chimeric antigen receptor for hematological malignancies · prof. renato cunha, m.d. - ph.d. bone...
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Chimeric Antigen Receptor for Hematological Malignancies
Prof. Renato Cunha, M.D. - Ph.D.Bone Marrow and Cell Therapy Program - HC-FMRP-USP
Experimental Transplantation and Immunology Laboratory - CTC
Ribeirão Preto Medical School - São Paulo University
São Paulo - SP
August 30th, 2019
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No conflict of interest to disclosure
The views expressed are my own and do not represent the opinion of
The Clinical Hospital and The Center for Cell Therapy of FMRP-USP
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1950 1960 1970 1980 1990 2000 2010 2015
Autologous
BMT
Allogeneic BMT Donor Lymphocyte Infusions
INF-α
Rituximab
(Anti-CD20)
Brentuximab
Vedotin
(Anti-CD30)
Checkpoint Inhibitors
Sipuleucel-T
IL-2
Tumor
Infiltrating
Lymphocytes
Blinatumomab
CAR T
Therapies
Tumor Specificity Increases Over Time
Timeline of Advances in Immunotherapy
Source: E Squared Communications
Courtesy by Sergio Giral
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The Graft-vs.-Tumor Effect and the Graft-vs.-Host Disease
The efficacy versus the adverse effects
Bleakley & Riddell; Nature Reviews Cancer 4, 371-380; 2004
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0,0
0,2
0,4
0,6
0,8
1,0
0 12 24 30 48 60 72
Título do Gráfico
Twins (N = 70)
T depletion (N = 401)
No GVHD (N = 433)
AGVHD only (N = 738)
CGVHD only (N = 127)
AGAVHD + CGVHD (N = 485)
Months
Pro
ba
bil
ity o
f R
ela
ps
eProbability of Relapse After HLA Identical Sibling Transplants for Early Leukemia
Evidence of Graft-vs.-Tumor Effect Supporting Allogeneic HSCT
Goldman JM et al Ann Int Med 108:806-14,1988
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Kolb HJ, et al. Blood. 1995;86(5):2041-2050.
0
50
100
0 1 2 3 4 5 6
Título do Gráfico
Years After Transfusion
% P
rob
ab
ilit
y o
f S
urv
iva
l
CML / PCV N = 80
AML / MDS N = 26
ALL N = 20
Response to DLI in Patients With Recurrent Leukemia After Bone Marrow Transplant
Donor Lymphocyte Infusions Are Associated With Poor Efficacy in ALL
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Graft-versus-host disease
Source: Google Image
Source: Google Image
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Graft-versus-host disease
Source: Google Image
Source: Google Image
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T-cell anergy T-cell activation IL-12
IL-15
IL-2
CD28
4-1BB
OX40
Gutcher I, et al. J Clin Invest. 2007;117(5):1119.
Signal 1 Signal 2 Signal 3
Co-Stimulatory Ligands and Cytokines
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CAR T cell: Background
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Source: mskcc.org
1
2 3
4
CAR-Modified T Cells as Cancer Therapy
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T cell
Viral DNA
Insertion
Tumor cell
Expression of
CAR
CAR T cells
multiply and
release cytokines
Tumor cell apoptosis
CAR enables T cell to
recognize tumor cell antigen
Antigen
Slide created by E Squared - ASBMT
CAR T Cells: Mechanism of Action
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© 1996 Mike Clark
© 1994 Mike Clark
Fab rotation
Fc wagging
Fab elbow bend
VHCγ1
CL
VL
Cγ2
Cγ3
Fab arm waving
The antibody molecule
The IgG Molecule
The Structure of Antibodies
Courtesy: Michael Bishop
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Miller JF, Sadelain M. Cancer Cell. 2015;27(4):439-449.
CAR heavy and light chain chains are components of the B-cell
receptor
CARs integrate key components of intracellular TCR signaling and co-stimulatory
domains
ANTIGEN SPECIFICITY SIGNAL TRANSDUCTION / ACTIVATION
B Cell
T Cell
Tumor
Cell
CD28
CD3
TCR
CD3
scFv
CD28
CD3ζ
ε δ εγ
α β
CD3ζ
Chimeric Antigen Receptor Design
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15Sadelain M. J Clin Invest. 2015;125(9):3392-3400.
Variety of Anti-CD19 CAR T Constructs
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Time ~1 - 2 months
CA
R T
Cell #
Time 6 - 12 months
CAR.28.Z CAR.BB.Z
Both CD28-containing and 4-1BB–containing CAR T cells continue to be investigated.
Potential differences between CD28 and 4-1BB may help explain some of the clinical differences
that have been observed, including differences in the clinical course.
Co-Stimulation Plays a Major Role in Modulating T-Cell Expansion and Persistence
Courtesy by David MIklos
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Park J, et al. Discov Med. 2010;9(47):277-288.
Evolution in CAR Design
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• Infused at a single point in time
• HLA-independent antigen recognition, therefore universal
application
• Target antigens may include proteins, carbohydrates and glycolipids
• Active in both CD4+ and CD8+ T cells
• Rapid generation of tumor specific T cells
• Capable of rapid proliferation and persistence
• Minimal risk of GvHD
Advantages of CAR T Therapy
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CAR T Therapies: Manufacturing to Infusion
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1Apheresis
3
4 Infusion
Lymphodepletion
(Manufacturing)
Patients Return Home 2
T
Patient Journey: Manufacturing to Infusion
Source: ASTCT - E Squared Communications
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Generation of GMP-grade 19 -28z retroviral vector
stocks for clinical application
Ex vivo expansion of 19 -28z transduced patient
T cells under GMP conditions on the Wave®
Bioreactor
Cell Therapy and Cell Engineering Facility (CTCEF)
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• Lymphodepletion creates a “favorable” environment for CAR T-cell
expansion and survival in vivo:
- Potentially provides disease control
- Potentially eliminates tumor suppressor cells (Tregs)
- Provides homeostatic cytokines
- Upregulates tumor immunogenicity and reduces immune suppression
Lee DW, et al. Clin Cancer Res. 2012;18:2780-2790.
Lymphodepletion Is Necessary for Expansion of CAR T Cells
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Turtle CJ, et al. Blood. 2015;126:184.
CD4 and CD8 CAR T-cell persistence in NHL patients following infusion of
2 × 107 cells / kg after conditioning with (n = 6) or without (n = 3) fludarabine
Days After CAR T-Cell Infusion Days After CAR T-Cell Infusion
Cy / Flu, n = 6
No Flu, n = 3
CD
8+
EG
FR
t+ C
ell
s / µ
L
CD
4+
EG
FR
t+ C
ell
s / µ
L
1000–
100–
10–
1–
0.1–
0.01–
1000–
100–
10–
1–
0.1–
0.01–
Fludarabine + Cyclophosphamide Increases CAR T-Cell Expansion
Cyclophosphamide + fludarabine is the most commonly used regimen
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CAR T Therapies - Clinical Outcomes
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Clinical Outcomes - General Concepts
• Better clinical outcomes are associated with greater CAR T cell expansion
• CAR T cells persistence may be important for the maintenance of long
term remissions
• Antigen loss can lead to disease relapse
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CAR T Cells: A Living Cell
Cells Expand in Vivo
• Doses are relatively small (0.3 to 9x106 cells/Kg)
• Cells expand over 7 to 14 days
• Cell expansion is associated with:
- Tumor burden
- Clinical effectiveness
- Toxicity
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CAR T Cells Expand in Vivo: anti-CD19 T Cells persist for aproximately 28 day
Percentage of T Cells Expressing CAR
Absolute Number of CAR T Cells
Number of Copies of CAR Gene
Lee DW et al. Lancet 2014
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Great Numbers of Circulating anti-CD19 CAR T cells are Associated with Better Clinical Responses
Lee DW et al. Lancet 2014
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0
25
50
75
100
0 1 2 3 4 5
Título do Gráfico
Fielding A, et al. Blood. 2007;109(3):944-950. Tavernier E, et al. Leukemia. 2007;21:1907-1914.
MRC UKALL2 / ECOG2993 Study (n = 609) LALA-94 Study (n = 421)
Outcome of patients after 1st relapse
5-yr OS: 7%Outcome of patients after 1st relapse
2-yr OS: 11%
5-yr OS: 8%
Time (years)
Pe
rce
nta
ge
2P< 0.00001
Age < 20: 12%
Age 20 - 34: 7%Age 35 - 49: 4%
Age 50+; 3%0,0
0,2
0,4
0,6
0,8
1,0
0,0 1,5 3,0 4,5 6,0 7,5 9,0
Título do Gráfico
Time from Relapse (years)
Su
rviv
al P
rob
ab
ilit
y
[5%]
Poor Prognosis of Relapsed ALL in Adults
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Signaling
Domain
Gene
TransferPopulation CR Rate
Cytokine
Release
Syndrome
Neuro
ToxicitySite / Ref
CD28-
CD3ζ
Gamma-
retrovirus
N = 16 (ALL)
Adults
88% 43% severe 25%
Gr3- 4
MSKCC
Davila et al STM 2014
CD28-
CD3ζGamma-
retrovirusN = 21 (ALL)
Peds & AYA67%
(ITT)76% CRS
(28% severe)
29% NCI
Lee et al Lancet 2015
4-1BB-
CD3ζ
Lentiviral N = 30 (ALL)
25 Peds,
5 Adults
90% 100%
(27% Severe)
43% UPenn / CHOP
Maude et al NEJM 2014
4-1BB-
CD3ζ
Lentiviral N = 30 (ALL)
Adults
93% 83% 50%
severeSeattle
Turtle et al JCI 2016
1. Frey NV, Porter DL. Am J Hematol. 2016;91(1):146-150.
2. Jackson N, et al. Nat Rev Clin Oncol. 2016;13(6):370-383.
Anti-CD19 CAR T Cells Have Dramatic Activity in Relapsed and Refractory ALL
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Anti-CD19 CAR T Cells Have Dramatic Activity in Relapsed and Refractory ALL
Maude et al. NEJM 2018
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KTE-C19 JCAR017
Clinical TrialZUMA-3
NCT02614066
ZUMA-4
NCT02625480NCT01865617
Phase Phase 1 / 2 Phase 1 / 2 Phase 1 / 2
Dose Level
0.5 × 106 CAR T cells / kg
1 × 106 CAR T cells / kg
2 × 106 CAR T cells / kg
1 × 106 CAR T cells / kg
2 × 106 CAR T cells / kg
2 × 105 to 2 × 107 EGFRt+
cells / kg
Conditioning Chemotherapy
Cyclophosphamide (900
mg / m2× 1 day) + fludarabine
(25 mg / m2 / day × 3 days)
Cyclophosphamide (900
mg / m2× 1 day) + fludarabine
(25 mg / m2 / day × 3 days)
Low-dose Cy / Flu or
Cy ± etoposide
Evaluable Patients (N) R / R adult ALL (n = 24)R / R pediatric and adolescent
ALL (N = 7)R / R adult B-ALL (N = 30)
Response Rates CR = 71% CR = 100% CR = 93%
1. Shah BJ, et al. ASH 2017. Abstract 888.
2. Lee DW, et al. ESMO 2017. Abstract 1008PD.
3. Turtle C, et al. J Clin Invest. 2016;126(6):2123-2138.
Additional Anti-CD19 CAR T Therapies in Commercial Development for R / R B-ALL
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Anti-CD22 CAR T Cells
• Phase 1 dose escalation / expansion study currently sponsored by NCI (NCT02315612)
• Patients: children and young adults with relapsed / refractory CD22+ ALL (N = 30)
- 22 patients treated at expansion dose (1 × 106 transduced CAR T cells / kg)
- Prior transplant: N = 18
- Prior anti-CD19 CAR T cells: N = 14
• CR = 76% (16 / 21 patients evaluable for response)
Shah NN, et al. ASH 2017. Abstract 809.
CAR T Therapy for CD19-Negative R / R B-ALL
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• SCHOLAR-1, a retrospective, international, patient-level, multi-institution study and the largest reported analysis of outcomes in patients with refractory large B-cell lymphoma, demonstrated that these patients have a very poor prognosis1
- N = 636 (post-rituximab era, 2000 - 2017)
- ORR = 26%
- CR rate = 7%
- Median OS = 6.3 months
- These results provided a benchmark for evaluation of new approaches
CR, complete response; ORR, objective response rate; OS, overall survival.
1. Crump M, et al. Blood. 2017;130:1800-1808.
2. Neelapu SS, et al. Ann Oncol. 2017;28(suppl 5):v403-v427. Abstract 1161P.
3. Neelapu SS, et al. ASH 2017. Abstract 579.
OVERALL SURVIVAL
SCHOLAR-1 (Retrospective Non-Hodgkin Lymphoma Research)
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Long Term Follow-up Diffuse Large B-Cell Lymphoma Patients treated with CD19-CAR T Cells
TisagenlecleucelSchuster SJ et al. NEJM 2019
AxicabtageneLocke F et al. Lancet Onc 2019
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CD19 CAR T Cells for Chronic Lymphocytic Leukemia (n=14): ORR=57% CR=29%
Porter DL et al. Sci Translation Medicine 2015
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CD19 CAR T Cells for Chronic Lymphocytic Leukemia (n=14): ORR=57% CR=29%
Porter DL et al. Sci Translation Medicine 2015
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bb2121 CART-BCMA LCAR-B38M CAR-BCMA KTE-585
Clinical TrialNCT02658929
(CRB-401 study)NCT02546167 NCT03090659 NCT02215967 NCT03318861
Phase Phase 1 Phase 1 Phase 1 / 2 Phase 1 Phase 1
Dose Level
Dose escalation:
50, 150, 450, 800, and
1,200 × 106 CAR T cells
Cohort 1: 1 - 5 × 108 CAR T cells
alone
Cohort 2: Cy + 1 - 5 × 107 CAR T
cells
Cohort 3: Cy + 1 - 5 × 108 CAR T
cells
0.17 or 1.05 × 106 CAR T
cells / kg
4 dose levels, 0.3 × 106,
1 × 106, 3 × 106, and 9 × 106
CAR+ T cells / kg
Dose escalation
Infusion Single infusion
Split-dose infusions (10% on
day 0, 30% on day 1, and 60%
on day 2)
Infused on 3 days (d0, d2,
and d6)Single infusion Single infusion
Conditioning
Chemotherapy
Fludarabine (30 mg / m2)
and cyclophosphamide
(300 mg / m2) daily for
3 days
Cohort 2 and 3:
Cy (1.5 g / m2) on day -3
Fludarabine (25 mg / m2) and
cyclophosphamide (250
mg / m2) daily for 3 days
300 mg / m2 of
cyclophosphamide and 30
mg / m2 of fludarabine daily
for 3 days
Fludarabine and
cyclophosphamide for 3 days
Response
RatesORR = 89% (N = 18)
Cohort 1: 6 / 9 patients
responded
Cohort 2: 2 / 5 patients
responded
ORR = 100% (N = 5)Dose level 4: 9 / 11 patients
responded
1. Kochenderfer JN, et al. ASH 2017. Abstract 740.
2. Cohen AD, et al. ASH 2017. Abstract 505.
3. Mi JQ, et al. ASH 2017. Abstract 3115.
4. Brudno J, et al. ASH 2017. Abstract 524.
5. https://clinicaltrials.gov/ct2/show/record/NCT03318861. Accessed March 2018.
Several Anti-B-Cell Maturation Antigen (BCMA) CAR T Therapies Are in Development for Multiple Myeloma
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Anti-BCMA CAR T Cell: 81% ORR ; 63% VGRR
Brudno J et al. JCO 2018
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CAR T-Cell Trials Are Now Global
Clinical trials.gov search term “chimeric antigen receptor”
235 trials ongoing as of May 29, 2019
Clinical TrialsCAR T Therapy Is a Rapidly Growing Technology
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Number of Clinical Trials Targets Currently Being Investigated
Total Phase 1 Phase 2
Lymphoma 105 89 44
B-cell lymphoma 56 47 25 CD19, CD20, CD22, CD30
ALL 43 37 17 CD19, CD22, CD7
CLL 36 30 18 CD19, CD20, CD22
Non-Hodgkin lymphoma 67 58 29 CD19, CD30, CD22, CD20
DLBCL 24 20 14 CD19, CD20, CD22
MCL 16 14 11 CD19, CD20, CD22
FL 15 13 9 CD19, CD20, CD22
Burkitt lymphoma 14 13 5 CD19, CD20, CD22
Hodgkin lymphoma 11 9 3 CD19, CD30, NY-ESO
Leukemia 90 76
B-cell leukemia 36 30 17 CD19, CD5, CD20, CD22, CD30, CD33, CD123, BCMA
AML 12 9 3 CD7, CD33, CD123
MM 13 11 4 CD19, BCMA, CD138, NY-ESO
www.clinicaltrials.gov. Search term “chimeric antigen receptor”. Accessed 5.18.2017
Ongoing CAR Trials in Hematologic Malignancies
www.clinicaltrials.gov. Search term “chimeric antigen receptor.” Accessed May 18, 2017.
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No. of Clinical Trials Targets Currently Being Investigated
Astrocytoma 7 HER2, EGFRvIII, IL13Rα2
Glioblastoma 7 HER2, EGFRvIII, IL13Rα2, NY-ESO
Breast 13 HER2, EpCAM, cMET, Mesothelin, ROR1, MUC1,
CEA, CD70, CD133, NY-ESO
Colorectal 9 CEA, EGFR, MUC1, HER2, CD133,
HCC 11 Glypican-3 (GPC3), MUC1, EPCAM, NY-ESO
NSCLC 5 PD-L1, MUC1, ROR1, CEA, NY-ESO
Melanoma 3 cMET, GD2, CD70, NY-ESO
Mesothelioma 4 FAP, mesothelin
Neuroblastoma 8 GD2, CD171, NY-ESO
Ovarian 7 Mesothelin, CD70, HER2, CD133, CEA, NY-ESO
Pancreatic 13 Mesothelin, Prostate Stem Cell Antigen (PSCA),
CD70, MUC1, HER2, CD133, NY-ESO
Stomach 8 EPCAM, CEA, MUC1, HER2, NY-ESO
Thoracic 5 MUC1, ROR1, PD-L1
www.clinicaltrials.gov. Search term “chimeric antigen receptor.” Accessed May 18, 2017.
Ongoing CAR Trials in Solid Tumors
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CAR T Therapies: Management of the CAR T Patient
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• No significant acute infusional toxicity
• Tumor lysis syndrome
- Rarely occurs; effector cell expansion requires time negating massive tumor lysis
• Cytokine release syndrome (CRS)
- Life-threatening if not managed by expert multidisciplinary team
- May include cardiac events, hepatotoxicity, or renal toxicity
• Neurologic toxicity
- 3 subtypes: acute, delayed, idiosyncratic
• Cytopenias
- Macrophage activation syndrome (MAS) or HLH is a very rare and severe form
• B-cell aplasia and hypogammaglobulinemia
CAR T Therapy: Toxicity
Source: ASTCT - WG discussion - E Squared Communications
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The hallmark presenting sign of CRS is FEVER which occurs shortly after infusion of CAR T cells
Organ System Symptoms and Findings
Constitutional Fever + / – rigors, malaise, fatigue, anorexia, myalgias, arthralgias, nausea, vomiting, headache
Skin Rash
Gastrointestinal Nausea, vomiting, diarrhea
Respiratory Tachypnea, hypoxemia
CardiovascularTachycardia, widened pulse pressure, hypotension, increased cardiac output (early), potentially diminished cardiac
output (late)
Coagulation Elevated D-dimer, hypofibrinogenemia + / – bleeding
Renal Azotemia
Hepatic Transaminitis, hyperbilirubinemia
NeurologicHeadache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations,
tremor, altered gait, seizures
Lee DW, et al. Blood. 2014;124(2):188-195.
CRS: Clinical Signs and Symptoms
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46Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.
CRS Toxicities by Organ System
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47Kochenderfer JN, et al. J Clin Oncol. 2017;35(16):1803-1813.
Anti-CD19 CAR T Cells Release IFN-γ, Granzyme B, IL-10, and TNF-α
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Locke, et al. AACR 2017. Abstract #CT020.
Cytokine Profiles Observed in Patients Treated With CAR T Cells anti-CD 19
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May occur within minutes or hours but generally appears within days or weeks
Coincides with maximal T-cell expansion
CRS
Neurologic events
DAYS 14 2870
CAR T-cell expansion
CAR T-cell infusion
Lee DW, et al. Blood. 2014;124(2):188-195.
Typical Onset and Resolution of CRS and Neurologic Events
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CRS grade correlates with peak IL-6 and IL-2RA levels in patients treated with CTL019
Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139.
IL-6
IL-2
RA
c
Peak Cytokine Levels Correlate With CRS Severity
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Turtle CJ, et al. J Clin Invest. 2016;126(6):2123-2138.
Higher peak IL-6 and IFN-γ levels are observed in
patients requiring ICU care
Elevations of serum C-reactive protein (CRP) and ferritin
correlate with the occurrence of severe CRS requiring ICU
care
c c
Peak Cytokine Levels Correlate With CRS Severity Requiring ICU Care
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Maude SL, et al. N Engl J Med. 2014;371(16):1507-1517.
c c
CRS Severity Correlates With Peak Cytokine Levels and Baseline Disease Burden
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53Kochenderfer JN, et al. J Clin Oncol. 2017;35(16):1803-1813.
c
Peak Cytokine Levels Correlate With Response to Anti-CD19 CAR T Therapy
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• Management of CRS is based on clinical parameters, not laboratory values
- Ferritin, CRP, serum cytokines should only be used to support the diagnosis
• CRS can be fairly well managed with high level of clinical surveillance, fluids,
and vasopressors
- CRS requires continuous monitoring
• The IL-6 receptor antibody tocilizumab is the consensus first line treatment for
CRS
- Not currently recommended for prophylactic use as impact on T-cell expansion and persistence is not known. This is
currently being investigated
• Second line treatment for CRS varies by protocol and / or institutional guidelines
- Steroids are effective for treating CRS, however they are lymphotoxic
- The IL-6 antibody siltuximab stops the production of IL-6 and is currently being investigated
CRS Management
Source: ASTCT - WG discussion - E Squared Communications
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• IL-6 receptor inhibitor
• Blocks IL-6-mediated effects
• Monoclonal antibody with t1/2 ~21 days
• Indicated for the treatment of rheumatologic disorders
• Dosing for CRS management is based on clinical parameters
- Dosing of tocilizumab varies by protocol and / or institutional guidelines
• Most common doses: 4 mg / kg or 8 mg / kg
• Maximum dose: 800 mg
- Timing of second dose of tocilizumab also varies by protocol and / or institutional guidelines
• Range: every 2 to 12 hours
Tocilizumab
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Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.
Response to Tocilizumab
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Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.
Response to Tocilizumab
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• Concurrent with CRS and high fevers
• Result of elevated cytokines
• Common; some degree of neurotoxicity occurs in nearly all CAR T patients
• Symptoms include decreased attention, confusion, disorientation, delirium and ataxia
• Effectively resolved with tocilizumab
Acute
• Occurs within days to weeks; following CRS; often on resolution of CRS
• Range of symptoms: confusion, mental status changes, encephalopathy, seizures, hallucinations, aphasia, and coma
• Generally reversible: typical duration ~3 days
Delayed
• Rare
• Idiosyncratic
• Rapid acute onset
• Requires immediate ICU transfer and intervention with mannitol with or without anti-seizure medications
• May be fatal
Cerebral Edema
Each type of neurological toxicity is likely due to different manifestations of CAR T therapy (different underlying
physiologies), responds to different mechanisms, and has a different likelihood of reversibility
Types of Neurologic Toxicity
Source: ASTCT - WG discussion - E Squared Communications
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ASCTC Consensus - Grading of Neurologic ToxicityEncephalopathy assessment toolsImmune effector cell associated encephalopathy
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61Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.
Toxicity Preventive and Supportive Care Interventions
Tocilizumab • Left ventricular ejection fraction < 40% by echocardiogram;
• Creatinine .2.5-fold higher than the most recent level prior to CAR T-cell infusion;
• Norepinephrine requirement at a dose .2 mg/min for 48 h since the first administration of norepinephrine,
even if administration is not continuous;
• SBP of 90 mm Hg that cannot be maintained with norepinephrine;
• Oxygen requirement of FiO2 .50% or more for more than 2 h continuously;
• Dyspnea that is severe enough to potentially require mechanical ventilation;
• Activated PTT .23 the upper limit of normal; Clinically-significant bleeding; and
Creatine kinase .53 the upper limit of normal for longer than 2 d
Methylprednisolona • CRS toxicity refractory to tocilizumab
Dexamethasona • Grade 3 neurologic toxicities, with the exception of headaches, that last continuously for 24 h or longer;
• Grade 4 neurologic toxicity of any duration; and
• Any generalized seizure
Interventions for Patients Receiving CAR T Cells at the NCI
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• Different antibody variable chain designs
• Different hinge regions and costimulatory domains
• Different viral vectors
• Multiple infusions
• Humanized constructs
• Modifying lymphodepleting or debulking chemotherapy
• Modifying cellular composition
The FuturePotential Modifications to CAR T Therapy
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CAR T Initiatives:
Center for Cell-based Therapy
Ribeirão Preto Medical School - São Paulo University
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Universidade de São Paulo
Faculdade de Medicina de Ribeirão Preto
Departamento de Clínica Médica
Divisão de Hematologia
Unidade de TMOFundação Hemocentro
Centro de Terapia Celular
Estudos Clínicos
Br-CART-Paltform
Pesquisa Translacional
Equipe Multiprofissional
Experimental Transplantation and Immunology Branch,
NCI, NIH
“benchmarking”
National Gene Vector Biorepository, NIH
CAR T-cell anti-leucemia
CAR T-cell anti-linfoma
CAR T-cell anti-mieloma
CAR T-cell anti-CD19
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CTC - Ribeirão Preto & ETIB - NCI/NIH
Objetivo:
• Estabelecer a primeira plataforma de produção e uso terapêutico de Células T que expressam receptor de antígeno quimérico (CAR T-cell) Br-CART-Platform
• A Br-CART-Platform desenvolverá alvos terapêuticos direcionados para:
Leucemias agudas
Mieloma múltiplo
Linfomas
• Transferência de tecnologia (ETIB-NCI/NIH CTC-RP) para a produção e desenvolvimento de toda a linha de
produção:
Aquisição de novos clones para expressão do receptor quimérico
Desenho dos plasmídeos
Produção dos ventores lentivirais
Validação in vitro e in vivo (camundongos)
• Complementar ao projeto em desenvolvimento pelo CTC com o antígeno CD19
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Acknowledgements
Bone Marrow Transplantation Unit
Thalita Costa
Fabiano Pieroni
Ana Stracieri
Daniela Moraes
Juliana Bernades
Maria Carolina Oliveira
Belinda Simões
Center for Cell-based Therapy
Diego Clé
Virginia Castro
Elaine Soares
Maristela Delgado
Samia Caruso
Taisa Fernandes
Amanda Mizukami
Lucas Souza
Rodrigo Calado
Dimas Covas