Durable remission in pediatric ALL with CAR T-cell therapy

David M. Barrett, MD/PhD Center for Childhood Cancer Research

Children’s Hospital of Philadelphia Perelman School of Medicine

University of Pennsylvania Philadelphia, PA

Disclosures for David M. Barrett, MD, PhD

Royalty N/A

Receipt of intellectual property/ Patent holder

N/A

Consulting fee N/A

Speakers bureau N/A

Fees for non-CME services N/A

Contracted research N/A

Ownership interest (stocks, stock options)

N/A

Other N/A

N/A = Not Applicable (no conflicts listed) Presentation includes discussion of off-label or unapproved use of a drug or medical device

Roadblocks to Successful Cellular Immunotherapy for Cancer

PROBLEM

• Targeting

• Expansion ex vivo

• Expansion in the host

• Persistence

• Effector:Target ratio –

create sufficient effector

cells for clinical success

SOLUTION

• CAR or TCR

• GMP cell culture

• ?Young T cells

• ?Memory T cells

• Need evidence for

efficacy, not just safety,

in phase 1

Abbreviations: CAR, chimeric antigen receptor; GMP, good manufacturing practice; TCR, T-cell receptor

CART19: Chimeric Antigen Receptor T cells against CD19

Redirecting the Specificity of T cells–

Proposed Mechanism of Action of

CTL019 cells

• Gene transfer technology is used to

stably express CARs on T cells,

conferring novel antigen specificity1,2

• CTL019 cells can thus be directed

against any tumor cell that expresses

the CD19 surface antigen

• CTL019 therapy takes advantage of

the cytotoxic potential of T cells

thereby killing tumor cells in an

antigen-dependent manner1,3

• Persistent CTL019 cells consist of

both effector (cytotoxic) and central

memory T cells3

1. Milone MC, et al. Mol Ther. 2009;17:1453-1464.

2. Hollyman D, et al. J Immunother. 2009;32:169-180.

3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73.

T cell

CD19

Native TCR

Tumor cell

CTL019 cell

Dead tumor cell

Anti-CD19 CAR construct

High Rates of Remission Induction in ALL with CTL019

Over 110 patients have been treated with CTL019

(CLL, ALL, NHL)

• Pediatric ALL cohort (N=25): – 22/25 CRs (88%), 3 after blinatumomab

– 6 relapses,

including 2 CD19(-) relapses (1 after blinatumomab)

• All ALL (N=30) (pediatric plus adult):

– 27/30 CRs (90%)

– 7 total relapses

– Short follow-up (median 8 months, range 2-30 months)

Patient Characteristics

Maude SL et al. N Engl J Med 2014;371:1507-1517

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CT

L019

D+1 D+15 D+21

CR No CR

Persistence of

CTL019 cells

>=145 days*

Range 15-512

*many ongoing

28 days

Range 11-45

p<.05

Persistence out to 6-30 months in responding patients

Peripheral Expansion of CTL019 Cells

Maude SL et al. N Engl J Med 2014;371:1507-1517 and unpublished data from Barrett DM

Proliferation and Persistence of CTL019 by QPCR

Maude SL et al. N Engl J Med 2014;371:1507-1517

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Day (post infusion)

0 5 10 15 20 25 30

Cel

ls (

10^3

per

uL

)

0

2

4

6

8

10

time post infusion vs ANC

time post infusion vs ALC

time post infusion vs WBC

steroids

etanercept

tocilizumab

Lymphocyte and Neutrophil Reconstitution in a Refractory ALL Patient after CTL019

Ce

lls (

10

3 p

er

µL)

Grupp SA et al. NEJM 2013;368:1509-1518

Efficient Trafficking of CTL-019 T Cells to CNS in ALL

CSF

Day 23

Blood

Day 10

Grupp SA et al. NEJM 2013;368:1509-1518

Morphology of CARs In Vivo

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Persistence of CTL019 by Flow Cytometry

Maude SL et al. N Engl J Med 2014;371:1507-1517

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B Cell Aplasia in Peripheral Blood

Maude SL et al. N Engl J Med 2014;371:1507-1517

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CTL019 Toxicities

• B cell aplasia

observed in all responding patients to date

managed with IVIg replacement therapy

• Tumor lysis syndrome (TLS)

may be delayed for 20 to 50 days post infusion in CLL

• Cytokine release syndrome (CRS)

reversible, on-target toxicity

Severity related to tumor burden: Treat MRD as outpatient?

• Macrophage activation syndrome (HLH / MAS)

• Neurotoxicity

Significant confusion, aphasia

Occurs in a small number of patients and after CRS

Massive Elevations in IL-6, IFN-γ, IL-2R & GM-CSF After

CTL019 in responding pts

CHP959-117 NR CHP959-118 CR mild CRS CHP959-120 CR severe CRS

Out of range

100

Elevations in IL-6 correlate with CRS*

Any

CR

CR,

Severe CRS

CR,

Mild CRS

IL-6

(pg/mL)

450 4669 23

Abbreviations: CRS, cytokine release syndrome; IL-6, interleukin 6; IFN-γ, interferon-γ; GM-CSF, granulocyte

macrophage colony-stimulating factor

*preliminary analysis

Maude SL et al. N Engl J Med 2014;371:1507-1517 and unpublished data from Barrett DM

Tocilizumab

• 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

• Typically given monthly

• Rare side effects of transaminitis and neutropenia

• We have used 8 mg/kg (4mg/kg possible in <30 kg)

Teachey DT . . . Grupp SA. Blood 2013;121:5154-5157

Blinatumomab Causes HLH/MAS as Well, Reversible With Tocilizumab

Elevated cytokines

• IL-10 (5338 pg/mL)

• IL-6 (681 pg/mL)

• INF-γ (192 pg/mL)

• IL-2R (4872 pg/mL)

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Correlates with severe CRS: serum markers

Maude SL et al. N Engl J Med 2014;371:1507-1517

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Correlates with severe CRS: cytokines

Maude SL et al. N Engl J Med 2014;371:1507-1517

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Correlates with severe CRS: disease burden highly predictive

Maude SL et al. N Engl J Med 2014;371:1507-1517

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Overall Survival after CTL019 infusion

Maude SL et al. N Engl J Med 2014;371:1507-1517

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CHP101– BM MRD Testing

Grupp SA et al. NEJM 2013;368:1509-1518

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CHP101 – CD19 (-) Recurrence

Grupp SA et al. NEJM 2013;368:1509-1518

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What Is the Potential for Immunotherapy?

• Consolidate patients with MRD

• Reinduce remission

• Produce MRD (-) state prior to allo SCT

• Bridge to SCT

• Multicenter trial/s in pediatric ALL

CTL019 Development Plan

• Pediatrics leads the way

• Breakthrough Therapy designation

• First multisite trial now open

and enrolling

• Global ALL trial 2015

• Target for registration

submission: 2016

TCSL

Simon Lacey Jos Melenhorst Yolanda Mahnake Tatiana Mikheeva Kathleen Haines Akhil Kotian Erica Suppa Irina Kulikovskaya Jennifer Wright

CVPF

Bruce Levine Anne Chew Julio Cotto Zoe Zheng Alexey Bersenev

Patients and Families

CHOP Nursing

CTO Lisa Speicher

CHOP StemCell Lab Giuliana Pierson Yongping Wang CHOP Vector Core PA Dept. of Health

ACC Translational Research

Carl June Carmine Carpenito Michael Milone Yangbing Zhao

HUP Noelle Frey David Porter CHOP Study Staff

Christine Strait Margie Tartaglione Trish Hankins Colleen Callahan Center for Childhood Cancer Research John Maris

Stephan Grupp David Teachey Alix Seif Shannon Maude

Acknowledgements