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Immunogenomic Approaches to More Effective Childhood Cancer Therapies

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Immunogenomic Approaches to More Effective Childhood Cancer Therapies Immunogenomic approaches to more effective childhood cancer therapies Kris Bosse, MD Children’s Hospital of Philadelphia (CHOP) University of Pennsylvania Perelman School of Medicine 1 Many Thanks • CHOP/Penn – John Maris – Samantha Buongervino – Maria Lane – Sharon Diskin – Hakon Hakonarson – Kate Krytska – Ben Garcia – Bruce Pawel – Dan Martinez – Dimitri Monos • SBF-Su2C and Moonshot Projects – And many others • UCSC • PPTC Investigators – Crystal Mackall and Kara Davis – David Haussler – Malcolm Smith – Paul Sondel and Ken DeSantes – Sofie Salama • Funding sources for presented – Poul Sorensen and Kirk Schultz – Nikolaos Sgourakis work – Dimiter Dimitrov and Dontcho Jelev – Nabil Ahmed and Will Parsons – NIH, SU2C, St. Baldrick’s, – Mike Jensen and Julie Park • U of Tubingen ALSF, Evan Foundation, – Michael Taylor, Uri Tabor – Stefan Stevanovic Damon Runyon Cancer – and Daniel Morgenstern – Daniel Kowalewski Research Foundation, – Terry Fry and Lia Gore – Moreno Di Marco Zymeworks, Tmunity 2 – Nirali Shah and Rosie Kaplan Poul Sorensen and Patrick Sullivan (Advocate) Michael Jensen Michael Taylor Paul Sondel Terry Fry Dimiter Dimitrov John Maris (Leader) Crystal Mackall (Co-Leader) Rosie Kaplan Nabil Ahmed 3 Immunogenomics to Create New Therapies for High-Risk Childhood Cancers: Expanding the targetable cell surfaceome Class Cluster of Differentiation CD19, CD22, CD99, CD276 CD24,CD33, CD123, CD44v6 Adhesion and Motility Molecules L1CAM, NCAM1 MCAM, ALCAM, CRLF2 Cell Surface Receptors and IL13RA2 SLC6A2, CHRNA5, TEM8 Transporters Gangliosides GD2, GD3 ECM-interacting proteins MSLN, MUC1 STEAP1, CAMKV, PAPPA, DLL3, DLK1 Proteoglycans CSPG4, GPC2 Receptor Tyrosine ERBB2, ALK, FGFR4, ROR1 MET, FLT3 Kinases Peptides (oncogenic NBL peptides fusions, etc.) HLA-A2 L1CAM, L1 cell adhesion molecule; NCAM1, neural cell adhesion molecule 1; MCAM, melanoma cell adhesion molecule; ALCAM, activated leukocyte cell adhesion molecule; CRLF2, cytokine receptor like factor 2; IL13RA2, interleukin 13 receptor subunit alpha 2; SLC6A2, solute carrier family 6 member 2; CHRNA5, cholinergic receptor nicotinic alpha 5 subunit; TEM8, tumor endothelial marker 8; GD2, GD2 ganglioside; GD3, GD3 ganglioside; MSLN, mesothelin; MUC1, mucin 1 cell surface associated; STEAP1, six transmembrane epithelial antigen of the prostate 1; CAMKV, CaM kinase like vesicle associated; DLL3, delta like canonical notch ligand 3; DLK1, delta like non-canonical notch ligand; PAPPA, pappalysin 1; CSPG4, chrondroitin sulfate proteoglycan 4; GPC2, glypican 2; ERRB2, Erb-B2 receptor tyrosine kinase 2; ALK, anaplastic lymphoma kinase; FGFR4, fibroblast growth factor receptor 4; ROR1, receptor tyrosine kinase like orphan receptor 1; MET, MET proto-oncogene receptor tyrosine kinase; FLT3, Fms related tyrosine kinase 3; NBL, neuroblastoma 4 Cure rates for childhood cancers have improved dramatically in the latter decades of the last century, but….. • Treatments are toxic and survivors have life-long disabilities • Cure rates not improving any longer • Relapsed pediatric cancer is lethal ALL-HR ALL post-SCT AML NHL 1,0 ,8 ,6 ,4 probability of overall survival overall of probability ,2 0,0 0 2 4 6 8 10 years post relapse diagnosis Brain Tumors Ewing Sarcoma Osteosarcoma Rhabdomyosarcoma Neuroblastoma 5 ALL-HR, high-risk acute lymphocytic leukemia; ALL post-SCT, acute lymphocytic leukemia post-stem cell transplant; Courtesy of Dr. Stefan Pfister, DFKZ, Heidelberg AML, acute myeloid leukemia; NHL, non-hodgkins lymphoma Recent credentialing of pediatric cancer immunotherapies Anti-GD2 monoclonal antibody Anti-CD19 chimeric antigen for neuroblastoma receptor (CAR) T cells for ALL Yu, NEJM 2010 Maude, NEJM 2015 FDA approved 2015 FDA approved 2017 6 Rationale for a focused pediatric immunotherapy effort Vastly different tumors and hosts • Childhood Cancers • Adult Cancers • Minimal environmental influence • Major environmental influences • Low mutation burdens • High mutation burdens • FDA approved immunotherapies • Majority of FDA approved solely synthetic immunotherapies activate • Host immune system naïve adaptive immunity • Cancer surfaceome reflects • Host immune system exhausted developmental origins • Cancer surfaceome reflects • Lack of targets tissue of origin • Lack of targets 7 Neuroblastoma • Embryonal cancer • Misappropriation of normal sympathetic neurodevelopmental pathways • Median age of diagnosis = 17 months • Important pediatric problem MYCN • 12% of childhood cancer mortality GPC2 ALK LIN28B • Diverse clinical courses • Phenotype defined by tumor genomic alterations (MYCN amplification) 8 Cheung and Dyer, Nat Rev Cancer, 2013 MYCN, MYCN Proto-Oncogene BHLH Transcription Factor High-risk neuroblastoma has a poor prognosis 100 Low-risk • Observation and/or surgery 80 Intermediate-risk • Surgery • Outpatient chemotherapy (2-8 cycles) 60 • Surgery (1 month) 40 • Intensive induction chemotherapy EFS Probability (%) (%) Probability EFS High-risk (6 months) • MIBG therapy (2 months) 20 • Myeloablative chemotherapy with stem cell rescue (Auto-BMT) x 2 (4 months) 0 • Radiation therapy (1 month) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 • GD2 immunotherapy (7 months) Years 9 MIBG, Metaiodobenzylguanidine; BMT, bone marrow transplant Discovery and validation of new pediatric cancer cell surface molecules for immune-based therapies Select for lineage specificity and oncogenic dependency ADC, antibody-drug conjugate; 10 Malone, CF and Stegmaier, K, Cancer Cell 2017 ADCC, antibody-dependent cellular cytotoxicity Identification of GPC2 as a differentially expressed cell surface molecule in high-risk neuroblastoma Tumor Normal tissues 11 Bosse, Cancer Cell, 2017 GPC2 is a cell surface heparan sulfate proteoglycan • Glypicans (1-6) are cell surface signaling co-receptors GPC2 • GPC2 co-receptor unknown • GPC2 locus on chromosome 7q • 7q copy number gain present in majority of MYCNwt high-risk neuroblastomas GAGs • GPC3 being developed by several groups as an immunotherapeutic target in liver cancers GPI anchor Intracellular signaling 12 Kurosawa, N et al. 2001, Mythreye, K et al. 2009, Melo, SA et al. 2015, Grobe, K et al. 2015 GPC2 functions as an oncoprotein *p < 0.0001; **p < 0.001 13 Bosse, Cancer Cell, 2017 GPC2 is a direct MYCN target gene located on chromosome 7q22 *p < 0.05; **p < 0.01; ***p < 0.0001; ns, not significant 14 Bosse, Cancer Cell, 2017 GPC2 is highly expressed on the neuroblastoma stem cell COG-N-421x GD2 CD133 CD117 ABCG2 Stem cell marker GPC2 NPT002x GD2 CD133 CD117 ABCG2 Stem cell marker GPC2 GPC2 15 Development of antibody-based reagents to target GPC2 D3-GPC2-scFv D3-GPC2-PBD *GPC2-expressing neuroblastoma cell line IC50 < 10 pm 16 Dimitrov, UPitt, Bosse, Cancer Cell, 2017 D3-GPC2-PBD causes prolonged tumor regression and progression free- survival in the murine NB-1643 PDX model NB-1643: GPC2Hi, MYCN amplified, ALK mutated, TP53 wild-type 17 Bosse, Cancer Cell, 2017 PDX, patient-derived xenograft; PFS, progression-free survival D3-GPC2-PBD eradicates locally advanced neuroblastoma PDX models COG-N-421x: GPC2Hi , MYCN amplified, ALK wild-type, TP53 wild-type 18 The GPC2-directed D3 Fab binds a conformational epitope 19 Jean-Philippe Julien, Sick Kids Fab, fragment antigen binding; BSA, binding surface area D3-GPC2-PBD binds tumor specific GPC2 epitopes GPC2 FL (62 kDa) 5’ 1 2 3 4 5 6 7 8 9 10 3’ GPC2 -001 Tumor GPC2 Ex5-10 (34 kDa) 5 6 7 8 9 10 Normal GPC2-003 tissue N C 20 Jean-Philippe Julien, Sick Kids GPC2 is highly expressed in many human cancers 21 Cancer cell line encyclopedia (CCLE) data D3-GPC2-PBD potently eradicates the small cell lung cancer (SCLC) H526 xenograft GPC2 ABCG2 CD133 CD44 CD87 Stem cell marker GPC2 22 GPC2 clinical translation • GMP-grade ADC manufacturing ongoing • Parallel trials in neuroblastoma and SCLC planned • CAR T cell companies developing GPC2-directed CARs with plans for Phase 1 trials in 2020-21 • Bispecific GPC2-directed therapeutics being developed • T cell engagers • GPC2 and other neuroblastoma specific cell surface proteins 23 GMP, good manufacturing practice; CAR, chimeric antigen receptor Multi-omics approach to discovering and validating new cell surface molecules for immune-based therapies Surfaceome Generation Prioritization Limited Normal Tissue Expression Validation and Functional Studies Proteomics Samples: Cell lines (n=12), PDX (n=10), • Immunofluorescence (IF) Tumors (n=43) GTeX, Human Proteome, etc. • Flow cytometry • Immunohistochemistry (IHC)* Method: Sucrose gradient Epigenomics ultracentrifugation followed by LC-MS/MS Transcriptomics *Pediatric Cancer and Normal Tissue Microarrays (TMAs) Samples: Cell Line (n=40), Genomics • Genetic manipulation of targets PDX (n=30), • Select for oncogenic dependency Tumors (n=2,242) • Preclinical proof-of-concept Method: RNA-sequencing and microarray LC-MS/MS; liquid chromatography with tandem 24 Amber Weiner Available Drug? mass spectrometry; RNA, ribonucleic acid DLK1 is highly expressed in a subset of high-risk neuroblastomas PDX Model ALK CD276 GPC2 DLK1 L1CAM NCAM1 COG-452 COG-421 COG-415 NB1643 COG-453 COG-519 COG-424 CHLA-79 EBC1 Fly MYCN-Amplified Not Amplified 25 DLK1 expression is driven by a super-enhancer element Identification of a DLK1 super-enhancer in a subset of neuroblastoma cell lines COG-N-415 Be2C SKNAS NB69 6 6 3 5 5 Differential H3K27ac signal at 5 4 4 4 2 3 DLK1 locus in neuroblastoma cell lines 3 3 DLK1 DLK1 2 2 2 1 ) 1 5 1 1 - 0 COG-N-415 0 0 0 150 Kelly Kelly NBLS NB1643 LAN5 6 5 8 5 Be2C 5 4 100 input)(x10 4 NBLS DLK1 6 - 4 3 3 NGP 3 DLK1 4
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