Maurice Alexander, PharmD, BCOP, CPP Clinical Specialist, Blood and Marrow Transplant UNC Bone Marrow Transplant and Cellular Therapy Program

Exploiting the Immune System: Chimeric Antigen Receptor-T Cell Therapy for Hematologic Malignancies

Disclosures

• I have the following disclosures

• Off-label use disclosure

– This session will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US

Company Role

Juno Therapeutics Advisory Board

Jazz Pharmaceuticals Advisory Board

Objectives

• Understand the engineering process and administration of chimeric antigen receptor-T (CAR-T) cells

• Interpret clinical data for the use of CAR-T cells in the management of hematologic malignancies

• Describe the management of toxicities associated with CAR-T therapy

CAR-T ENGINEERING AND ADMINISTRATION STRATEGIES

CAR-T cell Therapy for Hematologic Malignancies

Chimeric Antigen Receptor-T (CAR-T) Cells

• Chimeric Antigen Receptors (CARs) – Recombinant molecules that target a

specific antigen

– Mediate cell activation

• T-cells – Activated after CAR exposure to the

cancer antigen

– Destruction of tumor cells and

proliferation of CAR-Ts

Kulemzin SV, et al. Acta Naturae 2017;9(1):6-14.

Ramos CA, et al. Annu Rev Med 2016;67:165-183.

CAR-T Engineering Process

Mato A, et al. Blood 2015;126:478-485.

CAR-T Engineering

Batlevi CL, et al. Nat Rev Clin Oncol 2016;13(1):25-40.

Lymphodepletion

• Depletes endogenous lymphocytes

• Elimination of regulatory T cells

• Removal of competing targets

• Prevents T-cell mediated responses against CARs

• Improves CAR-T persistence

• May include disease-targeted agents

. Gattinoni L, et al. J Exp Med 2015;202(7):907-912.

CAR-T Infusion • Dosing

– 1 x 105 – 1 x 108 cells/kg

– Dose level associated with both response and toxicity

– No uniform/standard dose

• Infusion strategies

– Single infusions

– Fractionated/multiple infusions

Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.

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

Lee DW, et al. Lancet 2015;385:517-28.

Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.

Audience Response Question 1

Which of the following components of CAR-T cells have been modified for enhancement of activity in newer generation CAR-Ts?

a. Antigen recognition domain

b. Hinge/Spacer

c. Transmembrane domain

d. Signaling/Costimulatory domain

CLINICAL DATA CAR-T cell Therapy for Hematologic Malignancies

CD19 Expression

Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.

Acute Lymphoblastic Leukemia (ALL) • Relapsed/refractory disease remains a challenge

– Initial CR: > 80%

– Refractory: ~20%

– Relapse: > 50%

• Responses to salvage therapies are poor

Fielding AK, et al. Blood 2007;109:944-950.

Gokbuget N, et al. Blood 2012;120(10):2032-2041.

Relapse number Previous therapy Salvage treatment

number CR Rate

1st Chemotherapy 1st ~40%

2nd Chemotherapy 2nd ~30%

1st Stem Cell Transplant 1st ~20%

CR: Complete Remission

CAR-T Cell Therapy for ALL Study Population

Lympho- depletion

Costimulation/ Cell dose (cells/kg)

Response Rate N (%)

Davila ML, et al. Sci Transl Med 2014

N = 16 Adults

Cy CD28

3 x 106 CR: 14 (88)

CRm: 12 (75)

Maude S, et al. NEJM 2014

N = 30 Peds (25) Adults (5)

Various 4-1BB

8 x 105 – 2 x 107 CR: 27 (90)

CRm: 23 (77)

Lee DW, et al. Lancet 2015

N = 21 Peds (16) Adults (5)

Cy/Flu CD28

1 x 106 – 3 x 106 CR: 14 (70)

CRm: 12 (60)

Turtle CJ, et al. J Clin Invest 2016

N = 32 Adults

Cy Cy/Etop Cy/Flu

4-1BB 2 x 105 – 2 x 107

CR: 27 (93) CRm: 25 (86)

Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.

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

Cy: Cyclophosphamide; Flu: Fludarabine; Etop: Etoposide; CR: Complete remission; CRm: Complete molecular remission

Lee DW, et al. Lancet 2015;385:517-28.

Turtle CJ, et al. J Clin Invest 2016;126(6):2123-2138.

CAR-T Cell Therapy for ALL

Study Proceeded to

transplant Comments

Davila ML, et al. Sci Transl Med 2014

44% overall 70% of eligible

No relapse in transplanted patients; Follow up: 2 -24 months

Maude S, et al. NEJM 2014

10% overall Sustained responses for up to 2 years

Lee DW, et al. Lancet 2015

48% overall 83% of eligible

No relapse in transplanted patients; Median follow up: 10 months

Davila ML, et al. Sci Transl Med 2014;6(224):224ra25.

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

Lee DW, et al. Lancet 2015;385:517-28.

Chronic Lymphocytic Leukemia (CLL)

Agent Response

Rate Survival Comments

Ibrutinib ORR: 63%

CR: 0% 6-month PFS: 88%

1-yr OS: 90% Similar responses in high-risk patients

Ibrutinib + Rituximab

ORR: 95% CR: 8%

18-month PFS: 78% 18-month OS: 84%

High-risk population Median DOR: 15.4 months

Idelalisib + Rituximab

ORR: 81% CR: 0%

6-month PFS: 45% 1-year OS: 92%

Frail population Similar responses in high-risk patients

Venetoclax ORR: 79% CR: 20%

15-month PFS: 69% Similar responses in high-risk patients

Median DOR: 24 months

Venetoclax + Rituximab

ORR: 86% CR: 51%

2-year PFS: 82% 2-year ongoing response: 89%

Byrd JC, et al. N Engl J Med 2014;321:213-223.

Burger JA, et al. Lancet Oncol 2014;15:1090-1099.

Furman RR, et al. N Engl J Med 2014;370:997-1007.

ORR: Objective response rate; CR: Complete response; PFS: Progression-free survival; OS: Overall survival; DOR: Duration of response

Roberts AW, et al. N Engl J Med 2016;374(4):311-322.

Seymour JF, et al. Lancet Oncol 2017;18:230-40.

CAR-T cell Therapy for CLL

Porter DL, et al. Sci Transl Med 2015;7(303):303ra139.

Porter DL, et al. Blood 2014;124(21):1982.

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

Study N ORR

N (%) CR

N (%) DOR

(months)

Porter DL, et al. Sci Transl Med 2015 14 8 (57) 4 (29) 5-53

Porter DL, et al. Blood 2014 23 9 (39) 5 (22) NR

Kalos, et al. Sci Transl Med 2011 3 3 (100) 2 (67) 7-11

Kochenderfer, et al. JCO 2015 4 4 (100) 3 (75) 4-23

Kochenderfer, et al. Blood 2012 4 3 (75) 1 (25) 7-15

Brentjens R, et al. Blood 2011 8 1 (13) 0 (0) 6

Kochenderfer, et al. J Clin Oncol 2015;33(6):540-549.

Kochenderfer, et al. Blood 2012;119(12):2709-2720.

Brentjens R, et al. Blood 2011;118(18):4817-4828.

ORR: Objective response rate; CR: Complete response; DOR: Duration of response

CAR-T Therapy for Lymphoma

Study Population CAR Response Rate

N (%)

Turtle, et al. Sci Transl Med 2016

N = 32 R/R NHL

CD19 ORR: 19 (63) CR: 10 (33)

Locke, et al. Mol Ther 2017

N = 7 R/R DLBCL

CD19 ORR: 5 (71) CR: 4 (57)

Wang C, et al. Clin Cancer Res 2017

N = 18 R/R HL

CD30 ORR: 7 (39)

CR: 0 (0)

Turtle CJ, et al. Sci Transl Med 2016;8(355):355ra116.

Locke FL, et al. Mol Ther 2017;25(1):285-295.

Wang C, et al. Clin Cancer Res 2017;23(5):1156-1166.

R/R: Relapsed/refractory; NHL: Non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; HL: Hodgkin lymphoma; ORR: Objective response rate; CR: Complete response

Multiple Myeloma (MM)

• CD19 expression in MM

– Minor component of the MM clone

– CD19 CAR-T activity despite low level expression

Garfall AL, et al. N Engl J Med 2015;373(11):1040-1047.

Blanc V, et al. Clin Cancer Res 2011;17(20);6448-6458.

CAR-T Therapy for MM • Alternative targets: CD38, CD56, CD138, BCMA

Study N CAR Responses

N (%)

Guo, B, et al. J Cell Immunother 2016

5 CD138 SD: 4 (80)

Ali SA, et al. Blood 2015

11 BCMA sCR: 1 (9)

VGPR: 2 (18) PR: 1 (9)

Cohen AD, et al. Blood 2016

6 BCMA sCR: 1 (17)

VGPR: 1 (17)

Fan F, et al. J Clin Oncol 2017

19 BCMA sCR: 14 (74) VGPR: 4 (21)

PR: 1 (11)

Guo B, et al. J Cell Immonther 2016;2:28-35.

Ali SA, et al. Blood 2015;126:LBA-1.

Cohen AD, et al. Blood 2016;128:1147.

Fan F, et al. J Clin Oncol 2017;35 (suppl; abstr LBA3001).

BCMA: B-cell maturation antigen; SD: Stable

disease; sCR: Stringent complete response;

VGPR: Very good partial response; PR: Partial

response

Audience Response Question 2

Clinical data for CAR-T therapy in hematologic malignancies suggest which of the following? a. CAR-T responses in ALL are typically transient,

requiring additional therapy b. Complete remissions have been reported in up to 90%

of patients with ALL c. Patients with ALL are unlikely to be able to proceed to

stem cell transplant after receiving CD19 CAR-T therapy

d. CD19 is the ideal CAR-T target antigen for multiple myeloma and has resulted in high CR rates

MANAGING TOXICITIES CAR-T cell Therapy for Hematologic Malignancies

Cytokine Release Syndrome (CRS) • Non-antigen specific toxicity

• Results from widespread immune activation

– Elevation of systemic cytokines

• Reversible, but potentially fatal

Organ System Signs/Symptoms

Constitutional Fevers, rigors, malaise, myalgias/arthralgias

Gastrointestinal Nausea, vomiting, diarrhea

Cardiovascular Tachycardia, hypotension

Renal Azotemia, renal failure

Hepatic Transaminitis, hyperbilirubinemia

Neurologic Altered mental status, confusion, delirium, seizures, etc.

Respiratory Tachypnea, hypoxia

Lee DW, et al. Blood 2014;124(2):188-195.

Brundo JN, et al. Blood 2016;127(26):3321-3330.

CRS: Grading Grade Signs/Symptoms

1 Constitutional symptoms; requires only symptomatic management

2

Hypotension (responsive to fluids or low dose vasopressor) Oxygen requirement < 40% Grade 2 organ toxicity

3

Hypotension (requiring high dose or > 1 vasopressor) Oxygen requirement ≥ 40% Grade 3 organ toxicity Grade 4 transaminitis

4 Ventilator support required Grade 4 organ toxicity

5 Death

Lee DW, et al. Blood 2014;124(2):188-195.

CRS: Risk Factors • CAR-T cell dose

• Burden of disease

Lee DW, et al. Lancet 2015;385:517-28.

Cytokine Elevations

Lee DW, et al. Lancet 2015;385:517-28.

C-Reactive Protein (CRP) Interleukin-6 (IL-6)

Association between CRP and IL-6

Neurotoxicity • Spectrum of neurologic symptoms

– Confusion/delirium to obtundation

– Seizure activity

• Pathogenesis

– Direct CAR-T toxicity on CNS tissues vs. generalized T-cell mediated inflammatory state

Lee DW, et al. Lancet 2015;385:517-28.

Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.

CRS and Response

Lee DW, et al. Lancet 2015;385:517-28.

Response Rate

Rate of CRS CRS in

Responders CRS in non-Responders

Comments

14/21 16/21 14/14 2/7 All 6 grade 3-4 CRS cases

in responders

Management of CRS

• Grade 1-2

– Supportive measures

• Grade 3-4

– Tocilizumab

• Inhibits soluble (sIL-6R) and membrane-bound (mIL-6R) IL-6 receptors

• Dosing – 4-8 mg/kg (max 800 mg) IV over 1 hour x 1

– Repeat if lack of response

• No CNS penetration

Brundo JN, et al. Blood 2016;127(26):3321-3330.

Management of CRS • Corticosteroids

– Indicated for:

• Tocilizumab refractory CRS

• Grade 3-4 neurotoxicity

– Methylprednisolone 1-2 mg/kg IV every 12 hours

– Dexamethasone 5-10 mg IV every 6-12 hours

Brundo JN, et al. Blood 2016;127(26):3321-3330.

Davila ML, et al. Sci Transl Med 2014;6(224);224ra25.

B-Cell Aplasia

• On-target off-tumor toxicity

• Potential measure of persistence of CD19-targeted CAR-T cells

• Prolonged B-cell aplasia in patients with sustained remissions

• Immunoglobulin deficiencies

– Intravenous immunoglobulin (IVIG) replacement

Dai H, et al. J Natl Cancer Inst 2016;108(7):djv439.

Audience Response Question 3

JR is a 54 year-old male with ALL s/p CD19 CAR-T infusion. JR becomes hypoxic and hypotensive,

ultimately requiring intubation and pressor support. He also has mild confusion. He is given tocilizumab 8 mg/kg IV x 1. Twelve hours later he continues to be hypotensive requiring an

additional pressor, has progressive renal compromise, moderate reduction in alertness

and inability to express speech.

Audience Response Question 3

What is the best approach for the management of JR’s CRS at this time?

a. Dexamethasone 10 mg IV every 12 hours

b. Repeat tocilizumab 8 mg/kg IV x 1

c. Repeat tocilizumab 8 mg/kg IV x 1 and add dexamethasone 10 mg IV every 12 hours

d. Methylprednisolone 1 mg/kg IV every 12 hours

Where Are We Now? Company/

CAR Trial

Trial Population

Response Rates

Approval Status/ US Adopted Name (USAN)

Novartis CTL019

Eliana N = 88

Age 3-23 B-ALL

CR: 83% CRm: 83%

Breakthrough status 7/2014 Granted FDA priority review 2017

tisagenlecleucel-T

Novartis CTL019

Juliet N = 141 Adults DLBCL

ORR: 59% CR: 43%

Breakthrough status 4/2017 BLA filed 2017

tisagenlecleucel-T

KITE KTE-C19

Zuma-1 N = 111 Adults

NHL

ORR: 82% CR: 54%

Breakthrough status 7/2015 Granted FDA priority review 2017

axicabtagene ciloleucel

KITE KTE-C19

Zuma-3 N = 11 Adults B-ALL

CR: 75% CRm: 75%

Trial ongoing

Juno JCAR017

Transcend N = 39 Adults NHL

ORR: 75% CR: 67%

Trial ongoing

Buechner J, et al. EHA Learning Center 2017; 181763.

Schuster SJ, et al. EHA Learning Center 2017; 183934.

Locke, FL, et al. AACR 2017. Abstract nr [CT019].

Shah BD, et al. J Clin Oncol 2017;35 (suppl; abstr 3024).

Abramson JS, et al. Blood 2016;128:4192.

Summary

• Improvements in CAR-T engineering have enhanced clinical efficacy

• CAR-T therapy offers an effective treatment option in the relapsed/refractory setting for hematologic malignancies, particularly ALL

• Toxicities, such as CRS and neurotoxicity, can be fatal and warrant prompt management

Maurice Alexander, PharmD, BCOP, CPP Clinical Specialist, Blood and Marrow Transplant UNC Bone Marrow Transplant and Cellular Therapy Program

Exploiting the Immune System: Chimeric Antigen Receptor – T Cell Therapy for Hematologic Malignancies