powerpoint presentation...design single-arm, open-label, international, multicenter, phase ii trial...

1/29/2020

1

Updates in Cellular Therapy

Lauren DeRespiris, PharmD, BCOP

Bone Marrow Transplant Clinical Pharmacy Specialist

Memorial Sloan Kettering Cancer Center

New York, NY

Disclosures

• I have no actual or potential conflict of interest in relation to this presentation

• I will discuss off-label use and/or investigational use of CAR T-cell therapy

2

Objectives

• Evaluate updated clinical trial results supporting the use of chimeric antigen receptor (CAR) T-cell therapies in acute lymphoblastic leukemia (ALL) and large B-cell lymphoma (LBCL)

• Discuss the new consensus grading system for cytokine release syndrome (CRS) and neurotoxicity associated with immune effector cell therapies

• Describe the use of CAR T-cell therapies targeting B-cell maturation antigen (BCMA) and in combination with other agents

• Summarize the existing literature, advantages, and disadvantages of donor-derived allogeneic CAR T-cell therapies

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What is CAR T-cell Therapy?

• T-cells genetically engineered to express chimeric antigen receptors (CARs) that recognize specific antigens on tumor cells

• CARs are recombinant receptor constructs composed of an extracellular single-chain variable fragment (scFv) derived from an antibody, a hinge/spacer peptide, and a transmembrane domain, linked to the intracellular T-cell signaling domains of the T-cell receptor

• CARs engage molecular structures without antigen processing by the target cell and independent of major histocompatibility complex (MHC)

• Activation and proliferation results in destruction of malignant cells

• Considered a “living drug”

• Created from patient’s own blood (autologous)

Subklewe M, et al. Transfus Med Hemother. 2019;46:15-24.

Maus MV, et al. Blood. 2014;123:2625-35.

4

CAR T-cell structure

• scFv antigen-recognition domain—Confers antigen specificity

• Transmembrane domain—Anchors the CAR to the cell surface—Connects the extracellular domain to the

intracellular signaling domain

• Costimulatory domain• CD28 or 4-1BB

• Enhances cytokine production

• CD3ζ-derived activation domain—Mediates downstream signaling during T-cell

activation

June CH, et al. N Engl J Med. 2018;379:64-73. 5

From Manufacturing to Infusion

6Frey NV, et al. Am J Hematol. 2016;91:146-50.

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CAR T-cell Therapy in ALL and LBCL

7

FDA Approved CD19 CAR T-Cell Therapies

Kymriah. [Package Insert]. Novartis Pharmaceuticals Co. East Hanover, NJ; 2018.

Yescarta. [Package Insert]. Kite Pharma, Inc. Santa Monica, CA; 2019.8

Tisa-cel(KymriahTM)

Axi-cel(Yescarta®)

FDA approved

indication

Pediatric or young adult

patients up to 25 years old with refractory or in second or later

relapse B-cell ALL

Adult patients with R/R LBCL

after two or more lines of therapy (DLBCL, high grade

BCL, DLBCL arising from

follicular lymphoma)

Adult patients with R/R LBCL after

two or more lines of therapy (DLBCL, PMLBCL, DLBCL arising

from follicular lymphoma)

Construct antiCD19-41BB-CD3ζ antiCD19-CD28-CD3ζ

Viral vector Lentivirus Retrovirus

Dose≤50 kg: 0.2-5 x 106 cells/kg

>50 kg: 0.1-2.5 x 108 cells0.6-6 x 108 cells

2 × 106 cells/kg

Max 2 × 108 cells/kg

LymphodepletionFlu 30 mg/m2 daily x 4 days +

Cy 500 mg/m2 daily x 2 days

Flu 25 mg/m2 + Cy 250 mg/m2

daily x 3 days orBendamustine 90 mg/m2 daily x

2 days

Flu 30 mg/m2 + Cy 500 mg/m2

daily x 3 days

Tisa-cel: tisagenlecleucel | Axi-cel: axicabtagene ciloleucel

PMLBCL: primary mediastinal large B-cell lymphoma

Flu: fludarabine | Cy: cyclophosphamide

R/R: relapsed refractory

ELIANA – Phase II Study

9

TISA-CEL (KYMRIAH™)

Design Single-arm, open-label, international, multicenter, phase II trial

Patients N=75Children and young adults with R/R B-cell ALL (ages 3-21 years old at diagnosis)

Lymphodepleting chemotherapy

Flu 30 mg/m2 daily x 4 doses + Cy 500 mg/m2 daily x 2 doses or

cytarabine 500 mg/m2 daily x 2 days + etoposide 150 mg/m2 daily x 3 days

T-cell dose (median) 3.1 x 106 cells/kg

Primary endpoint Best overall response of complete remission (CR) or CR with incomplete blood count recovery (CRi) within 3 months

Secondary endpoints CR/CRi with undetectable minimal residual disease (MRD), DoR, EFS, OS, cellular kinetics and safety

Maude S, et al. N Engl J Med. 2018;378:439-48.

DoR: duration of responseEFS: event free survival

OS: overall survival

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ELIANA – Phase II Study

10

Safety

CRS (all grades) 77%

Grade 3 21%

Grade 4 25%

Neurotoxicity 40%

Grade 3 13%

Cytopenias not resolved by day 28 37%

Deaths within 30 days

1 cerebral

hemorrhage, 1 relapsed diseaseMaude S, et al. N Engl J Med. 2018;378:439-48.

Efficacy

CR/CRi 81%

6 months 12 months

Relapse free survival (RFS) 80% 59%

EFS 73% 50%

OS 90% 76%

Baseline Characteristics

Median age, years (range) 11 (3-23)

Number of prior lines of therapy, median (range) 3 (1-8)

Prior alloHCT 61%

Disease status

Primary refractory 8%

Chemo-refractory or relapsed

92%

Morphologic blast count in marrow, median

74%

CRS: cytokine release syndrome

HCT: hematopoietic cell

transplantation

Tisa-cel Real World Experience in ALL

• Center for International Blood and Marrow Transplant Research (CIBMTR) data in R/R pediatric or young adult B-cell ALL, N=159

Grupp S, et al. Blood. 2019;134. Abstr 2619. https://ash.confex.com/ash/2019/webprogram/Paper129279.html. Accessed January 1, 2020. 11

6 months


Median age, years (range) 12.6 (0.6-25.9)


Prior alloHCT 32%

Efficacy

CR 88%

DoR 77%

EFS 68%

OS 94%

Safety

CRS, grade ≥3 13.3%

Neurotoxicity, grade ≥3 8.6%

ELIANA vs. Tisa-cel Real World Experience

Maude S, et al. N Engl J Med. 2018;378:439-48.

Grupp S, et al. Blood. 2019;134. Abstr 2619. https://ash.confex.com/ash/2019/webprogram/Paper129279.html. Accessed January 1, 2020. 12

ELIANA ALL Real World Tisa-cel

Patients infused, N= 75 159

Median age, years (range) 11 (3-23) 12.6 (0.6-25.9)

Karnofsky score 90-100, % 66.7 66.7

ORR, % 81 88

CR, % 88 81

Grade ≥3 CRS, % 47 13

Grade ≥3 neurotoxicity, % 13 9

Tocilizumab, % 48 Not reported

Steroids, % Not reported Not reported

CRS Grading scale PENN PENN

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ZUMA-1 – Phase II Study

Neelapu S, et al. N Engl J Med. 2017;377:2531-44.13

DLBCL: diffuse large B-cell lymphomaTFL: transformed follicular lymphoma

AXI-CEL (YESCARTA®)


Patients N=111R/R LBCL, including DLBCL (76%) and PMLBCL (8%) or TFL (16%)


Flu 30 mg/m2 daily + Cy 500 mg/m2 daily days −5, −4, −3

T-cell dose (median) 2×106 cells/kg

Primary endpoint Objective response rate (ORR)

Secondary endpoints DoR, progression-free survival (PFS), OS, incidence of adverse events, and blood levels of CAR T-cells and serum cytokines

ZUMA-1 – Phase II Study

14

Safety (Grade ≥3)

8.7 months 15.4 months

CRS93% (all grades)

13%

No further reports

of CRS

Neurotoxicity, 28%No further reports

of neurologic events;

10 patients with

serious AEs;

8 with infection

Neutropenia 78%

Anemia 66%

Thrombocytopenia 58%

Febrile

neutropenia35%

Neelapu S, et al. N Engl J Med 2017;377:2531-44.

Efficacy

Median follow-up 8.7 months 15.4 months

ORR 82% 82%

CR 54% 58%


Patients infused 101


≥3 prior lines of therapy* 69%

History of primary refractory disease 26%

History of resistance to two consecutive lines

53%

Refractory subgroup at entry:

Primary refractory 2%

Refractory to second-line or subsequent therapy

77%

Relapse after aHCT 21%

aHCT: autologous hematopoietic cell transplantation

*Systemic bridging chemotherapy not allowed after leukapheresis

ZUMA-1 – Updated Analysis

15Locke FL, et al. Lancet Oncol. 2019;20:31-42.

Median DoR: 11.1 months (95% CI 4.2-NE)

ORR: 84/101 (83%) CR: 59/101 (58%)

CI: confidence intervalNE: not estimable

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ZUMA-1 – Updated Analysis

Locke FL, et al. Lancet Oncol. 2019;20:31-42.16

Median PFS : 5.9 months (95% CI 3.3-15.0)

Median OS : Not reached (95% CI 12.8-NE)

Axi-cel Real World Experience in LBCL

• CIBMTR data in R/R LBCL, N=295

Pasquini M, et al. Blood. 2019;134. Abstr 764. https://ashpublications.org/blood/article/134/Supplement_1/764/426967/Post-Marketing-

Use-Outcomes-of-an-Anti-CD19?searchresult=1. Accessed January 1, 2020.17

ECOG: Eastern Cooperative Oncology Group

SD: stable disease | PD: progressive disease



Performance status (ECOG)

1 43%

2 5%

Transformed lymphoma 27%

Chemotherapy resistant 66%

Double/triple hit 36%

Prior aHCT 34%

Efficacy

CR 52%

PR 18%

No response/SD 8%

PD 16%

Safety

CRS 83%

Grade ≥3 10%

Neurotoxicity 61%

ZUMA-1 vs. Axi-cel Real World Experience

Neelapu S, et al. N Engl J Med. 2017;377:2531-44.

Pasquini M, et al. Blood. 2019;134. Abstr 764. https://ashpublications.org/blood/article/134/Supplement_1/764/426967/Post-Marketing-Use-Outcomes-of-an-Anti-

CD19?searchresult=1. Accessed January 1, 2020.

18

ZUMA-1 Real World Axi-cel


Median age, years (range) 58 (23-76) 61 (19-81)

ECOG 0/1, % 100 77

ORR, % 82 70

CR, % 58 52

Grade ≥3 CRS, % 13 14

Grade ≥3 neurotoxicity, % 28 Not reported

Tocilizumab, % 43 70

Steroids, % 27 26

CRS Grading scale LEE ASTCT

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JULIET – Phase II Study

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TISA-CEL (KYMRIAH™)


Patients N=165Adults with R/R DLBCL (79%) or TFL (19%)


Flu 25 mg/m2 + Cy 250 mg/m2 × 3 days (73%) OR Bendamustine 90 mg/m2 × 2 days (19%)

T-cell dose (median) 3.1 x 108 cells

Primary endpoint Best ORR

Secondary endpoints DoR, OS, PFS, safety, cellular kinetics data

Schuster SJ, et al. New Engl J Med. 2019;380:45-56.


Schuster SJ, et al. New Engl J Med. 2019;380:45-56.20


Patients infused 111


Number of prior lines of therapy

2 44%

3 31%

4-6 21%

Bone marrow involvement 7%

Double/triple-hit 27%

Refractory DLBCL 55%

Prior aHCT 49%

Received bridging therapy 92%

Safety

CRS 58%

Grade 3 14%

Grade 4 8%

Neurotoxicity 21%

Grade 3 7%

Grade 4 5%

Infection (Grade ≥3) 20%

Cytopenia not resolved by day 28 (Grade ≥3)

32%

Febrile neutropenia (Grade ≥3) 15%


Schuster SJ, et al. New Engl J Med. 2019;380:45-56. 21

NR: not reached

ORR: 52% (95% CI 41-62)CR: 40%

Median PFS: NR

Median DoR: NR

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Schuster SJ, et al. New Engl J Med. 2019;380:45-56. 22

Median OS: 12 months

Estimated PFS: 83% at 12 months

Tisagenlecleucel Real World Experience in DLBCL

• CIBMTR data in R/R DLBCL, N=70

Jaglowski S, et al. Blood. 2019;134. Abstr 766. https://ashpublications.org/blood/article/134/Supplement_1/766/426985/Tisagenlecleucel-Chimeric-Antigen-Receptor-

CAR-T?searchresult=1. Accessed January 1, 2020.23




Prior aHCT 22.9%

Prior alloHCT 5.7%

Efficacy

Viability

≥80%

(n=23)

Viability

60-80%

(n=21)

ORR 61% 57%

CR 39% 38%

PR 22% 19%

No response/SD 9% 0

PD 30% 33%

Safety

CRS, grade ≥3 4.3%

Neurotoxicity, grade ≥3 4.3%

JULIET vs Tisa-cel Real World Experience

Schuster SJ, et al. New Engl J Med. 2019;380:45-56.

Jaglowski S, et al. Blood. 2019;134. Abstr 766. https://ashpublications.org/blood/article/134/Supplement_1/766/426985/Tisagenlecleucel-Chimeric-Antigen-

Receptor-CAR-T?searchresult=1. Accessed January 1, 2020. 24

JULIET LBCL Real World Tisa-cel


Median age, years (range) 56 (22-76) 65.1 (18.5-88.9)

ECOG 0/1, % 100 81

ORR, % 52 60

CR, % 40 38

Grade ≥3 CRS, % 22 4.3

Grade ≥3 neurotoxicity, % 12 4.3

Tocilizumab, % 14 41

Steroids, % 10 9

CRS Grading scale PENN ASTCT

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TRANSCEND-NHL-001

Abramson J, et al. Blood. 2019; 134. Abstr 241. https://ashpublications.org/blood/article/134/Supplement_1/241/426207/Pivotal-Safety-and-Efficacy-Results-from-

Transcend?searchresult=1. Accessed January 1, 2020. 25

LISOCABTAGENE MARALEUCEL: 4-1BB costimulatory domain, defined ratio of viable CD4+:CD8+ T-cells, truncated human epidermal growth factor receptor (EGFRt)

Design Single-arm, open-label, international, multicenter, phase I trial

Patients N=268Adults with R/R LBCL


Flu + Cy

T-cell dose 50×106, 100×106, or 150×106

Primary endpoint Treatment-emergent adverse events (TEAEs)

ORR

Secondary endpoints CR rate, DOR, PFS, PFS ratio, OS

TRANSCEND-NHL-001

Abramson J, et al. Blood. 2019; 134. Abstr 241.

https://ashpublications.org/blood/article/134/Supplement_1/241/426207/Pivotal-Safety-and-

Efficacy-Results-from-Transcend?searchresult=1. Accessed January 1, 2020. 26

Efficacy

ORR 73%

CR 53%

Median DoR 13.3 months

Median DoR in CR NR

Median PFS 6.8 months

Median OS 19.9 months

Safety

CRS 42%

Grade ≥3 2%

Neurotoxicity 30%

Grade ≥3 10%

Prolonged cytopenia, grade ≥3

37%



≥4 prior lines of therapy 26%

Prior aHCT 34%

Prior alloHCT 3%

Chemo-refractory 67%

Never achieved CR 44%

Received bridging therapy 59%

Audience Response Question #1

The recently presented real world tisa-cel experience in LBCL indicated that CAR T-cells with <80% viability lead to a comparable ORR as CAR T-cells with >80% viability.

A. True

B. False

27

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Toxicities of CAR T-cell Therapy and Management Strategies

28

Toxicities of CAR T-cell Therapy

• No significant acute infusional toxicity

• CRS

• Neurologic toxicity

• Cytopenias

• B-cell aplasia and hypogammaglobulinemia

29Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15:47-62.

CRS

• Most common toxicity of CAR T-cell therapy

• Syndrome resulting from immune activation correlating with CAR T-cell expansion and elevations of serum inflammatory markers and cytokines

—IFNγ, TNFα, IL-2, IL-6, IL-8, IL-10, sgp130, soluble IL-6R, soluble IL-2Rα, GM-CSF, MCP-1

—C-reactive protein (CRP) and ferritin

• May present as non-infectious flu-like syndrome—Fever, malaise, myalgias

• Can progress to life-threatening vasodilatory shock, capillary leak, hypoxia and multi-organ failure

30

Frey N, et al. Biol Blood Marrow Transplant. 2019;25:e123-7.

Teachey DT, et al. Cancer Discov. 2016;6:664-79.

Hay KA, et al. Blood. 2017;130:2295-2306.

IFN: interferon | TNF: tumor necrosis factor

IL: interleukin | sgp: soluble glycoprotein | R: receptor

MCP: monocyte chemoattractant protein

GM-CSF: granulocyte-macrophage colony-stimulating factor

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CRS

• Onset usually within first week after CAR T-cell therapy—Peaks within 1-2 weeks

—Earlier in axi-cel than tisa-cel

• Patients at high risk of severe CRS:—High disease burden

—Higher infused CAR T-cell dose

—Addition of fludarabine to lymphodepletion

• Predictors of severe CRS—Endothelial activation elevations of angiopoietin-2 and von Willebrand factor

31

Frey N, et al. Biol Blood Marrow Transplant. 2019;25:e123-7.

Teachey DT, et al. Cancer Discov. 2016;6:664-79.

Hay KA, et al. Blood. 2017;130:2295-2306.

CRS Grading Systems

32

Lee Criteria Penn Scale MSKCC Criteria CARTOX Criteria

Grade 1 Symptoms are not life threatening and require

symptomatic treatment only (fever, nausea,

fatigue, headache, myalgias, malaise)

Mild reaction: treated with supportive care

(antipyretics, antiemetics)

Mild symptoms requiring

observation or supportive

care only (antipyretics, antiemetics,

pain medication)

Temperature 38°C

Grade 1 organ toxicity

Grade 2 Symptoms require and respond to moderate

intervention:

• Hypoxia: responsive to < 40% oxygen

• Hypotension: responsive to fluids or 1 low-

dose vasopressor

• Grade 2 organ toxicity

Moderate reaction:

• Requires IV therapies or parenteral nutrition

• Some signs of organ dysfunction (i.e., grade

2 Cr or grade 3 LFTs) related to CRS

• Hospitalization for CRS-related symptoms

including fevers with associated neutropenia

• Hypotension requiring vasopressors <24 h

• Hypoxia or dyspnea requiring supplemental

oxygen <40%

• Hypotension responds to IV fluids or low-

dose vasopressor

• Hypoxia requiring FiO2 <40%

• Grade 2 organ toxicity

Grade 3 Symptoms require and respond to aggressive

intervention

• Hypoxia: requires oxygen ≥40%

• Hypotension: requires high-dose or multiple

vasopressors

• Grade 3 organ toxicity or grade 4 LFTs

More severe reaction requiring hospitalization

• Moderate signs of organ dysfunction (grade 4

LFTs or grade 3 Cr) related to CRS

• Hypotension treated with IV fluids or low-

dose pressors

• Coagulopathy requiring FFP or

cryoprecipitate

• Hypoxia requiring supplemental O2 (nasal

cannula oxygen, high-flow O2, CPAP or

BiPAP)

• Hypotension requiring any vasopressors 24 h

• Hypoxia or dyspnea requiring supplemental

oxygen 40%

• Hypotension needing high-dose or multiple

vasopressors

• Hypoxia requiring FiO2 40%

• Grade 3 organ toxicity or grade 4

transaminitis

Grade 4 Life-threatening symptoms

• Requirement for ventilator support

• Grade 4 organ toxicity (excluding

transaminitis)

Life-threatening complications

• Hypotension requiring high-dose pressors

• Hypoxia requiring mechanical ventilation

• Life-threatening symptoms

• Hypotension refractory to high dose

vasopressors

• Hypoxia or dyspnea requiring mechanical

ventilation

• Life-threatening hypotension

• Needing ventilator support

• Grade 4 organ toxicity except grade 4

transaminitis

Lee DW, et al. Blood. 2014;124:188-95.

Porter D, et al. J Hematol Oncol. 2018;11:35.

Park JH, et al. N Engl J Med. 2018;378:449-59

Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15:47-62.

LFT: liver function test

FFP: fresh frozen plasma

CPAP: Continuous Positive Airway Pressure

h: hour

CRS Grading: ASTCT Recommendations

33

CRS Parameter Grade 1 Grade 2 Grade 3 Grade 4

Fever Temperature

≥38◦C

Temperature

≥38◦C

Temperature

≥38◦C

Temperature

≥38◦C

With

Hypotension None Not requiring

vasopressors

Requiring a

vasopressor with or without

vasopressin

Requiring multiple

vasopressors (excluding

vasopressin)

And/or

Hypoxia None Requiring low-flow

nasal cannula

Requiring high-

flow nasal cannula,

facemask,

nonrebreather

mask, or Venturi

mask

Requiring positive

pressure (CPAP, BiPAP, intubation

and

mechanical

ventilation)

Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-38. BiPAP: Bilevel Positive Airway Pressure

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Neurotoxicity

• CAR T-cell-related encephalopathy syndrome (CRES)

• Immune effector cell-associated neurotoxicity syndrome (ICANS)

• Manifestations can vary; waxing and waning of symptoms may occur—Mild to moderate symptoms

• Headache, tremor, mild aphasia, mild movement disorders

—Toxic encephalopathy with preserved alertness is common• Diminished attention, disorientation, confusion, language disturbances

—Severe cases• Focal neurological deficits, generalized tonic/clonic seizures, coma, intracranial hemorrhage,

cerebral edema

Gust J, et al. Cancer Discov. 2017;7:1404-9.

Santomasso BD, et al. Cancer Discov. 2018;8:958-71.

Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-38.34

Neurotoxicity

• Exact mechanism remains to be determined but potential explanations:— Systemic inflammation and cytokine production leads to endothelial activation, coagulopathy, and blood brain barrier (BBB)

dysfunction elevation of CSF cytokines

• Median onset ~4-5 days after CAR T-cell infusion— Often during CRS or after CRS has resolved

• Risk factors— Pre-existing neurologic comorbidities

— Severe CRS

— High disease burden

— Higher infused CAR T-cell dose

— Addition of fludarabine to lymphodepletion

• Predictors of severe neurotoxicity— Earlier and higher fevers

— Higher peak concentrations of CRP and higher early ferritin levels

— High levels of proinflammatory cytokines (IL-2, IL-6, IL-10, IL-15, IFNγ, TNFα)



Rice J, et al. Curr Treat Options Neuro. 2019;21.35

CSF: cerebral spinal fluid

Neurotoxicity Grading: ASTCT Recommendations


ICE: Immune Effector Cell-Associated Encephalopathy

ICP: intracranial pressure

EEG: electroencephalogram

Grade 1

(Mild)

Grade 2

(Moderate)

Grade 3

(Severe)

Grade 4

(Life-threatening)

ICE 7-9 3-6 0-2 Unable to assess

Depressed level of

consciousness

Awakens spontaneously

Awakens to voice

Awakens only to tactile stimulus Patient is unarousable or requires vigorous or repetitive tactile stimuli

to arouse; stupor or coma

Elevated

ICP/cerebral

edema

N/A N/A Focal/local edema on

neuroimaging

Diffuse cerebral edema on

neuroimaging; decerebrate

or decorticate posturing; or cranial

nerve VI palsy; or papilledema; or

Cushing's triad

Seizures N/A N/A Any clinical seizurethat resolves rapidly or

nonconvulsive seizures on EEG

that resolve with intervention

Life-threatening prolonged seizure (>5 min); or repetitive clinical or

electrical seizures without

return to baseline in between

Motor findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis

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ICE Score


Parameter Points

Orientation to:

• Year• Month

• City

• Hospital

4

Naming

• Ability to name 3 objects 3

Attention

• Count backwards from 10 to 1 or from 100 by 10s1

Writing

• Write a standard sentence1

Follow commands

• Ability to follow simple commands1

Total: 10 points

Grade 1: 7-9 (mild), Grade 2: 3-6 (moderate), Grade 3: 0-2 (severe)

Principles of CRS and Neurotoxicity Management



Rice J, et al. Curr Treat Options Neuro. 2019;21.

Hay KA, et al. Blood. 2017;130:2295-2306.38

CRS

• Symptomatic management of mild CRS is universal

• Tocilizumab is the consensus first line treatment for severe CRS

• IL-6R antagonist; therefore may increase IL-6 levels and worsen neurotoxicity?

• Corticosteroids typically reserved for tocilizumab-refractory CRS

• Siltuximab

• Binds directly to IL-6, therefore no risk of increase in IL-6 levels

Neurotoxicity

• Tocilizumab not effective

• Does not penetrate CSF

• May increase IL-6 levels and worsen neurotoxicity

• Corticosteroids consensus first line treatment

• No universal guideline for toxicity management;

protocols vary by institution

• Rates of CRS and neurotoxicity vary between

products, disease states, and patient characteristics

Example CRS and Neurotoxicity Management Algorithm

Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15:47-62. 39

*Dexamethasone 10 mg IV q6h or methylprednisolone 1 mg/kg IV q12h#Methylprednisolone 1 g/day x 3 days followed by a rapid taper

Grade CRS Neurotoxicity CRS + Neurotoxicity

1 Supportive Care Supportive Care Supportive Care

2 Tocilizumab Steroids* Tocilizumab + steroids*

3 Tocilizumab Steroids* Tocilizumab + steroids*

4 Tocilizumab +

high-dose steroids#

ICU/critical care

High-dose steroids#

ICU/critical care

Tocilizumab +

high-dose steroids#

ICU/critical care

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Steroids Do Not Influence CAR T-cell Efficacy and Kinetics

Patients with

B-Cell ALL

Steroids for CRS

N=42

CR 95.2%

MRD (-) CR 80%

No steroids for CRS

N=26

CR 92.3%

MRD (-) CR 79.2%

Liu S, et al. Blood. 2019; 134. Abstr 228. https://ashpublications.org/blood/article/134/Supplement_1/228/426096/Corticosteroids-Do-Not-

Influence-the-Efficacy-and. Accessed January 1, 2020. 40

Grade 3 CRS = 10

Grade 2 CRS = 30

GVHD = 1

Neurotoxicity = 1

p=.344p=.249

Average CAR T-cell counts higher in steroid group: Day 11 (p=0.0302)

Day 15 (p=0.0053)Day 20 (p=0.0045)

Day 30 (p=0.0028)

Except Day 7 when CAR T-

cells began to expand (p=0.9815)

Flu + Cy followed by CAR T-cell infusion

Earlier Steroid Use with Axi-Cel in r/r LBCL

• ZUMA-1 non-randomized safety expansion to evaluate effect of earlier steroid use on rates of CRS and neurotoxicity (Cohort 4)

• Early steroid intervention for Grade 1 CRS and neurotoxicity if no improvement after 3 days of supportive care

• Lymphodepletion: Flu + Cy

• CAR T-cell dose: 2 × 106 cells/kg

Topp M, et al. Blood. 2019;134. Abstr 243. https://ash.confex.com/ash/2019/webprogram/Paper126081.html. Accessed January 1, 2020.41

Baseline Characteristics, n=41


Performance status, ECOG 1 49%

Disease stage III/IV 70%

DLBCL 63%

TFL 24%

PMLBCL 5%

HGBCL 7%

Refractory to ≥ 2nd-line therapy 68%

Relapsed to ≥ 2nd-line therapy 12%

Received ≥ 3 lines of therapy 63%

Relapsed after aHCT 20%

Earlier Steroid Use with Axi-Cel in r/r LBCL

• Median follow up: 8.7 months (range 2.9-13.9)

Topp M, et al. Blood. 2019;134. Abstr 243. https://ash.confex.com/ash/2019/webprogram/Paper126081.html. Accessed January 1, 2020.

Locke FL, et al. Lancet Oncol. 2019;20:31-42.42

Results

Cohort 4 Locke, et al.

ORR 73% 83%

CR 51% 53%

Median PFS 11.3 months 5.9 months

Median DoR 8.9 months 8.1 months

Median OS NR NR

CAR T-cell expansion

59 cells/µL 42 cells/µL

Adverse Events

Cohort 4 Locke, et al

Grade ≥3 CRS 2% 11%

Grade ≥3 neurotoxicity

17% 32%

Management of Adverse Events

Cohort 4 Locke, et al

Steroids 73% 27%

Tocilizumab 76% 43%

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Lenzilumab

• GM-CSF one of many elevated chemokines implicated in the pathogenesis of CRS

• GM-CSF serum levels most significantly associated with the development of grade 3 or 4 neurotoxicity based on correlative studies from ZUMA-1

• Neutralization of GM-CSF is a potential strategy to reduce CRS and neurotoxicity

— Lenzilumab anti-GM-CSF mAb

• GM-CSF blockade improves survival in a mouse model of CRS/NT without impacting efficacy

• Planned phase I/II trial of lenzilumab + axi-cel in R/R DLBCL

Sterner RM, et al. Blood. 2019;133:697-709.43

mAb: monoclonal antibody

Anakinra

• Competitively inhibits IL-1 binding to interleukin-1 type I receptor (IL-1RI)—Blocks the biologic activity of IL-1 alpha and beta

• Macrophage produced IL-1 has been linked with CRS and neurotoxicity

• Mouse model of CAR T-cell–associated CRS and neurotoxicity—Anakinra administration prevented both CRS and neurotoxicity

Norelli M, et al. Nat Med. 2018;24:739-48.44

CAR T-cell Signaling

• CAR T-cell activation involves:—Autophosphorylation of the SRC family kinase lymphocyte-specific protein tyrosine kinase

(LCK)

—LCK-mediated phosphorylation of CD3ζ and ζ-chain of TCR-associated protein kinase 70 kDa(ZAP70)

—Induction of transcription factors such as nuclear factor of activated T-cells (NFAT) and nuclear factor κ light-chain enhancer of activated B cells (NF- κB)

• Interfering with this cascade would control the function of CAR T-cells

Mestermann, K et al. Sci Transl Med. 2019;11:eaau5907.

Weber EW, et al. Blood Adv. 2019;3:711–17.45

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Dasatinib

• Tyrosine kinase inhibitor dasatinib interferes with LCK and inhibits phosphorylation of CD3ζ and ZAP70

• Dasatinib induces a function-off state in CD8+ and CD4+ CAR T-cells —Immediate onset—Can be sustained for several days without affecting T-cell viability

• Halts cytolytic activity, cytokine production, and proliferation of CAR T-cells in vitro and in vivo

• Dose can be titrated to achieve partial or complete inhibition of CAR T-cell function

• Discontinuation leads to rapid and complete reversal of inhibition

Mestermann, K et al. Sci Transl Med. 2019;11:eaau5907.

Weber EW, et al. Blood Adv. 2019;3:711–717.46

Prophylactic Tocilizumab

• Safety expansion cohort added to ZUMA-1

• 8 mg/kg tocilizumab administered on day 2 after axi-cel, n=31

• 3% grade 4 CRS, 29% grade 3 neurotoxicity, 6% grade 4 neurotoxicity

• Early use of tocilizumab may reduce the incidence of severe CRS but not neurotoxicity

Locke FL, et al. Blood. 2017;130. Abstr 1547. https://ashpublications.org/blood/article/130/Supplement%201/1547/79746/Preliminary-Results-of-

Prophylactic-Tocilizumab?searchresult=1. Accessed January 1, 2020.

Neelapu S, et al. N Engl J Med. 2017;377:2531-44.47

ZUMA-1, n=101

Grade ≥3 CRS, % 13

Grade ≥3 neurotoxicity, % 28

Investigational Studies for CRS and/or Neurotoxicity

www.clinicaltrials.gov. Accessed January 1, 2020.48

NA: not applicable

Trial Phase Planned N

Primary Endpoints

Treatment

NCT04071366 II 62 Grade ≥2 CRS Itacitinib for CRS prevention

NCT04148430 II 90Rate of severe

neurotoxicity

Anakinra for CRS and

neurotoxicity prevention

NCT04150913 II 20Rate of

neurotoxicityAnakinra for neurotoxicity

NCT04048434 NA 34 IL-6 changeExtracorporeal Cytokine

Adsorption (Cytosorb) for CRS and neurotoxicity

NCT03696784 I 12

Safety and tolerability of iC9-

CAR19 T-cells

CAR T-cells targeting CD19 containing the inducible caspase 9 safety switch

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JJ is a 58 y/o male with relapsed DLBCL treated with tisa-cel. Two days post CAR T-cell infusion, JJ is febrile to 39.5°C, tachycardic, hypotensive to 82/58 mm Hg. He was started on 2 L IVF and broad-spectrum antibiotics. His blood pressure improves with fluids. What grade CRS did JJ encounter according to the ASTCT CRS Grading Scale?

A. Grade 1

B. Grade 2

C. Grade 3

D. Grade 4

49

Future Perspectives

CAR T-cells in Multiple Myeloma

CAR T-cells in Combination with Ibrutinib and Immune Checkpoint Inhibitors

50

Clinical Trials in Progress

https://clinicaltrials.gov/ct2/results/map?cond=Car+T+cell+therapy&map=. Accessed December 20, 2019.51

3

12715

3 131

6

Region Number of

Studies

World 287

East Asia 131

Europe 15

North America 129

Middle East 3

Canada 3

Pacifica 6

7

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Charrot S, et al. HemaSphere. 2019;3:2.52


Charrot S, et al. HemaSphere. 2019;3:2. 53

B-cell Maturation Antigen (BCMA)

• Member of the tumor necrosis factor (TNF) superfamily—Ligands: B-cell activating factor (BAFF) and a proliferation-inducing

ligand (APRIL)

• Highly expressed on malignant plasma cells in MM— Increased expression associated with progression of disease

• Functions to maintain long-lived plasma cell homeostasis—Essential in regulating B-cell maturation and differentiation

• BCMA shed from the surface of plasma cells leads to soluble BCMA (sBCMA) detectable in circulation

—Higher concentrations of sBCMA associated with poorer outcomes

• Low level expression on healthy differentiated B-cells; no other normal cells/tissues express BCMA

Timmers M, et al. Front Immunol. 2019;10:1613.

Cohen AD, et al. J Clin Invest. 2019;129:2210–21.54

MM: multiple myeloma

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Phase I NCI BCMA CAR

• Single-center, open-label phase I trial in patients with R/R MM, N=16

• CD28 costimulatory domain, gamma-retroviral vector, dose levels: 0.3, 1, 3, and 9 ×106 CAR T-cells/kg

• Lymphodepletion: Flu 30 mg/m2 and Cy 300 mg/m2 daily on days −5 to −3

Brudno JN, et al. J Clin Oncol. 2018;36:2267–80.55

NCI: National Cancer Institute


Median lines of prior therapy 9.5

High risk cytogenetics 40%

Del(17p) 33%

Refractory to last treatment 63%

Results

PR or better 13 (81%)

Median EFS 31 weeks

DoR >1 year 5 (31%)

DoR > 6 months 9 (56%)

Adverse Events

Grade 3-4 CRS 6 (37.5%)


Tocilizumab 5 (31%)

Tocilizumab + steroids 4 (25%)

Phase I idecabtagene vicleucel BCMA CAR (CRB-401)

• Multicenter, open-label phase I trial in patients with R/R MM, N = 33

• 4-1BB costimulatory domain, lentiviral vector, dose levels: 50, 150, 450, or 800 x 106 cells (idecabtagene vicleucel also referred to as bb2121)

• Lymphodepletion: Flu 30 mg/m2 and Cy 300 mg/m2 daily on days −5 to −3

Raje N, et al. N Engl J Med. 2019;380:1726–37.56


Median lines of prior therapy 7

Carfilzomib 91%

Pomalidomide 94%

Daratumumab 82%

High risk cytogenetics 46%

Refractory to last treatment 64%

Previous aHCT 97%

Results

ORR 28 (81%)

Median PFS 11.8 months

CAR T-cell expansion associated with response

Adverse Events

CRS 25 (76%)

Grade 3 CRS 2 (6%)

Neurotoxicity, all grades 14 (42%)

Grade 3 neurotoxicity 0

Phase 1/2 CARTITUDE-1

• Open-label phase 1/2 trial of JNJ-4528 in R/R MM, N=25

• Two BCMA-targeting single-domain antibodies, median dose 0.73 x 106 cells/kg

• Lymphodepletion: Flu 30 mg/m2 and Cy 300 mg/m2 daily x 3 days

Madduri D, et al. Blood. 2019;134. Abstr 577. https://ashpublications.org/blood/article/134/Supplement_1/577/426449/Results-from-CARTITUDE-1-A-Phase-1b-

2-Study-of-JNJ?searchresult=1. Accessed January 1, 2020. 57

PI: Protease inhibitorIMiD: immunomodulatory

VGPR: very good partial response


Lines of prior therapy, median (range) 5 (3-16)

Triple refractory to a PI, IMiD, and anti-CD38 antibody

88%

Penta-refractory 36%

Results

ORR 91% sCR n=4

CR n=2 VGPR n=7

Adverse Events

Grade 1-2 CRS 80%

Grade 3 CRS / grade 5 CRS n=1 / n=1

Grade 1 neurotoxicity /

grade 3 neurotoxicityn=2 / n=1


Tocilizumab / steroids 91% / 27%

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Published Results of CAR T-cells targeting BCMA

1. Raje N, et al. N Engl J Med. 2019;380:1726–37. 2. Cohen AD, et al. J Clin Invest. 2019;130:2210-21. 3. Brudno JN, et al. J Clin Oncol. 2018;36:2267–80.

4. Madduri D, et al. Blood. 2019;134. Abstr 577. https://ashpublications.org/blood/article/134/Supplement_1/577/426449/Results-from-CARTITUDE-1-A-Phase-1b-2-

Study-of-JNJ?searchresult=1. Accessed January 1, 2020. 5. Zhao WH, et al. J Hematol Oncol. 2018;11:141.58

CAR T-cell

productPhase N=

Median prior

lines of therapyORR (n=)

Response

duration

Idecabtagene

vicleucel11 33 7 85% (28)

Median PFS:

11.8 months

CAR T BCMA

(UPENN)2 1 25 7 48% (12)Median DoR:

4 months

NCI CAR

BCMA3 1 16 9.5 81% (13)Median EFS:

7.3 months

JNJ-45284 1 25 5 91% (15) 1 year PFS: 53%

LCAR-B38M5 1 57 3 88% (50)

Median DoR:

14 monthsMedian PFS:

15 months

Investigational BCMA CAR T-cells


SLAMF7: Signaling lymphocytic activation molecule family member 7

Trial Phase Planned N Primary Endpoints

Treatment

KarMMa-3 (NCT03651128)

III 381 PFSbb2121 vs standard triplet

regimens in R/R MM

KarMMa-2 (NCT03601078)

II 181 PFSbb2121 in R/R MM and high-risk MM

KarMMa (NCT03361748)

II 150 ORR bb2121 in R/R MM

CARTIFAN-1 (NCT03758417)

II 60 ORR JNJ-4528 in R/R MM

CARTITUDE-1 (NCT03548207)

I/II 118Safety, ORR

JNJ-4528 in R/R MM

NCT03958656 I 42 Safety Anti-SLAMF7 in R/R MM

CRB402 (NCT03274219)

I 74 Safety bb21217 in R/R MM

bb21217

• Uses same CAR construct as idecabtagene vicleucel (bb2121)

• Cultured with the phosphoinositide 3-kinase inhibitor (PI3K) inhibitor bb007 to enrich for T-cells displaying a memory-like phenotype

• CAR T-cells enriched for this phenotype may persist and function longer than nonenriched CAR T-cells

Berdeja JG, et al. Blood. 2019; 134. Abstr 927. https://ash.confex.com/ash/2019/webprogram/Paper126660.html. Accessed January 1, 2020. 60

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CD19 CAR T-cell Therapy + Ibrutinib

• Phase I/II in R/R chronic lymphocytic leukemia (CLL)

• JCAR014: investigational anti-CD-19 CAR T-cell product, 4-1BB costimulatory domain, lentivirus vector, defined ratio of CD4+:CD8+ T-cells

• JCAR014 + ibrutinib (n=17) vs JCAR014 (n=19), lymphodepletion: Flu + Cy

Gauthier J, et al. Biol Blood Marrow Transplant. 2019;25:S9-10.61

Results

Ibrutinib No ibrutinib p value

CR + PR 88% 56% 0.06

Adverse Events

IbrutinibNo

ibrutinibp value

Grade ≥1 CRS 76% 89% 0.39

Grade ≥3 CRS 0% 26% 0.05


IbrutinibNo

ibrutinibp value

Age, median (years) 65 61 0.34

Richter’s

transformation18% 21% 1.00

Complex karyotype 76% 89% 0.40

17p deletion 76% 63% 0.48

Prior alloHCT 12% 16% 0.69

CAR T-cells + Immune Checkpoint Inhibitors

• Possible causes of CAR T-cell failure—CAR T-cell exhaustion

—Immunosuppressive tumor-microenvironment

• Rationale for immune checkpoint inhibitors—Checkpoint proteins PD-1 and PD-L1 are expressed on CAR T-cells and tumor

microenvironment

—PD-1 and PD-L1 upregulated after CAR T-cell infusion

—PD-1/PD-L1 blockade may augment CAR T-cell activity and reverse CAR T-cell exhaustion

Cherkassky L, et al. J Clin Invest. 2016;126:3130–44.

Galon J, et al. J Clin Oncol. 2017;35. Abstr 3025. https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.3025. Accessed January 1, 2020.62

PD-1: programmed death-1

PD-L1: programmed death-1 ligand

PLATFORM – Durvalumab + lisocabtagene maraleucel

• Phase 1/2 study in R/R B-cell NHL, ≥2 prior lines of therapy, N=18

• Durvalumab 1500 mg IV infusion starting day 29—Every 4 weeks up to 1 year

• DLBCL, n=10

• FL, n=1

• Age range 53-78 years

Siddiqi TJ, et al. Hematol Oncol. 2019;37;171-2.63

Results

ORR 91%

CR 64%

Adverse Events

Fever, CRS, neurotoxicity, cytopenia, fatigue

7

Hemolytic anemia, fatigue, rash

3

No CRS after durvalumab

NHL: non-Hodgkin lymphoma

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ZUMA-6 Phase 1 – Atezolizumab + Axi-cel

• Phase 1 study in R/R DLBCL, ≥2 prior lines of therapy, N=12

• Atezolizumab 1200 mg IV every 21 days x 4 doses

—Day 21 Cohort 1 (n=3)



• Must have received prior CD20-targeting and anthracycline-containing regimen, ECOG ≤2

• Median age 55 years, range 30-66

Jacobson CA, et al. Biol Blood Marrow Transplant. 2019;25:S173.64

Results

ORR 90%

CR 60%

CAR T-cell expansion >2-fold higher than in ZUMA-1

Adverse Events (Grade ≥3)

CRS 25%

Neurotoxicity 50%

Anemia 75%

Encephalopathy 42%

Neutropenia 42%


The published results of phase I/II studies utilizing anti-BCMA CAR T-cells have shown ORRs in MM as high as:

A. 60%

B. 70%

C. 80%

D. 90%

65

Allogeneic CAR T-cells

66

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Limitations of Autologous CAR T-cells

Graham C, et al. Cells. 2018;7.67

Cost

Harvest and manufacturing

failures

Contamination with tumor

cells

T-cell dysfunction

Product variability

Disease progression

during manufacture

Allogeneic CAR T-Cells

• Donor derived

—Previous hematopoietic stem cell transplant (HSCT) donor

—Virus-specific CAR T-cells

—Gene-edited healthy donor CAR T-cells

• Theoretical advantages

—Easier and cost-effective manufacturing

—Reduced time to CAR T-cell infusion

—Increased probability of healthy CAR T-cell generation

• Barriers

—Graft versus host disease (GVHD)

—Rejection

Graham C, et al. Cells. 2018;7:1-11.68

Universal ‘off the shelf’ CARs

Allogeneic CAR T-Cells

Ruella M, et al. BioDrugs. 2017;31:473–81. 69

Donor derived CAR T-cell

Virus-specific CAR T-cell

Gene-edited CAR T-cell

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Preliminary Data on UCART19

• Allogeneic, genetically modified CAR T-cell product from healthy donor cells

—4-1BB costimulatory domain

• TRAC and CD52 genes knocked out to allow for administration in non-HLA matched patients

Benjamin R, et al. Blood. 2018;132. Abstr 896.

https://ashpublications.org/blood/article/132/Supplement%201/896/266300/Preliminary-Data-on-Safety-

Cellular-Kinetics-and?searchresult=1. Accessed January 1, 2020.70

aGVHD: acute GVHD

TRAC: T-cell receptor alpha constant

UCART: universal chimeric antigen receptor T-cells

Results, n=16

CR or CRi, n (%) 14 (88)

MRD negative, n (%) 12 (86)

5 patients remain in molecular remission 4.5-16.4 months post UCART19

Adverse Events, n=18

CRS, Grades 1-2 14

CRS, Grades 3-4 3

Neurotoxicity, Grades 1-2 6

aGVHD, Grade 1 2

Viral infections, Grades 1-4 8

Prolonged cytopenias, Grade NR 4

Investigational Allogeneic CAR T-cells


DLT: dose limiting toxicity

Trial Phase Planned N Primary Endpoints

Treatment

NCT02746952(CALM)

I 30 DLT, SafetyUCART19, anti-CD19 allogeneic

CAR T-cell in adult R/R ALL

NCT02808442(PALL)

I 18 SafetyUCART19, anti-CD19 allogeneic CAR T-cell in pediatric R/R ALL

NCT03939026

(ALPHA)I/II 24 DLT, ORR

ALLO-501, anti-CD19 allogeneic CAR T-cell in R/R LBCL or FL

NCT03190278

(AMELI-01)I 59 DLT, Safety

UCART123, anti-CD123 allogeneic CAR T-cell in R/R AML

NCT04093596

(UNIVERSAL)I 90 DLT

ALLO-715, anti-BCMA allogeneic CAR T-cell in R/R MM

DLT: Dose limiting toxicity


• Compared to autologous CAR T-cells, allogeneic CAR T-cells have the potential to:

A. Decrease graft-versus-host disease

B. Decrease rejection

C. Increase contamination with tumor cells

D. Increase the probability of healthy CAR T-cell generation

72

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Conclusions

• CD19 CAR T-cells are the most successful and best known CAR therapy providing durable responses in pediatric/young adult B-cell ALL and adult LBCL

• Unique toxicities of CRS and neurotoxicity may occur—Strategies for uniform grading to be used across clinical trials and the postapproval clinical setting

recently published

• Clinical trials evaluating the use of CAR T-cells in combination with other agents, in other malignancies, and versus standard of care therapies are ongoing

• Allogeneic CAR T-cell therapy may overcome barriers to current FDA approved products

73

References

• June CH, et al. N Engl J Med. 2018;379:64-73.

• Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-38.

• Frey N, et al. Biol Blood Marrow Transplant. 2019;25:e123-7.

• Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15:47-62.

• Hay D, et al. Br J Haematol. 2018;183:364–74.

• Teachey D, et al. Nat Rev Clin Oncol. 2018;15:218.

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powerpoint presentation...design single-arm, open-label, international, multicenter, phase ii trial...

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