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CHIMERIC ANTIGEN RECEPTORS FOR ACUTE LEUKEMIA
David M.Barrett, MD, PhD
2
Disclosures• None
Overview of AntiCD19 CAR Constructs
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4-1BB:• Enhances early expansion and long-term
persistence in vitro1,2
• Induces central memory T-cell differentiation for enduring protection and immunosurveillance in vitro1
• Metabolic profile supports gradual sustained expansion (oxidative metabolism)
CD28:• Involved in early and rapid expansion
with limited long-term persistence in vitro2
• Correlated with effector memory T-cell differentiation known to provide immediate protection in vitro1
• Metabolic profile supports rapid expansion (glycolytic metabolism)
2nd generation CARs 3rd generation CAR1
(in current trials) First-generation CARs lacked a costimulatory domain and often did not elicit antitumor effects1
Anti-CD19
Antigen-Binding Domain (scFv)
Hinge and Transmembrane
Intracellular Signaling Domain(s)
CD3-ζ
CD28/4-1BB:• The impact of 4-1BB/CD28
combined costimulatory domains on expansion, persistence, and central memory is being investigated1
CD28
CD3-ζ
Anti-CD19
4-1BB/CD28
CD3-ζ
Anti-CD19
4-1BB
CD3-ζ
Anti-CD19
1. Kawalekar OU et al. Immunity. 2016;44(2):380-390. 2. Milone MC et al. Mol Ther. 2009;17(8):1453-1464.
This information is based on animal model data. No head-to-head comparisons of the clinical efficacy of these costimulatory domains have been conducted.
The Life Cycle of Cell Therapy
Annu Rev Med. 2014;65:333-47. doi: 10.1146/annurev-med-060512-150254
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ELIANA: Pivotal Phase 2 Study
• Tisagenlecleucel (CTL019) produced at a central manufacturing site with global distribution
• 25 sites across 11 countries in North America, Europe, and Asia-Pacific
Manufacturing sites
* *
*
ELIANA was the first global, multicenter trial of CAR T cell therapy in pediatrics
Maude et al. NEJM 2018Updated ASH 2018
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Patients With No MRD Detected in D28 Bone Marrow by NGS Had Superior Outcomes
ASH 207
1.0
0.8
0.6
Prob
abili
ty
0.4
0.2
0
0 90 180 270 360 450Time (days)
540 630 720
P = 0.00026
ELIANA/ENSIGNDOR in CR Patients (n = 50)
810 900
1.0
0.8
0.6
Prob
abili
ty
0.4
0.2
0
0 90 180 270 360 450Time (days)
540 630 720
P = 0.00039NGS MRD=0NGS MRD>0
D28 MRD StatusNGS MRD=0NGS MRD>0
D28 MRD Status
ELIANA/ENSIGNOS in CR Patients (n = 50)
810 900 990
a Tisagenlecleucel infusion at Day = 1. CR, complete remission; DOR, duration of response; MRD, minimal residual disease; NGS, next-generation sequencing.
a a
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Overall Safety and AEs of Special Interest Within 8 Weeks After Infusion
• Majority of AEs occurred in the first 8 weeks after tisagenlecleucel infusion
• No cases of cerebral edema reported
ASH 2018
Patients(N = 79)
AESIa All Grades, % Grade 3, % Grade 4, %Cytokine release syndromeb 77 22 27Infections 43 20 4Cytopenias not resolved by day 28 42 18 18Neurological events 39 13 0Tumor lysis syndrome 5 5 0
a Occurring within 8 weeks of tisagenlecleucel infusion. b Cytokine release syndrome was graded using the Penn scale.AESI, adverse events of special interest.
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N Engl J Med. 2018 Feb 1;378(5):449-459.
Yescarta
Nat Med. 2018 Jan;24(1):20-28
11Blood. 2019 Apr 11;133(15):1652-1663
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J Clin Invest. 2019 Mar 12;130. pii: 125423. doi:10.1172/JCI125423.
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Phase 1 Study of CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia (ALL)Liora M Schultz, Kara L. Davis, Christina Baggott, Christie Chaudry, Anne CunniffeMarcy, Sharon Mavroukakis, Bita Sahaf, Katherine A Kong, Lori S Muffly, Stephen Kim, Everett H Meyer, Terry J. Fry, Haiying Qin, David B. Miklos and Crystal L. Mackall
Blood 2018 132
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Early Clinical Experience of CD19 x CD22 Dual Specific CAR T Cells for Enhanced Anti-Leukemic Targeting of Acute Lymphoblastic LeukemiaRebecca Gardner, Colleen Annesley, Olivia Finney, Corinne Summers, Adam J. Lamble, Julie Rivers, Kaelin Crews, Lauren Huang, Christopher Brown, Stephanie Mgebroff, Catherine Lindgren, Karen Spratt, Josh Gustafson, Adam Johnson, Julie R. Park and Michael C. Jensen
• T cells are transduced with two separate lentiviral vectors that direct the expression of a CD19-specific FMC63/4-1BB CAR and a CD22-specific m971/4-1BB CAR creating three distinct populations of CAR T cells (anti-CD19, anti-CD22, and anti-CD19x 22).
• A CR was achieved in 5/7 (71%) subjects by day 21, 4 of which were MRD negative
Blood 2018 132:278
16
Simultaneous Targeting of CD19 and CD22: Phase I Study of AUTO3, a BicistronicChimeric Antigen Receptor (CAR) T-Cell Therapy, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia StudyPersis J Amrolia, Robert Wynn, Rachael Hough, Ajay Vora, Denise Bonney, Paul Veys, Kanchan Rao, Robert Chiesa, Muhammad Al-Hajj, Shaun P Cordoba, Shimobi Onuoha, Ekaterini Kotsopoulou, Nushmia Z Khokhar, Martin Pule and Vijay G R Peddareddigari
Blood 2018 132:279
• 6/8 patients achieved MRD negative CR at 1 month. • In patients treated at doses <3 x 106/kg, 3 responded but subsequently relapsed. • No loss of CD19 or CD22 was noted in patients that relapsed. • All 4 patients treated at the higher dose of 3 × 106 CAR T cells/kg had an MRD
negative CR with ongoing remission and B-cell aplasia, with the longest follow up of 4 months
Preliminary Data on Safety, Cellular Kinetics and Anti-Leukemic Activity of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a Pool of Adult and Pediatric Patients with High-Risk CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic LeukemiaReuben Benjamin, Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Oana Ciocarlie, Nitin Jain, Elias J. Jabbour, Marcela V. Maus, Matthiew Frigault, Nicolas Boissel, Jerome Larghero, Andre Baruchel, Mohamad Mohty, Barbara De Moerloose, Adrian Bloor, Noelle V. Frey, Amina Zinaï, Svetlana Balandraud, Anne Philippe, Sylvain Fouliard, Ludiane Gauthier, Jeanne Pauly, Cyril Konto, Candy Bermingham, Paul Veys and WaseemQasim
• 88% of evaluable pts (14/16) achieved CR or CRi by D42 • 86% (12/14) of these pts were MRD negative by flow • Among 12 pts achieving MRD-, 5 pts remain in molecular remission 4.5 to 16.4
months post UCART19. In total, 11 pts underwent allo-SCT
Blood 2018 132:896
Universal CAR - Cellectis
18
19
Teachey, et al., Cancer Discov, 2016
Macrophage Activation Syndrome may be a final common pathway for CRS
Cytokines other than IL-6 predict CRSCombined Cohort: spg130+IFNg+IL1RA
Specificity
Sens
itivi
ty0.
00.
20.
40.
60.
81.
0
1.0 0.8 0.6 0.4 0.2 0.0
AUC=.93
PPV=.75,NPV=.94Sens=12/14=.86Spec=31/35=.89
*
Pediatric cohort: IFNg+IL13+MIP1a
Specificity
Sens
itivi
ty0.
00.
20.
40.
60.
81.
0
1.0 0.8 0.6 0.4 0.2 0.0
AUC=.98
PPV=.92,NPV=1Sens=11/11=1
Spec=26/27=.96
*
Full cohort (adults+peds)sgp130+IFNg+IL1RA
Pediatric cohortIFNg+IL13+MIP1a
Teachey et al., Cancer Discovery, 2016
21
CRS definition (ASTCT consensus)• CRS: “a supraphysiologic response following the activation or engagement of ...T
cells for therapeutic intent. Symptoms can be § “Progressive”§ “must include fever at the onset”§ “may include hypotension, capillary leak (hypoxia) and end organ dysfunction”
• CRS should be applied to any T-cell activating/engaging therapy, not just CAR T cells
• As new, effective immunotherapies (non-T cell) are developed, the definition may need to be altered.
22
Tocilizumab aka “toci”
• IL-6 receptor antagonist• Blocks IL-6 mediated effects
• Indicated in:§ juvenile idiopathic arthritis (JIA)§ Rheumatoid arthritis (RA)§ In Japan, indication for Castleman’s Disease
• Given once or twice
• Rare side effects of transaminitis and neutropenia
• Now approved for CRS treatment
Grupp et al, NEJM 2013
23
Neurotoxicity ()§Seen across CD19 immunotherapy trials with CAR T
cells (NCI, CHOP/UPENN, MSKCC, Seattle) as well as blinatumomab
§Delirium, confusion, encephalopathy, rare seizures§ In our experience: generally untreated, fully resolves§No cerebral edema seen in tisagenlecleucel studies § Cerebral edema is a major toxicity seen in some trials
– may be highly product and disease specific
24
Mechanisms of Relapse
CD19+ relapse due to short persistence
T-cell intrinsic?
Immune-mediated rejection?
CD19: relapse due to antigen escape
Is CD19 deleted/mutated/no longer
expressed?
25Br J Haematol. 2019 Feb 27. doi: 10.1111/bjh.15812.
How big a deal is lineage switch?
CD19 negative KMT2A leukemia after 3 years of B cell aplasia
PI:Shannon Maude
AALL1721 Trial Design
MRD ≥1%HR Induction
HR Consolidation
MRD ≥0.01%
Continue protocolChemotherapy
Proceed to CTL019 infusion when available
Leukapheresis
Screen and Enroll
CTL019 Manufacture
Infusion
de novo NCI HR B-ALL
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Opportunities for improvement
• Cost• Manufacturing is first generation. There are HUGE
opportunities for better process –speed, success rates, cost of goods, automation
• Release criteria• We don’t have a potency assay that predicts in vivo
performance
Rapidly Evolving CAR-T Landscape
U Penn ClinicalDavid PorterNoelle FreyElizabeth HexnerCHOP Clinical/Study StaffShannon MaudeColleen CallahanAmanda DinofiaLisa WrayDiane BaniewiczAmy BarryMark DuckworthClaire White Cate GironeLaura Motley Amazing CRC staff
Penn/CHOP Cell TherapyTCSL
Simon LaceyJos MelenhorstMinnal GuptaIrina KulikovskayaJeff Finklestein Farzana NazimuddinVanessa Gonzalez
CVPFBruce LevineDon Siegel
Patients and Families
CHOP Stem Cell LabYongping WangStephan Kaudake
CHOP PICU
Penn/ACC TRP
Carl JuneAnne ChewAmy MarshallWhitney GladneyElizabeth VelosoDana HammillPam Shaw Adaptive TcR
CHOP Cell Therapy LabSteve GruppDavid TeacheyAlix SeifJessica Perazzelli