deniger, … Cooper 2014 Clin Cancer Res
T cells Kudo, … Campana 2014 Cancer ResNK cells Chu, ... Yu, Hofmeister 2014 Leukemia NK cells* Denman, ... Cooper, Lee 2012 PLoS OneNKT cells Heczey, ... Metelitsa 2014 Blood
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Broadening the clinical appeal of genetically modified T cells
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Approaches to manufacture and distribution of engineered T cells
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T cells are rendered as a drug
Insert CAR or TCR
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CAR
Patient
CD19
Intended response
B-cell leukemia/lymphomaHLAs
TCRαβ
Normal cells
HLAs
Unwanted response
Recognize “non-self” (Donor →Patient)
GVHD
Gene insertion:Retrovirus/lentivirus
Sleeping BeautymRNA
Artificial nuclease
Eliminating TCR on CAR+ T cells
Blood. 2013 Aug 22;122(8):1341-9Blood. 2012 Jun 14;119(24):5697-705 Cellectis/Pfizer
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Summary
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Inter- and intra-tumor heterogeneity
Infuse T cells with one or more specificityPersonalized for the patient and the disease
“N=1” trial paradigm 27
T cells are precision tools
CAR+ T cells
CAR+ T cells
CAR+ T cells
CAR+ T cells
CAR+ T cells
TCR+ T cells
TCR+ T cells
TCR+ T cells
TCR+ T cells
TCR+ T cells
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Power-law curveThe teaching of Beyoncé
Cost of distribution
Num
ber o
f pur
chas
es
Number of artists
Brick & Mortar
iTunes
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Power-law curveThe new industrialization of T cells
Cost of distribution
Number of trials
Num
ber o
f pati
ents
Traditional Med Centers
Immuno-oncology at Med Centers1
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The N=1 approach has been shown for non-genetically modified T cells
Evidence of tumor regression after treatment with a highly pure population of V22+
ERBB2IP mutation–reactive CD4+ T cells.
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COMMERCIALIZATION OF T-CELL THERAPIES
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Cell Immunotherapy of Cancer – Deals 2012-2014
LC 10/22/2014. Data from Sheridan 2013, 2014 Nat Biotechnol; Herper 2014 Forbes; MDA Strategic Alliances web page; Companies Internet web sites; current news.
Institution Amount Year Emphasis
Adaptimmune $104M 2014 Series A financing, enhanced TCR(s) to cancer specific antigens (NY-ESO-1, …)
Amgen-Micromet $1.16B 2012 Acquisition. BiTES, including Blinatumomab (CD3&CD19 bispecific antibody)
Argos Therapeutics $42M 2013 Dendritic cell personalized kidney cancer vaccine AGS-003
AstroZeneca/MedImmune-Amplimmune $225M* 2013 PD-1 inhibitor AMP-514; preclinical B7 pathway molecules. * up to $275M milestones.
AstroZeneca/MedImmune-MDA 2014 Research – Moon Shot Program’s Immunotherapy platform
Bellicum Pharmaceuticals $69M* 2014 CAR T-cells, iCasp-9 inducible suicide gene switch (2014 series C $55M; 2014 series B $14M)
Bellicum Pharmaceuticals-Ariad $50M 2014 Bellicum worldwide exclusive license to Dimerizer (ex. AP1903) for use in human cell therapies for all diseases.
Bluebird Bio-Celgene $225M* 2013 Chimeric antigen receptor (CAR) T-cells; *up to $225M per product
Bristol-Myers Squibb-Five Prime Ther. $50M* 2014 Two immune checkpoint pathways. * up to $300M milestones
Bristol-Myers Squibb 2014 Nivolumab (anti-PD-1) FDA approval (Ipilimumab, anti-CTLA, was approved in 2011)
Cell Medica $15 2012 CPRIT Commercialization award. EBV+ tumor cells antigen specific T-cells in collaboration with BCM.
GlaxoSmithKline-MDA $335M* 2012 OX40L mimicking mAbs (co-stimulation)
Johnson&Johnson/Janssen Biotech-MDA 2014 Research – Moon Shot Program’s Immunotherapy platform
Jounce Therapeutics $47M 2013 Series A funding. Founders: Allison, Gajewski, Pardoll, Sharma, Weiner
Juno Therapeutics $300M 2013 Chimeric antigen receptor (CAR) T-cells (MSKCC, FHCRC CAR T-cells)
Lion Biotechnologies $23M 2013 Tumor infiltrating lymphocytes (TILs, Rosenberg-NCI). SAB: Hwu, Radvanyi, Yee.
Kite Pharma-NCI/NIH $128M 2014 Rosenberg CAR T-cell therapies (CART’s)
Merck-Ablynx $20M* 2014 Immune checkpoint targeting nanobodies. * plus up to $2.3B royalties
Merck-Pfizer 2014 Collaboration: PD-1 inhibitor pembrolizumab (MK-3475); TKI Inlyta; 4-1BB agonist
Merck-Incyte 2014 Collaboration: PD-1 inhibitor pembrolizumab (MK-3475) plus INCB24360 IDO inhibitor
Novartis-CoStim 2014 Acquisition. Co-stimulatory pathways pipeline
Novartis-Dendreon $43M 2012 Novartis bought cell manufacturing plant (i.e. for UPenn CAR T-cells)
Novartis-UPenn $20M* 2012 Chimeric antigen receptor (CAR) T-cells. * plus milestones and royalties.
Pfizer-Cellectis $110M 2014 CAR T-cells, TALEN genome engineering. * plus up to $2.9B milestones
Pfizer-MDA 2014 Research – Moon Shot Program’s Immunotherapy platform
Pierre Fabre-Aurigene 2014 AUNP-12, 29 amino acid peptide based PD-1 inhibitor (license)
Roche-Immatics $17M* 2013 Access to Immatics proprietary TUMAP peptide vaccines. * plus up to $1B research funding and milestones.
Roche-Inovia $10M* 2013 Two of Inovia’s preclinical therapies. * Plus up to $412M in funding and potential milestones.
UNUM Therapeutics $12M 2014 Series A funding. Founder: Dario Campana. T-cells with CD16 FcReceptors to bind mAbs.