CAR T cells - ER Congressi · 2017-03-01 · Prior transplant history not stated. Dosing Varied...
Transcript of CAR T cells - ER Congressi · 2017-03-01 · Prior transplant history not stated. Dosing Varied...
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Carl June
May 9, 2016
CAR T cells
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Company name
Research
support Employee Consultant Stockholder
Speakers
bureau
Advisory
board Other
Novartis xx IP licensure / Royalty
Tmunity xx
Disclosures of: Carl June
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Topics
• New CAR designs
• CD19 CARs for lymphoma
• BCMA CARs for myeloma
• Combination immunotherapy:
=> CARs meet checkpoints
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Tesniere, et al. Discovery Med (2009) Hannahan and Weinberg. Cell (2000)
Hallmarks of Cancer: Immune Escape and Tolerance
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Lafferty and Cunningham Model of Immunologic Tolerance: 1975
Potential outcomes:
APC
Type #2
Ag/MHC
TcR CoR
Signal 1
TcR CoR
Potential outcomes:
Ag/MHC
Ligand
APC
Type #1
Signal 1 Signal 2
Anergy T cell death
Clonal expansion Effector functions
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Approaches to Overcome Self Tolerance: ACT and Checkpoint Therapies
Checkpoint
Therapies
ACT
Therapies
TILs
CAR T cells TCR T CellsMaus MV et al. Blood. 2014;123:2625.
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Essential factors for augmenting adoptive immunotherapy
Which Lymphocyte
Subset?
Optimize Ex Vivo
Expansion Synthetic Biology:
Genetic Reprogram
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Design of CAR T Cells
Using Synthetic Biology to Overcome Tolerance Creation of Bi-specific CAR T cells
Extracellular
Intracellular
ζ
First Generation
CD4 / CD8z CARs
VH
VLV
L
VHV
H
VLV
L
VH
ζ ζ
First Generation
scFv CARs
VH
VLV
L
VHV
H
VLV
L
VH
Second Generation
scFv BBz CARs
ζ ζ
4-1BB
Finney, 2003
Imai, 2004
Milone, 2009
Carpenito, 2009
CD28
VH
VLV
L
VHV
H
VLV
L
VH
Second Generation
scFv CD28z CARs
ζζ
Roberts, 1995
Finney, 1998
Maher, 2002
CD27
ICOS
VH
VLV
L
VHV
H
VLV
L
VH
Second Generation
scFv CD27z CARs
scFv ICOSz CARs
ζζ
Song, 2012
Guedan, 2014
Duong, 2013
Kuwana, 1987
Eshhar, 1993
Irving & Weiss, 1991
Letourneur, 1991
Romeo, 1991
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Pearce EL, Science 2013
CTLs with limited glucose uptake had a molecular profile characteristic of
memory precursor cells and an increased capacity to enter the memory pool
compared with cells taking up high amounts of glucose Sukumar M et al JCI 2013
Metabolic Features of Natural T cells
Seahorse assay Higher Spare Respiratory Capacity memory T cells
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Oxygen consumption profiles of CAR T cells
Kawalekar et al, Immunity 44: 380, 2016 Days post CD19 stim
Cell s
ize (
fL)
0 4 8 12 16 20 24 280
100
200
300
400
500
600
CD19-28z
CD19-BBz
Cytosolic signaling domain has differential effects on cell volume and oxygen consumption
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Increased mitochondrial biogenesis in 4-1BBζ CAR T cells
CD8+ T cells: confocal microscopy
**** = P<0.0001
Mitochondrial counts
Nu
mb
er
of
mit
oc
ho
nd
ria
pe
r c
ell
Day
7
Day
14
Day
21
0
10
20
30
4028z
BBz
******
Kawalekar et al, Immunity 44: 380, 2016
28ζ
BBζ
Day 14 Day 21
2μmMitotracker
DiI – cell membrane stain
DAPI
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Persistence Central memory pool SRC Mitochondrial biogenesis
Persistence Effector memory pool SRC Mitochondrial biogenesis
Oxidative metabolism
Glycolytic metabolism
CAR-specific
activation
CAR-specific
activation
T cell
BBz CAR
28z CAR
CAR Signaling Domains Program Cells for Metabolic Fitness
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CAR T Cells: they are bionic!
CAR scFv or TCR can reprogram specificity of T cells for tumor target. Specificity is important to avoid toxicity
CAR signaling domains can reprogram T cell metabolism. This can enhance survival in tumor microenvironment and effector function:
•CD28 domains: enhance glycolysis via “Warburg” effect. This leads to enhanced effector function and decreased persistence
•4-1BB domains: enhance mitochondrial biogenesis, and are associated with enhanced persistence
• ICOS domains: enhanced persistence and cellular respiration in CD4 CAR T cells
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CAR T Cell trials: Examples at Penn and Novartis
Clinicaltrials.g
ov
CAR Target Indication
NCT02135406
NCT01626495
NCT02640209
NCT01747486
NCT02135406
UPENN
CHOP
CART19
CLL, ALL, DLBCL, Follicular
Lymphoma, Myeloma
NCT02215967
UPENN CART BCMA Myeloma
NCT02159716
NCT01897415
UPENN
CART Mesothelin Pancreatic cancer, ovarian cancer,
mesothelioma
NCT02465983
UCSF CART
Mesothelin plus
CART19
Pancreatic cancer
NCT01837602
UPENN CART cMet Triple negative breast cancer
NCT02209376
UPENN
UCSF
CART EGFRviii Glioblastoma
Institution CAR Target Indication
UPENN
CHOP
CART19
CLL, ALL, DLBCL, Follicular Lymphoma,
Myeloma
UPENN CART BCMA Myeloma
UPENN CART Mesothelin Pancreatic cancer, ovarian cancer,
mesothelioma
UCSF CART
Mesothelin plus
CART19
Pancreatic cancer
UPENN CART cMet Triple-negative breast cancer
UPENN
UCSF CART EGFRviii Glioblastoma
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Cummulative Patient Safety: Years of Genetically Modified T cells
University of Pennsylvania (as of Dec 2014)
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5-10d
Adult Chronic Leukemia Study Overview*
Porter DL, et al. N Engl J Med. 2011;365(8):725-733
Kalos M, et al. Sci Transl Med. 2011;3:95ra73
Grupp S, et al. N Engl J M ed 2013;368:1509-1518
* ClinicalTrials.gov #NCT01029366
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Circulating CTL019 in CLL: diagnostic challenge!
Bagg, Wasik et al
A
C
B
D
Recognition of CAR T cells can be a challenge
In CLL: CAR T or Richter’s transformation?
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CTL019 Phase I Trial for r/r CLL: 5 yr follow up Summary of patient baseline characteristics
N= 14 patients, protocol 04409 (NCT01029366)
Overall response rate: 57%
CR 4/14 (28%)
PR 4/14 (28%)
NR 6/14 (43%)
Characteristics Statistics, N(%)
N 14
Age at infusion in years
Mean (SD)
Median (range)
66.9 (8.1)
66 (51-78)
Gender
Male
Female
12 (85%)
2 (14%)
Number of prior therapies
Mean (SD)
Median (range)
5.3 (2.8)
5 (1-11)
P53 or 17p deletion
No
Yes
8 (57%)
6 (43%)
IGHV mutation
No
Yes
Unknown
9 (64%)
4 (29%)
1 (7%) Porter et al, Science Trans Med 2015
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Long term persistence and expression of CTL019 in CLL is associated with durable remission
Persistence for first year after infusion
co
pie
s /
mc
gg
DN
A
1e+1
1e+2
1e+3
1e+4
1e+5
1e+6
01-CR
gg
DN
A
1e+1
1e+2
1e+3
1e+4
1e+5
1e+6
03-PR
gg
DN
A
1e+1
1e+2
1e+3
1e+4
1e+5
1e+6
06-NR 07-NR
05-PR
Months (post infusion)
0 2 4 6 8 10 12
25-NR
10 120 2 4 6 8
gg
DN
A
1e+1
1e+2
1e+3
1e+4
1e+5
1e+6
18-NR
Months (post infusion)
02-CR 09-CR 10-CR
12-PR 22-PR
Months (post infusion)
0 2 4 6 8 10 12
17-NR
Months (post infusion)
0 2 4 6 8 10 12
14-NR
co
pie
s /
mc
co
pie
s /
mc
co
pie
s /
mc
Porter et al,
Science Trans Med 2015
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Key CAR-T Results: Pediatric/Young Adult ALL CTL019 (anti-CD19) JCAR017 (anti-CD19) JCAR018 (anti-CD22) KTE-C19 (anti-CD19)
Trial [sponsor] Phase I/IIa, NCT01626495 / CHP959 [Univ of Pennsylvania]
Phase I/II, NCT02028455 / PLAT-02 [Seattle Children’s Hospital]
Phase I, NCT02315612 [National Cancer Institute]
Phase I, NCT01593696 [National Cancer Institute]
Patient population 4-24 yrs*, ≥2nd r/r ALL (N=59), ≥2nd relapse or refractory (majority refractory to multiple prior therapies) [*enrolled adults too; efficacy data here is for pediatric cohort only]
1-26 yrs, r/r ALL (N=37, evaluable N=32); majority (>75%) have had 1 or 2 relapses; ~2/3 have had transplant
7-22 yrs, r/r ALL, (N=9, 7 assessed) all had undergone ≥1 prior alloHSCT and had been previously treated with a CAR-T
4-27 yrs, r/r ALL or NHL (N=46 infused; ALL n=45, DLBCL n=1). Prior transplant history not stated.
Dosing Varied lymphodepleting chemotherapy regimens used.
Target dosing 107-108 cells/kg. Median 4.3x106 cells/kg infused
Varied lymphodepleting strategies used
4 dose levels: 5x105-1x107 cells/kg; MTD 5x106 cells/kg
better risk-benefit profile with much lower 5x105 cells/kg dose
Induction chemotherapy with fludarabine 25 mg/m2 days -4,-3,-2 and cyclophosphamide 900 mg/m2 on day -2
Lowest dose: 3x105 cells/kg (6 pts treated). Next dose: 1x106 cells/kg (3 pts treated)
Initial 21 pts and all w low burden: low-dose chemo: fludarabine (25 mg/m2/day days -4 to -2) and cyc (900 mg/m2 day -2)
High disease burden: high-dose individualized chemotherapy regimen
Dose-finding: 1x106 or 3x106 cells/kg; MTD was 1x106 /kg
Response rate CR 93% (55/59) at 1 month, median f/u 12 mo
CR 91% (21/22) as of Sept 2015 data cut-off; CMR 91% (85% MRD-negative)
(Preliminary data) 2/7 pts had MRD-negative CR (1 at each dose), 2 with SD, 3 with PD, 2 pts too early to assess
CR 60%
Response durability 18 pts in remission >1 yr, 13 without further therapy
Longest CR: 7 mos In the 1 MRD-negative CR pt, sustained at 2 mo (relapsed at 3 mo)
Longest CR 28 mo (in pt with primary refractory ALL) Median LFS 17.7 mo (45.5% probability of LFS at 18 mo), based on 20 pts who achieved MRD-negative CR
Persistence of CAR T cells
Detectable 3 yrs or longer 3 mos In the 1 MRD-negative CR pt, 19% CAR T cells in bone marrow at 2 mo
68 days
Safety sCRS in 27% (8/30) among early (N=30) cohort/ CRS (all grades) 88% of larger pediatrics cohort (N=59). Severe AEs: 43% (13/30) neurotoxicity; self-limiting. 3 CRS-related deaths among adult pts (none among pediatric pts)
CRS 27% (n=22) 18% (n=22) neurotoxicity. No deaths reported
Max CRS was gr 2; no dose-limiting CRS. At lowest CAR-T dose, 1 pt had gr 3 diarrhea. No deaths reported
sCRS 7/46 (15%); grade 3/4 neurotox 3/46 (7%); no permanent neurocognitive decline No deaths reported.
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93% CR rate for r/r ALL after CTL019
• 59 r/r pediatric ALL pts: 55 in CR at 1 mo (93%) median f/u 12 mo
• 6 went to subsequent transplant, 1 to DLI
• 6 mo RFS: 76% (95%ci 65-89%)
12 mo RFS: 55% (95%ci 42-73%)
• No relapses past 1 year
• 18 patients in remission beyond 1 year
>200 patients with CLL, ALL, NHL, MM have gotten CTL019
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Some of Dr Grupp’s Pediatric Leukemia Patients
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White House Visit to UPENN
Vice President Biden: Moonshot Discussions, Feb 2016
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Vatican Conference, April 2016
Convegno internazionale promosso dal pontificio consiglio della cultura
Pope Francis and Nick Wilkins, ALL pt# 15
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Vatican Conference, April 2016
Convegno internazionale promosso dal pontificio consiglio della cultura
Pope Francis and Nick Wilkins, ALL pt# 15
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US sites
• Children’s Hospital of Philadelphia
• Cincinnati Children’s Hospital
• University of Wisconsin
• Children’s Medical Center of
Dallas/UTSW
• Children’s Mercy Kansas University
• Oregon Heath & Science University
• Stanford University
• University of Minnesota
• Children’s Hospital Los Angeles
• University of Michigan
• Duke University
Clinicaltrials.gov NCT02435849
Protocol closed to enrollment
Determine Efficacy and Safety of CTL019 in Pediatric Patients with Relapsed and Refractory B-cell ALL (ELIANA)
Ex- US
(Canada, Australia, EU, Japan)
• Royal Children’s Hospital (Australia)
• Hospital St. Justine (Canada)
• Ghent University (Belgium)
• Oslo Univ. Hospital (Norway)
• Kyoto (Japan)
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CAR T Cell Trials Are Now Global
Clinical trials.gov search term “chimeric antigen receptor”
88 trials ongoing as of December 10, 2015
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Moving beyond leukemia: CAR T for myeloma*
* clinicaltrials.gov
Institution CAR Protocol Title NCT02135406
UPENN
CART19
Pilot Study of Redirected Autologous T Cells Engineered To Contain Anti-
CD19 Attached To TCRζ And 4-1BB Signaling Domains Coupled With
Salvage Autologous Stem-Cell Transplantation (ASCT) In Multiple
Myeloma Patients With Early Relapse/Progression After Initial ASCT
NCT02215967
NCI
CART BCMA A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for
Previously Treated Multiple Myeloma
NCT02546167
UPENN
CART BCMA Pilot Study of Redirected Autologous T Cells Engineered To Contain an
Anti-BCMA scFv Coupled To TCRζ And 4-1BB Signaling Domains in
Patients With Relapsed and/or Refractory Multiple Myeloma
NCT02658929
NCI /
Bluebird Bio
CART BCMA A Phase 1 Study of bb2121 in BCMA-Expressing Multiple Myeloma
NCT01886976
Chinese PLA
General Hospital
CART 138 Clinical Study of Chimeric CD138 Antigen Receptor-modified T Cells in
Relapsed and/or Chemotherapy Refractory Multiple Myelomas
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BCMA (B-cell maturation antigen)
Maus and June, Clin Cancer Res 2013
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CART-BCMA Cells for Multiple Myeloma
clinicaltrials.gov NCT02546167
Pilot, first-in-human, 3+3 dose-escalation study
n=12-18 rel/ref MM patients (≥ 3 priors)
Primary obj: Safety
VH Linker VL CD8a
Hinge and TM 4-1BB CD3z
Signal
seq.
Anti-BCMA scFv
Adam Cohen Michael Milone
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CART-BCMA Cells for Multiple Myeloma
Overall Study Design
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CART-BCMA Cells for Multiple Myeloma
Subject #1
66M, IgG kappa MM dx’d April 2006
• 11 prior lines, progressing on last therapy
• Pre-treatment bone marrow bx: 70% MM cells
- FISH: gain CCND1, del17p, loss of MAF (16q)
- NGS: mutations in NRAS, TP53, TP53
CD45 lambda
kap
pa
CD
38
Pre-treatment marrow
Interim results
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CART-BCMA Cells for Multiple Myeloma
Subject #1
Interim results
2 x 108 CART-BCMA cells
=> no lymphodepletion
Grade 3 CRS responded to tocilizumab
Robust CART-BCMA expansion and persistence: similar to CART19
CD8
BC
MA
-CA
R
Pre-tx Day 7
PB CART cells
PB CART cells
CAR qPCR
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CART-BCMA Cells for Multiple Myeloma: Response
Subject #1
Interim results
Day 28 marrow: negative for myeloma by IHC and flow
Ongoing response (5+ months)
CD45 lambda
kap
pa
CD
38
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Combinatorial Cancer Immunotherapies:
Many possibilities
Vaccines
Cell Based
Therapies
Antibodies
Targeted Small
Molecule
Drugs
Cytokines
Radiation
Chemotherapy
•Chemotherapy
targets the tumor
•Immunotherapy
targets the
immune system
•How to combine?
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CAR T Cells and Checkpoint Antibody Therapies Have Potential Synergism at the Synapse
CAR
T cell
Morales-Kastresana A. Better Performance of CARs Deprived of the PD-1 Brake.
Clin Cancer Res. 2013;19(20):5546-8
Melero et al Evolving synergistic combinations of targeted immunotherapies to
combat cancer. Nature reviews Cancer. 2015;15(8):457-72.
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CAR T Cells and Checkpoint Antibody Therapies: Potential Synergism
CAR
T cell
John LB. Anti-PD-1 antibody therapy potently enhances the eradication of
established tumors by gene-modified T cells. Clin Cancer Res. 2013;19(20):5636-46.
Moon EK. Blockade of Programmed Death 1 Augments the Ability of Human T cells
Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer.
Clin Cancer Res. 2015.
Melero et al Evolving synergistic combinations of targeted immunotherapies to
combat cancer. Nature reviews Cancer. 2015;15(8):457-72.
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Summary and Conclusions
• Signaling domains in CAR T cells can influence persistence and metabolism
• Chimeric antigen receptor modified T cells directed against CD19 (CTL019) can
achieve durable responses in patients with relapsed or refractory CD19+
follicular lymphomas.
- All patients who achieved CR remain in CR.
• Single arm, open-label, multi-center, phase II study of efficacy and safety of
CTL019 in relapsed or refractory follicular lymphoma is planned for 2016.
• Sequential administration of checkpoint antagonists and CAR T cells is feasible,
and preliminary data suggests that this combination has activity
• CD19 and BCMA directed CAR T cells have promise for refractory myeloma
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Colleagues and Patients: Thank you!
PENN Medicine David Porter Noelle Frey Lynn Schuchter Gill Lab Saar Gill Marco Ruella Olga Shestova Lymphoma Team Elise Chong Sunita Nasta Jakub Svoboda Mariusz Wasik Dan Landsburg Anthony Mato Stephen Schuster
Center for Cellular Immunotherapies Anne Chew Regina Young Dana Hammill Katie Marcucci Omkar Kawalekar Avery Posey John Scholler Shannon McGettighan Biliang Hu Anthony Lin Mauro Castellarin Gabriela Plesa
T Cell Engineering Yangbing Zhao Jiangtao Ren Chongyun Fang Xiaojun Liu Shuguang Jiang
Milone Lab Michael Milone Roddy O’Connor Saba Ghassemi Selene Nunez-Cruz Myeloma Team Adam Cohen Al Garfall Michael Milone Ed Stadtmauer
CVPF Bruce Levine Don Siegel Suzette Arostegui Theresa Colligon Clare Taylor Anne Lamontagne Alex Malykhin Matt O’Rourke PDCS Jos Melenhorst Simon Lacey Joseph Fraietta Johnson Lab Laura Johnson Alex Cogdill Alina Boesteanu
CHOP Stephan Grupp David Barrett Shannon Maude David Teachey Novartis Usman Azam Celeste Richardson Jens Hasskarl Reshma Singh Keith Mansfield Jennifer Brogdon Glenn Dranoff