3 immunotherapy and cart peru 2016

Immunotherapy for B-cell Lymphomas: Focus on CART therapy and monoclonal antibodies and CART Therapy Julio C Chavez, MD Assistant Member Lymphoma Section Moffitt Cancer Center/University of South Florida Tampa, FL

Disclosures: Julio C Chavez • Jannsen: Speaker Bureau • Incyte: Advisory Board

Outline • Lymphomas and the Immune system – Role of immune system in cancer – Tumor immune escape as cancer mechanism – Opportunities for development of immune based therapies • Update in monoclonal antibodies – Ofatumumab – Obinutuzumab – Ublituximab • Update in conjugate antibodies – SGN CD19 – Pinatuzumab – Polatuzumab • Update on Bi-specific antibodies • CART therapy

Tumor Immunology: Overview

perforin granzyme

cytokines Resting T cell

Activated T cell TUMOR

Tumor antigen

LYMPH NODE

T cell clonal expansion TCR

MHC B7

Dendritic cell

CD28

Tumor-specific immune response

The Immunoediting Hypothesis: Shaping Tumor Development

Equilibrium

Elimination

CTL

CTL

T reg T reg NKT

Escape

T reg CTL

NK T cyto

NK

T reg

CTL

Genetic instability/tumor heterogeneity Immune selection Dunn GP, et al. Nat Immunol. 2002;3:991-998. Schreiber R, et al. Science. 2011;331:1565-1570.

Mittal D, et al. Curr Opin Immunol. 2014;27:16-25.

Immune evasion mechanisms by tumors

Role of PD-1 in Suppressing Antitumor Immunity Tumor cell

Patient’s T cells

MHC

TCR

T cell

PD-1

PD-L1

T-cell blockade

B7.1

MHC

T cells

TCR

PD-L1

Tumor cell growth

PD-1

Engineered Fc-domain

+ Anti-PD-L1

B7.1

T-cell activation Granzymes and perforin

Tumor cell death

• Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models • Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety Adapted from Spigel et al. Proc ASCO 2013;Abstract 8008.

Naked monoclonal Abs Conjugate monoclonal Abs

Tumor Target

Radioimmunotherapy Immunotoxins/ oncolytic virus

Cancer Immunotherapy Activate immune cells

Vaccines/ oncolotytic virus Checkpoint inhibitors Stimulatory agonists Cellular therapies

General Approaches for Cancer Immunotherapy Peptide vaccine DC vaccine Genetic vaccine IL-2 IFN IL-15 IL-21 Active immunotherapy Adoptive cell transfer immunotherapy

T cell cloning

CD20 CD137 OX40 CTLA-4 PD-1

TCR or CAR genetic engineering

have directly inspired and informed the growing field of ACT, and this is dramatically illustrated by chimeric antigen receptor T cells (CAR T cells). Other promising avenues that exploit this node include NK cell alloreactivity and stimulation of immune effector function by agonistic mAbs.

for example, virus antigens may be exclusively d on viral-associated malignant tissue as opp normal tissue (BOX 4).

CAR T cells, which have recently been sho clinically active, exploit synthetically engineer to bridge the nodes of targeting tumour surface and the boosting of effector functions. The sp of these CAR T cells for a tumour surface mole ders them independent of MHC restriction, them to overcome tumour escape mechanism disruption of antigen-presentation machinery The disappointing clinical efficacy of first-ge CARs led to the development of a second gen which added intracellular signalling domai co-stimulatory molecules — either CD137 (als as TNFRSF9) or CD28 — to a CD19-targeting In patients with relapsed or refractory CLL, in low numbers of these second-generation CD19 CAR T cells led to massive in vivo expansion killing and B cell aplasia. The long-term toxicity aplasia is an expected on-target, off-tissue resu CD19-targeted CAR; currently, patients are mented with probably life-long intravenous i globulin. Importantly, durable remissions ove

Immunotherapeutic advances in hematologic malignancies Philadelphia chromosome

The defining translocation in chronic myeloid leukaemia between two genes on the long arms of chromosome 22 (BCR) and chromosome 9 (ABL), resulting in a novel fusion protein (BCR–ABL) that can be targeted by ABL kinase inhibitors, such as imatinib.

Chimeric antigen receptor (CAR). A synthetically engineered receptor composed of a single-chain antibody fragment, to confer tumour recognition, coupled with intracellular signalling domains derived from the T cell receptor and a co-stimulatory molecule, most commonly either CD28 or CD137.

CAR T cells. ACT involves ex vivo manipulation of either naturally occurring or genetically engineered tumour-specific T cells that are subsequently infused into the patient. Two features are paramount to the success of ACT. First, insights gleaned from the study of the post-transplant immune milieu revealed that a preparative lymphodepleting regimen created ‘space’ for homeostatic expansion of the infused T cells. Mounting evidence from allo-HSCT and autologous stem cell transplantation (ASCT) preparative regimens suggests that increased levels of homeostatic cytokines (that is, IL-2, IL-15, IL-21 and IL-7) during the lymphopenic state accelerate the expansion of infused T cells66 and promote an activated phenotype with enhanced effector functions66,67. Second, the selection of an antigen against which the infused T cells will be targeted is essential for direct, tumour-specific T cell-mediated killing:

206 | APRIL 2015 | VOLUME 15

www.nature.com/review © 2015 Macmillan Publishers Limited. All rights reserved

Adapted from Bachireddy, Wu et al. Nat Reviews Cancer 2015

Monoclonal antibodies in B-cell malignancies

Potential Antibody Targets for B-Cell Lymphomas

CD37 CD23

CD40

CD52 CD74 CD80 Death receptors

CD22

HLA-DR

CD20 CD19

Surface immunoglobulin

CD5 B cell Cheson BD, et al. N Engl J Med. 2008;359;613-626.

Copyright Š [year of publication] Massachusetts Medical Society. All rights reserved.

CD20 Monoclonal An-bodies Drug

Antibody Type

Structure

Mechanism of Action ADCC/CDC/PCD

FDA Approval

Rituximab

I

Chimeric IgG1

++ / ++ / +

1997

Ofatumumab

I

Human IgG1 Kappa

+++ / ++++ / ++

2014

Obinutuzumab

II

Humanized IgG1, glycol-engineered

++++ / - / ++++

Veltuzumab

I

Humanized IgG1

++ / ++ / +

Phase I/II

PRO131921

I

Humanized IgG1

++ / ++ / +

discontinued

ADCC: An'body-dependent cell-mediated cytotoxicity CDC: Complement-dependent cytotoxicity PCD: Programmed cell death

2014

Rituximab : Proposed Mechanisms of Action

Complement fixation

Fcg receptors affinity with IgG1

ADCC

CR3 FcÎłR

Active signaling (apoptosis induction) CD20 on malignant cell surface

Chronic Lymphocytic Leukemia

Cumulative Probability of OS (%)

Estimate of OS According to Cytogenetics Median Events, n Total, n OS, yrs 95% CI Del(13q14) 27 155 -- NR Normal/+12 53 228 13.4 12.1-14.7 NOTCH1 M/SF3B1 M/del(11q22-q23) 41 99 5.6-11.5 8.5 TP53 DIS/BIRC3 DIS 57 101 3.4-6.5 5.0

100 80 60

Del(13q14) vs normal/+12

40

P = .0406

Normal/+12 vs NOTCH1 M/SF3B1 M/del(11q22-q23) P = .0082

20 P < .0001 0 0

5 10 Yrs From Diagnosis

Rossi D, et al. Blood. 2013;121:1403-1412.

NOTCH1 M/SF3B1 M/del(11q22-q23) vs TP53 DIS/BIRC3 DIS P = .0196

15

CLL8: Addition of Rituximab to FC in untreated CLL TreatmentNaïve, Active CLL Good Physical Fitness* N = 817

R A N D O M I Z E

FCR X6

FC x 6

*CIRS ≤ 6, creatinine clearance ≥ 70 mL/min).

Overall Survival

Progression-Free Survival 1.0 1.0 0.8

Cum Survival

Cum Survival

0.8 0.6

FCR

0.4

Median PFS: FCR: 57 months FC: 33 months

FC

0.2

HR 0.59, 95% CI 0.5-0.7, P < 0.0001

0.0 0

12

24

36

48

60

72

84

96

Time to Event [PFS] (months)

FCR

0.6

FC

0.4

FCR: 69.4% alive FC: 62.3% alive

0.2

HR 0.68 95% CI 0.535-0858, P < 0.001

0.0 0

12

24

36

48

60

72

84

Median OS: FCR: not reached FC: 86 months 96

Time to Event [PFS] (months)

Median observation time: 5.9 years Fischer K, et al. ASH Meeting Abstracts. 2012; Hallek M, et al. Lancet. 2010;379(9747):1381-1385.

Impact of Duration of Remission After FCR Survival of 156 patients after disease progression.

Overall Survival

Survival by Duration of Remission

1.0 1.0

0.8

Cumulative Survival

Cumulative Survival

0.8

0.6

0.4

0.2

0.0

â&#x2030;Ľ 6 years

0.6

3-5.9 years 0.4

1-2.9 years

0.2

Median Survival After Disease Progression = 51 months 0

12

24

36

48

60

72

84

Months

â&#x2030;¤ 1 year 0.0 96

108 120 132 144

P < 0.001 0

12

24

36

48

60

72

84

96 108 120 132 144

Months

Tam S, et al. Blood. 2014;124:3059-3064.

Regimens For CLL Can Have Substantial Toxicity and Generally Become Less Effective with Recurrent Treatment

RESPONSE

Unmet Medical Need Increases CHOP/R, CVP/R, BR, R, FCR

REMISSION DURATION

1st line

2nd line

3rd line

4th line

5th line

6th

7th

Drugs with new mechanisms of action are needed that have substantial single-agent activity and can be combined with current and emerging treatment options

Hallek, Hematology Am Soc Hematol Educ Program 2009

CLL: Agents approved • Small molecules – BTK inhibitors: Ibrutinib – PI3K inhibitors: Idelalisib – BCL2-inhibitors: Venetoclax • Monoclonal antibodies: – Rituximab – Ofatumumab – Obinutuzumab

Rituximab Maintenance After Chemotherapy Induction (Greil): Study Schema • Randomized, open-label, international, phase III study of maintenance with rituximab, an anti-CD20 therapy, after chemotherapy induction • Primary endpoint: PFS • Secondary endpoints: MRD, event-free survival (EFS), safety Maintenance

B-CLL (N = 263) • ECOG PS 0-2 • Written, informed consent

CR or PR from R-based induction 1st or 2nd line

Rituximab 375 mg/m2 q12wk for 24 months until PD (n = 134) Efficacy Observation (n = 129)

Greil al. ASH 2014. Abstract 20.

Rituximab Maintenance after Chemotherapy Induction (Greil): Efficacy Response (median follow-up of 17.3 months)

All Patients (N = 263)

ORR CR/CRi

58%

PR

42% Rituximab (n = 134)

Observation (n = 129)

PD

15%

28%

PFS rate

85%

76%

SD

P = 0.007 •

57% of patients were MRD negative by 8-color flow cytometry after induction

Greil al. ASH 2014. Abstract 20.

COMPLEMENT 1

Chlorambucil ± Ofatumumab, PFS*

Probability of PFS

Treatmentnaïve CLL patients ineligible for fludarabinebased therapy N = 447

1.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

R A N D O M I Z E

Ofatumumab + chlorambucil x 3-12 cycles Chlorambucil x 6 cycles *As assessed by an independent review committee.

Ofatumumab + Chlorambucil HR = 0.57 P < 0.001 0

4

8

Chlorambucil 12

16

20

24

28

32

36

40

44

48

52

Months Since Randomization

• • •

Median follow-up: 28.9 months Neutropenia most common: 26% combination vs 14% chlorambucil ≥ grade 3 infusion-related AE in 22 (10%) patients with chlorambucil/ofatumumab

Hillmen P, et al. Lancet. 2015;385(9980);1873-1883.

Idelalisib + Ofatumumab in CLL: Study Design •

Open-label randomized, phase III study

Stratified by del(17p) or TP53 mutation (either vs neither), IGVH mutation (mutated vs unmutated), recurrent disease status (refractory vs relapsed)

Fit or unfit pts with B-cell CLL that progressed < 24 mos from completion of last therapy and KPS ≥ 60 (N = 261) • •

IDELA 150 mg BID continuously + OFA 300 mg Wk 1, then 1000 mg q1w x 7 then q4w x 4 for 12 doses (n = 174) OFA 300 mg Wk 1, then 2000 mg q1w x 7 then q4w x 4 for 12 doses (n = 87)

Until disease progression or death from any cause

Primary endpoints: PFS Secondary endpoints: PFS in pts with del(17p)/TP53 mutation, OS, ORR, LNR rate, CR rate Jones J, et al. ASCO 2015. Abstract 7023.

Idelalisib + Ofatumumab in CLL: PFS

PFS

Progression Free (%)

All Pts 100

•

Events, n (%)

IDELA + OFA (n = 174)

OFA (n = 87)

76 (44)

54 (62)

80

Median PFS, mos (95% CI)*

16.3 (13.6-17.8)

8.0 (5.7-8.2)

60

Adjusted HR (95% CI)*

0.27 (0.19-0.39)

P value†

40

Median observation, mos

20 0

5

5.3

*Based on Cox proportional hazards with stratification factors †Based on stratified log-rank test

IDELA + OFA OFA

0

< .0001 11.1

10 15 Time (mos)

20

25

In del(17p)/TP53 subgroup, the median PFS for the IDELA + OFA group was 13.7 mos vs 5.8 for OFA alone (HR 0.32; 95% CI: 0.18-0.57; P value < .0001)

Jones J, et al. ASCO 2015. Abstract 7023. Reprinted with permission.

Phase III PROLONG Trial Design (NCT01039376) Eligibility prior to IA (n = 474) Relapsed CLL Complete (CR) or partial response (PR) after 2nd- or 3rd-line Tx for CLL No primary or secondary fludarabine-refractory CLL No prior maintenance Tx No known CLL transformation No chronic or active infectious disease requiring treatment

OFA maintenance 300 mg à 1,000 mg 1 wk later every 8 wk for up to 2 y (n = 238)

1:1

R Observation (n = 236)

IA = interim analysis • Premedication for patients receiving OFA included acetaminophen, antihistamines and glucocorticoids • Stratification was by number and type of prior treatments and by CR or PR after induction • Primary endpoint: Progression-free survival (PFS) van Oers MHJ et al. Proc ASH 2014;Abstract 21.

Efficacy Results

Outcome Median PFS Hazard ratio (p-value) Median time to start of next Tx Hazard ratio (p-value)

OFA (n = 238)

Observation (n = 236)

28.6 mo

15.2 mo

0.48 (<0.0001) 38.0 mo

27.4 mo

0.63 (0.0076)

• Median duration of OFA treatment: 12.5 mo • Median follow-up: 26.1 mo (OFA) versus 24.0 mo (observation) • At the time of interim analysis there was no difference in overall survival - Hazard ratio = 0.92; p = 0.74 van Oers MHJ et al. Proc ASH 2014;Abstract 21 (Abstract only).

OFA mPFS: 29.4 months (95% CI: 26.2,34.2) HR 0.50, p<0.0001

obs mPFS: 15.2 months (95% CI: 11.8, 18.8)

PROLONG study: Time to next treatment OFA median: 38.0 months (95% CI: 28.3, NR) HR 0.66, p=0.0108

stratified log-rank test

obs median: 31.1 months (95% CI: 21.6, NR)

stratified log-rank test

GA101: Mechanisms Of Action—Type I Versus Type II Antibodies Increased direct cell death

Increased ADCC Via increased affinity to the “ADCC receptor” FcgRIIIA

Unique type II epitope and elbow-hinge modification

Effector cell

B cell CD20

Lower CDC activity Due to recognition of type II epitope

FcgRIIIa Complement

Phase III CLL11 Trial: Chlorambucil Alone vs With Obinutuzumab vs With Rituximab

Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles (n = 118) Previously untreated CLL pts with comorbidities (CIRS score > 6 and/ or CrCl < 70 mL/min) (N = 781)

Obinutuzumab 1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 Chlorambucil (n = 333) 375

mg/m2

Rituximab IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 Chlorambucil (n = 330)

Goede V, et al. ASH 2013. Abstract 6.

Goede V, et al. N Engl J Med. 2014;370:1101-1110.

CLL11: Survival with Clb/Obinutuzumab vs Clb Alone or Clb/Rituximab in CLL HR: 0.18 (95% CI: 0.13-0.24; P < .001)

Probability of OS

0.8 0.6 0.4

O-Clb Clb 11.1

0.2 0

0

Probability of PFS

1.0

6

12

1.0

26.7 18

24

30

O-Clb R-Clb

0.2

26.7 15.2

0 0

6

12

18

0.4

O-Clb Clb

0.2 0

0

0.6 0.4

HR: 0.41 (95% CI: 0.23-0.74; P < .002)

0.6

6

12

18

24

30

36

1.0

HR: 0.39 (95% CI: 0.31-0.49; P < .001)

0.8

0.8

36

Probability of OS

Probability of PFS

1.0

0.8

HR: 0.66 (95% CI: 0.41-1.06; P = .08)

0.6 0.4

O-Clb R-Clb

0.2 0

24

30

36

39

Mos Goede V, et al. N Engl J Med. 2014;370:1101-1110.

0

6

12

18

24

Mos

30

36

39

Venetoclax/Rituximab in R/R CLL (Roberts): Study Schema • Phase Ib open-label, dose-escalation, multicenter study of ABT-199 + rituximab (R) and determination of phase II dose (RPTD) in R/R CLL/SLL • Primary endpoints: MTD, RPTD, and safety • Secondary endpoints: PK, preliminary efficacy • Exploratory endpoints: Biomarkers, pharmacogenetics, MRD status R/R CLL/SLL (N = 49) • ≤3 prior myelosuppressive regimens • ECOG PS 0-1 • Adequate marrow, renal and hepatic function • No prior SCT

ABT-199 20 mg/day until PD or toxicity (weekly ramp up to final dose of 200-600 mg) + Rituximab (R) 375 mg/m2 initially, then 500 mg/m2 monthly (6 total doses)

• AEs per NCI-CTCAE v4.0 • MTD per continual reassessment method • Responses per 2008 iwCLL criteria (CLL) and IWG criteria (SLL)

Roberts et al. ASH 2014. Abstract 325.

Venetoclax/Rituximab in R/R CLL: Safety •

10 patients discontinued therapy: 6 due to PD, 2 due to AEs and 2 withdrew consent

•

5 patients discontinued after CR/CRi

•

Preliminary PK data suggest a negligible effect of R on ABT-199 exposure

•

•

•

•

Treatment-emergent SAEs occurring in 2 or more patients included pyrexia (8%), febrile neutropenia (4%), infusion-related reaction (4%), and TLS (4%) TLS (n = 2) occurred after the first dose at 50 mg prior to dosing schedule modification; 1 experienced a fatal event No other fatal TLS occurred after dosing schedule modification No MTD was identified

All Grade

Grade ≥3*

Any

100%

71%

Neutropenia

49%

47%

Nausea

47%

--

Diarrhea

45%

--

Pyrexia

37%

--

Upper respiratory tract infection

37%

--

Cough

33%

--

Fatigue

33%

--

Headache

31%

--

Anemia†

22%

14%

Thrombocytopenia‡

22%

16%

Leukopenia

--

10%

Febrile neutropenia

--

6%

AEs (≥25%)

*Reported in 3 or more patients. †Hemolytic (n=2 grade 3). ‡Immune (n=2 all grade; n=1 grade 3).

Roberts et al. ASH 2014. Abstract 325.

ABT-199/Rituximab in R/R CLL: Efficacy Efficacy, n (%)

All (N = 49)

Evaluable (n = 44)

del(17p) (n = 9)

43 (88)

39 (89)

7 (78)

CR/CRi

15 (31)

15 (34)

2 (22)

PR

22 (45)

22 (50)

5 (56)

ORR

• 43/43 (100%) with post-baseline CT scan had ≥50% reduction in nodal mass • 23/35 (66%) with BM assessment had complete marrow clearance by morphology • 5 patients discontinued after CR/CRi; none had PD with continuing follow up • RPTD of ABT-199 was 400 mg/day based on safety data Dose, mg

N

Grade 3/4 AEs

Related grade 3/4 AEs

Grade 3/4 neutropenia

All GI AEs*

All related SAEs

Dose hold or reduction

ORR (CR+PR)

200

6

4 (67)

3 (50)

4 (67)

5 (83)

1 (17)

4 (67)

6 (100)

300

10

9 (90)

7 (70)

7 (70)

6 (60)

2 (20)

9 (90)

8 (80)

400

8

5 (63)

2 (25)

1 (13)

3 (43)

2 (25)

3 (38)

7 (87)

500

7

5 (71)

3 (43)

3 (43)

6 (86)

0 (0)

4 (57)

5 (71)

600

10

8 (80)

7 (70)

6 (60)

6 (60)

3 (30)

8 (80)

10 (100)

*1 grade 3/4 GI AE (400 mg dose).

Roberts et al. ASH 2014. Abstract 325.

Ongoing trials with obinutuzumab • Obinutuzumab + Venetoclax • Obinutuzumab + Ibrutinib • Obinutuzumab + acalabrutinib • Obinutuzumab + CC-122 • FUSION trial:

Non-Hodgkin Lymphoma

GELA Study of CHOP ± Rituximab in Older Patients with DLBCL: OS OS (%)

Survival Probability

1.0

R-CHOP

53

CHOP

36

0.8 0.6 0.4 0.2 P=0.0004 0.0 0

1

2

3

4

5

6

7

8

Years Coiffier et al. Blood2010

Primary Rituximab and Maintenance (PRIMA) Study 1.0

PFS 82%

Progression-free rate

0.8

Rituximab maintenance N=505

0.6 0.4

66% Stratified HR=0.50 95% CI 0.39; 0.64 P<0.0001

0.2 0

0

6

12 18 24 Time (months)

Observation N=513

30

36

50% reduced risk of progression with rituximab maintenance Salles et al. ASCO. 2010 (abstr 8004).

RESORT Study Design

Rituximab 375 mg/m2 qw × 4

aContinue

CR or PR

R A N D O M I Z E

Rituximab maintenancea 375 mg/m2 q 3 months

Rituximab retreatment at progressiona 375 mg/m2 qw × 4

until treatment failure

v No response to retreatment or PD within 6 months of R v Initiation of cytotoxic therapy or inability to complete RX

Kahl et al, 2014.

Maint Rituximab vs Retreatment in Low Tumor Burden FL (RESORT): Survival 100

2-sided log-rank P = .54

Cytotoxic Therapy–Free Survival (%)

Treatment Failure–Free Survival (%)

100 80 60 40

Median follow-up: 4.5 yrs

20 0

0

Retreatment Maintenanc e

1

At Risk Failure 3 Yrs, % 143 80 65 146 78 73

2

3

4

5 Yrs, % 50 53

5

6

7

Doses Received

Min 4 5

2-sided log-rank P = .03 60 40 Median follow-up: 4.2 yrs

20 0

Retreatment Maintenance

0

1

2

At Risk Cytotoxic 3 Yrs, % 143 28 84 146 8 95

3

4

5 Yrs, % 80 92

5

Yrs Since Random Assignment

Yrs Since Random Assignment RR (n = 120) MR (n = 130)

80

Max 16 31

Median 4.0 15.5

Kahl BS, et al. J Clin Oncol. 2014;32:3096-3102. Kahl B, et al. ASH 2011. Abstract LBA-6.

Mean 4.5 15.8

6

7

100

75

PFS (%)

75

50

50

HR: 0.21 (95% CI: 0.14-0.31; log-rank P < .0001)

25 0

0

1

2

3

4

5

6

50

0

HR: 0.73 (95% CI: 0.34-1.54; log-rank P = .40) 0

1

2 3 4 5 Yrs From Randomization

0

7

0

100

75

25

HR: 0.23 (95% CI: 0.16-0.32; log-rank P < .0001)

25

OS

100

OS (%)

PFS

Time to Start of New Treatment

100

No Histological Transformation (%)

No New Treatment (%)

Rituximab Maintenance vs Watchful Waiting in Asymptomatic FL: Outcomes

6

7

Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.

1 2 3 4 5 6 7 Time to Histological Transformation

75 50 HR: 0.62 (95% CI: 0.31-1.26; log-rank P = .19)

25 0

0

1

2

3

4

5

Yrs From Randomization

6

7

GADOLIN: Obinutuzumab + Bendamustine (OB) vs Bendamustine (B): Study Design •

Randomized, open-label, international phase III trial

Stratified by NHL subtype (FL vs other), prior therapies (≤ 2 vs > 2), refractory type, and geographic region

Rituximabrefractory CD20-positive indolent NHL (N = 413)

• •

Up to 6 28-day cycles

Bendamustine 90 mg/m2/day IV Days 1, 2 + Obinutuzumab 1000 mg IV Days 1, 8, 15 CR/PR/SD cycle 1; Day 1 cycles 2-6

For 2 yrs or until PD

Obinutuzumab maintenance 1000 mg IV q2m

Bendamustine 120 mg/m2/day IV Days 1, 2

Primary endpoint: PFS assessed independently Secondary endpoints: investigator-assessed PFS, OS, responses, safety, PK, PROs Sehn LH, et al. ASCO 2015. Abstract LBA8502.

Probability of PFS

GADOLIN: Bendamustine ± Obinutuzumab in Rituximab-Refractory iNHL (80% FL) O + B (n = 194) B (n = 202) IRF-Assessed PFS 71 (37) 104 (51) Events, n (%) 14.9 (12.8-16.6) Median PFS, mos (95% CI) NR (22.5-NR) Stratified HR (95% CI) 0.55 (0.40-0.74) Log-rank P value .0001

1.0 0.8 0.6 Median follow-up: 21 mos O+B B Censored

0.4 0.2 0

0

6

12

14.9 18

24 30 Mos

36

42

48

54

• Randomized, open-label, international phase III trial • Investigator-assessed median PFS O-B vs B: 29.2 vs 14.0 mos,

respectively; HR: 0.52 (95% CI: 0.39-0.70; P < .0001) • No significant OS difference observed in interim analysis Sehn LH, et al. ASCO 2015. Abstract LBA8502.

Slide credit: clinicaloptions.com

GAUSS Study Design: GA101 (Obinutuzumab) vs R (Rituximab) INDUCTION

Eligibility (N = 175) Relapsed, indolent NHL (FL: n = 149, nonfollicular indolent NHL: n = 26) Prior response to R-containing regimen lasting â&#x2030;Ľ6 mo

GA101 (n = 87) 1,000 mg, q1wk x 4

R R (n = 88) 375 mg/m2, q1wk x 4

Patients with no disease progression after induction received maintenance GA101 or R every 2 months for 2 years at the same dose.

Primary endpoint: Overall response rate (ORR) in the FL population Secondary endpoints: PFS, overall survival (OS), safety Sehn LH et al. Proc ASH 2011;Abstract 269.

GAUSS: Obinutuzumab vs Rituximab in Relapsed FL • Phase II randomized trial in

– ORR by independent review 44.6% with obinutuzumab vs 26.7%; P = .01 – No significant difference in PFS

Randomized treatment Obinutuzumab Rituximab

1.0

PFS (Proportion)

pts with relapsed CD20+ iNHL (N = 175) • In pts with FL (n = 149)

• Similar adverse event

profiles in both arms

Sehn LH, et al. J Clin Oncol. 2015;33:3467-3474.

0.8 0.6 0.4 0.2 0

HR: 0.93 (95% CI: 0.60-1.44; P = .74) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Mos 0 0

Slide credit: clinicaloptions.com

GAUDI Study: Obinutuzumab +CHOP and Obinutuzumab + FC Eligibility (N = 56) Relapsed or refractory FL

R

GA101 (1,600/800 mg) – Cycle 1: 1,600 mg d1,8 – Other cycles: 800 mg GA101 (400/400 mg) – 400 mg all cycles

• Patients were stratified by prior chemotherapy regimens before randomization: – CHOP (n = 28): 6-8, 21-d cycles – Fludarabine/cyclophosphamide (FC) (n = 28): 4-6, 28-d cycles • Patients responding to GA101 were offered maintenance treatment for 2 years or until progression.

Primary endpoint: Safety Secondary endpoint: Response rate Radford J et al. Proc ASH 2011;Abstract 270.

Response to Therapy (Abstract) Response*

G-CHOP (n = 28)

G-FC (n = 28)

ORR CR

96.4% 39.3%

92.9% 50.0%

PR

57.1%

42.9%

3.6%

0%

0%

3.6%

Stable disease Progressive disease

* Assessed by IWG criteria modified to classify unconfirmed CR as PR • 3.6% of patients in G-FC arm were not assessed.

• Response rates in the G-CHOP arm compared favorably to those in the rituximab in combination with CHOP cohort from the EORTC 20981 study in a matched-pair analysis.

Radford J et al. Proc ASH 2011;Abstract 270.

Ublituximab: Background •

Ublituximab (TG-1101, UTX) is a novel, chimeric monoclonal antibody that: – Targets a unique epitope on the CD20 antigen (green arrows) and – Glycoengineered to enhance affinity for all variants of FcγRIIIa receptors.

– Greater ADCC activity than rituximab and ofatumumab

•

Phase I trials of single agent ublituximab in patients with relapsed/refractory CLL and NHL reported impressive response rates with rapid and sustained lymphocyte depletion

Red: Amino acids contributing to ofatumumab binding Yellow: Amino acids essential for rituximab, but not ofatumumab binding Purple: Core amino acids of ublituximab epitope

ADCC, antibody-dependent cellular cytotoxicity Lunning M, et al. ASH (poster presentation) 2015. Abstract 1538.

Ublituximab + TGR-1202: Efficacy Patients Treated at the “Higher Doses” of TGR-1202 Best Percent Change from Baseline in Disease Burden CLL

RT

iNHL

MCL

DLBCL

25%

0%

G G

-25%

GG

G

G

G

-50%

-75% G

-100%

G = GCB

Lunning M, et al. ASH (poster presentation) 2015. Abstract 1538.

G

Ublituximab + TGR-1202: DLBCL Responses by Subtype (n=16)

Proportion of Progression Free

1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – 0.4 – 0.3 – 0.2 – 0.1 – 0.0 – 0

2

4

6

8

10

12

14

16

Time to Progression (months) Patients

ABC Unknown

18

20

§ ORR: – 33% (3/9) GCB – 0% (0/3) ABC – 50% (2/4) subtype unknown § Notable ac'vity has been observed par'cularly in pa'ents with GCB DLBCL § UNITY-DLBCL randomized study opening soon

GCB

Lunning M, et al. ASH (poster presentation) 2015. Abstract 1538.

Ublituximab + Ibrutinib: Efficacy Investigator Assessed Overall Response Rate and CR rate Ublituximab (UTX) + Ibrutinib vs. Ibrutinib Label

Response rate, %

100 90 80

33 %

70 60

17%

50 40 30 20 10 0

Ibrutinib (FDA label)

PR

CR

Ibrutinib + UTX

Kolibaba KS, et al. ASH (poster presentation) 2015. Abstract 3980.

UNITY-CLL 304: Phase 3 Trial for Patients with CLL Treatment-naïve or Previously Treated A Multi-center, Phase 3, Study of Ublituximab, a Glycoengineered Anti-CD20 mAb, in Combination with TGR-1202, an Oral PI3Kδ Inhibitor, Compared to Obinutuzumab + Chlorambucil, and Compared to Ublituximab or TGR-1202 Alone, in Patients with Treatmentnaïve or Previously Treated Chronic Lymphocytic Leukemia (CLL)

Key Eligibility Criteria:

§ ECOG Status 0, 1, or 2 § No prior exposure to a PI3K inhibitor § No prior exposure to obinutuzumab and/or chlorambucil

Ublituximab + TGR-1202

RANDOMIZE (1:1:1:1)

§ No limit on the number of prior lines of therapy

Obinutuzumab + Chlorambucil Ublituximab TGR-1202 Efficacy Endpoints: ORR, PFS

Ublituximab and TGR-1202 are investigational drugs and are not yet approved.

No claims on the safety or efficacy of these drugs are supported by the FDA.

Companion study of Ublituximab + TGR-1202 Available on progression

S C R E E N I N G

The GENUINE Phase 3 Trial

STRATIFICATION

By Prior Lines of Therapy

R A N D O M I Z E

Ublituximab + Ibru-nib

N=100 Part 1 ORR Subset

Ibru-nib N=100

• Design, endpoints, and statistics agreed to via Special

Protocol Assessment (SPA) • Enrolling ~330 patients with high-risk CLL • Part 1: ORR among first 200 patients • Part 2: PFS of all 330 patients – Part 1 to be analyzed following full enrolment of study

Part 2 PFS on All Pa-ents

Antibody-Drug Conjugates (ADCs)

Anatomy of an Antibody-Drug Conjugate (ADC) Linker stable in circulation Antibody targeted to tumor • Humanized monoclonal Ab (IgG1) • mAb with Fc modifications (modulate ADCC, CDC activity) • Other mAb fragments

• Linker biochemistry • Acid labile (hydrazone) • Enzyme dipeptides (cleavable) • Thioether (uncleavable) • Hindered disulfide (uncleavable) • Site of conjugation • Fc, HC, LC

Very potent chemotherapeutic drug • Tubulin polymerization inhibitors • Maytansines (DM1, DM4) • Auristatins (MMAE, MMAF) • DNA damaging agents • Calicheamicins • Duocarmycins • Anthracyclines (doxorubicin)

Modes of Anti-tumor Activity of ADCs

Tumor Cell

Tumor cytotoxicity is target-directed ADC-Ag binding → internalization in lysosomes → ADC degradation → release of toxin intracellularly → tumor cell death

Tumor Cells

Tumor cytotoxicity is target-enhanced (bystander effect) ADC-Ag binding → extracellular cleavage of toxin → release of toxin in local tumor environment → diffusion of toxin intracellularly to neighboring tumor cells → tumor cell death

Brentuximab Vedotin Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD30 monoclonal antibody

ADC binds to CD30 ADC-CD30 complex traffics to lysosome

MMAE is released MMAE disrupts microtubule network

G2/M cell cycle arrest Apoptosis

Indolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Polatuzumab Vedotin and Pinatuzumab Vedotin Activity in Rel/Ref NHL

clinicaloptions.com/oncology

Antibody With Potential Conjugation Sites for VC-MMAE (*)

ADC binds to receptor ADC in circulation

VC-MMAE (linker-drug)

MC -Cys

O S N O

Protease cleavage

VCPABC

O H NO NO N H H H 2N

HN O

ADC-receptor complex is internalized

MMAE

O OO OO O N N N N N O HO H OH

Apoptosis (cell Cytotoxic agent is Microtubule death) released in disruption lysosomes SAR-3419 CD-19 – DM4 SGN-CD19a CD19 – MMAF Pinatuzumab CD22 – MMAE Polatuzumab CD79 – MMAE Morschhauser F, et al. ASCO 2014. Abstract 8519.

Polatuzumab (CD79b ADC) + Rituximab vs Pinatuzumab (CD22 ADC) + Rituximab

Phase II ROMULUS: R/R FL (n = 41) R/R DLBCL (n = 81)

Arm A Rituximab 375 mg/m2 + Pinatuzumab Vedotin (CD22 ADC) 2.4 mg/kg

Biopsy at progression PD

R + CD79b ADC

Administered in every-21-day cycles up to 1 year

Arm B Rituximab 375 mg/m2 + Polatuzumab Vedotin (CD79b ADC) 2.4 mg/kg

PD

R + CD22 ADC

Endpoint evaluations: § TEAE per NCI CTCAE v4.0 § Antitumor activity per IWG criteria § Pharmacokinetic and pharmacodynamic evaluations Morschhauser F, et al. ASCO 2014. Abstract 8519.

Polatuzumab (CD79b) + R vs Pinatuzumab (CD22) + R: Best Responses* Responses

DLBCL

FL

R + CD22 ADC (n = 42)

R + CD79b ADC (n = 39)

R + CD22 ADC (n = 21)

R + CD79b ADC (n = 20)

57

56

62

70

24 (12-39) 33 (20-50)

15 (6-31) 41 (26-58)

10 (11-30) 52 (30-74)

40 (19-64) 30 (12-54)

SD, %

7

10

29

30

PD, %

21

30

5

0

Unable to evaluate, %

19

5

5

0

6.0 (2.9-12.2)

NR (2.6-NR)

5.8 (2.6-10.1)

NR (5.7-NR)

Objective response, % § CR (95% CI) § PR (95% CI)

Median duration of response, mos (95% CI)

*Investigator assessed.

Morschhauser F, et al. ASCO 2014. Abstract 8519.

Survival Rate

Polatuzumab (CD79b) + R vs Pinatuzumab (CD22) + R: PFS 1.0

DLBCL

0.8 0.6 0.4

CD22 + R CD79b + R

0.2 0 0

2

4

6

8

10

12

14

Median PFS, Mos (95% Cl) R + CD22 ADC (N = 42)

R + CD79b ADC (N = 39)

5.4 (2.8-8.4)

5.2 (4.1-NR)

16

Survival Rate

Mos 1.0 0.8 0.6 0.4 0.2 0

FL

CD22 + R CD79b + R 0

2

4

6

Mos

8

10

12

14

Median PFS for FL not reported due to insufficient duration of follow-up

Morschhauser F, et al. ASCO 2014. Abstract 8519.

SGN-CD19A in R/R NHL (Moskowitz): Study Schema • Ongoing phase I open-label, dose-escalation study of SGN-CD19A (anti-CD19 antibody drug conjugate) in R/R B-cell NHL • Primary endpoints: safety, MTD • Secondary endpoints: efficacy, PK, antitumor activity

R/R B-cell NHL (N = 44) • ≥12 years of age • Confirmed DLBCL or FL grade 3 • ECOG 0-1 • ≥1 prior systemic regimen • Prior intensive salvage therapy ± ASCT (DLBCL or FL3 only)

SGN-CD19A 0.5-6 mg/kg IV, day 1 of 21-day cycles

MTD Response by IWG 2007

Moskowitz et al. ASH 2014. Abstract 1741.

SGN-CD19A in R/R NHL (Moskowitz): Safety TEAEs (≥ 10%) Blurred vision

59%

Dry eye

39%

Fatigue

39%

Constipation

32%

Keratopathy

23%

Pyrexia

20%

• Median duration of treatment was 9.2 weeks (range, 3-36) • Low incidence of grade 3/4 AEs: 10% thromobocytopenia, 8% anemia, and

2% neutropenia • MTD not yet escalating to 6 mg/kg • 1 DLT of corneal epithelia keratopathy (3 mg/kg ) – Ocular AEs were most common in 35 (67%) patients – Time to onset of grade 3+ ocular events was ~2 cycles; improved in most patients through dose modication

• SGN-CD19A ADC plasma exposures were approximately dose proportional • Accumulation was observed following multiple dose administrations, consistent with a

mean terminal t1/2 of about 2 weeks, suggesting less frequent dosing might be possible Moskowitz et al. ASH 2014. Abstract 1741.

SGN-CD19A in R/R NHL (Moskowitz): Efficacy Response, n (%)

Evaluable (n = 43)

Relapsed (n = 17)

Refractory (n = 26)

ORR (95% CI)

13 (30) (17%-46%)

9 (53) (28%-77%)

4 (15) (4%-35%)

CR

7 (16)

5 (29)

2 (8)

PR

6 (14)

4 (24)

2 (8)

SD

13 (30)

4 (24)

9 (35)

PD

17 (40)

4 (24)

13 (50)

• Of 13 responders, 8 remain on study with follow-up times of 0.1-31 weeks

– 2 patients are no longer on study – 3 had subsequent PD or death, with DOR of 14, 19, and 31 weeks

• Current clinical trial: – Phase II randomized SGN CD19 + R-ICE vs R-ICE for R/R DLBCL as second line

Moskowitz et al. ASH 2014. Abstract 1741.

Bi-specific antibodies (BiTE)

Blinatumomab: Bispecific T-Cell Engager Antibody MOA § Blinatumomab[1] – Blinatumomab: bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19positive cells, resulting in serial lysis[2] – CD19: highly specific B-cell marker expressed throughout B-cell development and in >90% of B-cell lineage cancers[3] – Blinatumomab was approved in December 2014 by the FDA to treat pts with Ph- precursor B-cell ALL

1. Gökbuget N, et al. ASH 2014. Abstract 379.

2. Bargou R, et al. Science. 2008;321:974-977.

3. Raponi S, et al. Leuk Lymphoma. 2011:52;1098-1107.

T Cell

CD3

TCR

Blinatumomab CD19

B-precursor ALL cell

Blinatumomab for Relapsed/Refractory, B-Precursor, Ph-Negative ALL § Multicenter, single-arm, open-label phase II study Pts with Ph-, B-cell precursor ALL who were 18 yrs of age or older and were refractory after induction, had relapsed within 12 mos of CR1 or HCT, or were relapsed/refractory after salvage tx (N = 189)

Blinatumomab 9 µg/day CIV for 1 wk,* then 28 µg/day to 4 wks, then 2 wks off; up to 5 cycles

§ Primary endpoint: CR and CRh within the first 2 cycles § Median age: 39 yrs Dexamethasone premedication was required 1 h before tx initiation in each cycle. Pts who achieved CR/CRh after 2 cycles could receive 3 more cycles. *During cycle 1.

Topp MS, et al. Lancet Oncol. 2015;16:57-66.

Blinatumomab in Relapsed/Refractory ALL: Efficacy Outcome

All Pts (N = 189)

CR or CRh in first 2 cycles, %

43

CR in first 2 cycles, %

33

MRD negativity in first 2 cycles, %*

82

Median OS, mos § All pts § MRD-negative CR § MRD-positive CR

6.1 11.5 6.7

Median RFS, mos § CR + CRh § CR § CRh

5.9 6.9 5.0

Allogeneic HCT, %* § After CR § After CRh

40 44 22

100-day mortality after allogeneic HCT, %

11

*Of pts in CR or CRh. Topp MS, et al. Lancet Oncol. 2015;16:57-66.

Blinatumomab for the treatment of Relapsed/ Refractory non- Hodgkin lymphoma: Phase I results § Multicenter, single-arm, open-label dose escalation Phase I study

Pts with refractory CD19+ B-cell NHL who were 18 yrs of age or older. ECOG of 2 and no evidence of CNS involvement.

Blinatumomab CI dose escalation 0.5, 1.5, 5, 15, 30, 60 and 90 ug/m2/d

§ Primary endpoint: Safety and DLT § Secondary end points: CR and CRh within the first 2 cycles § Median age: 65 yrs (20 – 80) § Histologies: FL, MCL, DLBCL (relapsed post auto HSCT) Dexamethasone premedication was required 1 h before tx initiation in each cycle. Pts who achieved CR/CRh after 2 cycles could receive 3 more cycles. *During cycle 1.

Goebeler et al. J Clin Oncol 2016

Clinical responses • Responses at 0.5, 1.5 and 6 ug/m2/day were minimal • At target dose of 60 u/m2/day: – FL (n=15): ORR 80% (6 PR, 6 CR) – MCL (n=7): ORR 71% (2 PR, 3CR) – DLBCL (n=11): ORR 55% (2 PR, 4 CR)

Ongoing Phase II Study Design (NCT01741792) Eligibility (n = 25) DLBCL refractory to first or later therapy or relapsed after auto-HSCT or relapsed and ineligible for auto-HSCT

Blinatumomab, IV

Auto-HSCT = autologous hematopoietic stem cell transplant • Nine, 2 and 14 patients enrolled in cohorts I, II and III, respectively.

• Stage 1: Stepwise dosing (cohort I: 9, 28 and 112 µg/d) compared to constant dosing of 112 µg/d (cohort II).

• Based on the benefit/risk assessment from stage 1, stepwise dosing was chosen for cohort III in stage 2.

• Patients achieving response after 8 weeks could receive a 4-week consolidation cycle after a 4-week treatment-free period.

• All patients received prophylactic dexamethasone.

• Primary endpoint: ORR Viardot A et al. Proc ASH 2014;Abstract 4460;

Adverse Events • All patients (n = 25) experienced ≥1 adverse event (AE).

• The most common AEs were tremor (52%), pyrexia (44%), diarrhea

(24%), fatigue (24%), edema (24%) and pneumonia (24%).

• Grade 3 and 4 AEs occurred in 96% and 20% of patients,

respectively.

• Serious AEs occurred in 92% of patients.

– Most common: pneumonia (24%), device-related infection (16%) and pyrexia (16%)

• Seven patients (cohort I, n = 3; cohort II, n = 2; cohort III,

n = 2) had Grade 3 neurologic AEs. – Grade 3 AEs occurring in >1 patient were disorientation, encephalopathy, aphasia and epilepsy (n = 2 each).

Viardot A et al. Proc ASH 2014;Abstract 4460 (Abstract only).

Response to Blinatumomab n = 21*

Response ORR

43%

Complete response

4 (19%)

Partial response

5 (24%)

* Evaluable patients (cohort I, n = 7; cohort II, n = 1; cohort III, n = 13) • Four patients were not evaluable for ORR due to early treatment discontinuation (<1 week on target dose in the absence of disease progression): 1 due to investigator’s decision and 3 due to adverse events.

• All patients who responded did so within the first 8-week cycle.

• Among responders (n = 9), the median duration of response was 11.6 months.

Viardot A et al. Proc ASH 2014;Abstract 4460 (Abstract only).

CART therapy for B-cell lymphomas

"young" TIL were generated using a shortened preexpansion culture phase before rapid cell expansion, enabling produ within 5 to 7 weeks from the time of tumor collection.

Adoptive immune therapy The MD Anderson cell Cancer Center at the University of Texas at Houston (10) and at the Sheba Medical Center in Israel (1), where response rates of 40% or more were consistently achieved among patients who eventually received treatment.

Although these studies corroborated the original promising results, only 40% to as few as 27% of patients who underwent resection for TIL generation ultimately received TIL therapy (11); this attrition is due in part to disease progression, protocol-specific, and product-related exclusion criteriaâ&#x20AC;&#x201D;features that could be addressed by a shortened time to therapy from enrollment and modification of productrelease criteria. Although the original TIL protocol, commonly practiced at the NCI required 7 to 8 weeks from resection to TIL product, the young TIL protocol developed

by Tran and colleagues shortened the pre-expansion phase, eliminated exclusion of TIL cultures on the basis of absent in vitro activity, and produced a TIL product in 4 weeks (12);

www.aacrjournals.org

implementation of this proto Besser and colleagues (1), led enrollment ratio, with respons at least as favorable as those s 10% of patients failed to yiel 14% were excluded due to cli There remain, however, a resolved: Should ablative radi conditioning regimen, and w sidered for this risk-intense b Can a superior TIL effector p basis of in vitro phenotype ulation? Is there a clinical profile that can identify pati therapy? Furthermore, the tre with metastatic melanoma h and dramatic fashion over the

Clin Cancer

Yee. Clin Cancer Res 2013

Expression of CD19 and other B cell markers on B lineage cells B cell lymphomas and leukemias

preB-ALL

myelomas

Y

Y

Y Y

pre B

CD19 CD22 CD20

Y pro B

Y

Stem Cell

immature B

mature B

plasma cell

Chimeric Antigen Receptors: MOA • Chimeric antigen receptors[1]

– Genetically engineered receptors that combine anti-CD19 single chain variable fragment of an antibody with intracellular signaling domains of T cells – With the use of lentiviralvector technology, CTL019 T cells express a CAR with CD3 zeta and 4-1BB (CD137) signaling domains[2]

MHCindependent antigen engagement CD19 and induction of signalling

CD19+ tumor

scFV scFV

4-1BB (CD137) CD3 zeta

APC

1. Grupp S, et al. ASH 2014. Abstract 380.

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

CD28 4-1BB CD3 zeta

T cell

T cell

Proliferation, cytokine production, CTL function, tumor lysis

CAR T Cell Anatomy

Tumor Cell

• ScFv: antibody singlechain variable fragment • Permits antigen recognition

An-gen scF v

Co-s-mula-on domain (CD28, 4-1BB, CD134)

Antibody-like recognition + T-cell activating function • Extracellular

• Hinge

Signaling domain (CD3ζ)

CAR T Cell

• Intracellular • Signaling domains • T cell activation Jackson HJ, et al. Nat Rev Clin Oncol 2016;13(6):370-83.

Sharpe M, et al. Disease Models & Mechanisms 2015 8: 337-350

Tumor Cell

Tumor Cell

An-gen

An-gen

An-gen

scFv

scFv

Signaling domain

scFv

Co-s-mula-on domain Signaling domain

CAR T Cell

Tumor Cell

Co-s-mula-on domain

Signaling domain

CAR T Cell CAR T Cell

First Generation

Second Generation

Third Generation

CAR T Cell Design Jackson HJ, et al. Nat Rev Clin Oncol 2016;13(6):370-83.

Sharpe M, et al. Disease Models & Mechanisms 2015Â 8:Â 337-350

CAR T Cell Essentials

Klebanoff, et al. Nature Reviews Clinical Oncology 2014; 11: 685â&#x20AC;&#x201C;686

CAR T Cell Expansion • Approximately 2 weeks • Isolation and activation of T

cells – Different expansion platforms

• Produced ~12-14 days from ex vivo culture • Ideal cell dose unknown – 1x106 cells/kg – 1x107 cells/kg

Almåsbak H, et al. J Immunol Res 2016.

Mato A et al. Blood 2015;126:478-85.

Wang X, et al. Molecular Therapy 2016;3:16015 Dai H, et al. JNCI J Nat Cancer Inst 2016;108(7) Maus MV, et al. Blood 2014;123(17):2625-2635

Chimeric Antigen Receptor T Cells 5

1

4

2

3 Images courtesy of David Porter, MD; University of Pennsylvania

Phase 2a Study of CTL019 Cell Treatment in Extensively Pretreated CD19+ NHL: Study Design Key eligibility criteria • Adult histologically proven CD19+ relapsed or refractory DLBCL, FL, or MCL • DLBCL R/R after ASCT or ineligible for ASCT, or transformed from CLL/SLL or FL • FL with ≥2 prior CIT

regimens and PD <2 years after prior therapy • MCL relapsed or PD after or during 1st-line rituximab, relapsed after or not eligible for ASCT • Measurable disease

Enrollment started Feb 2014; data reported here through July 26, 2015.

Single IV dose of CTL019 cells, 1-4 days after chemotherapy

Immunophenotypic, cytokine and molecular studies performed at prespecified times after T cell infusion

Initial tumor response assessed 3 months after infusion using IWG response criteria

Collection of PB and BM samples

Primary Objectives: ORR at 3 months; determine response rate by lymphoma biology Secondary endpoints: Determine CTL019 cell manufacturing feasibility; safety; best response; PFS; determine in vivo expansion of CTL019 cells; determine effects on B cells and CD19 expression in vivo

• ECOG PS 0 or 1 Schuster et al. ASCO 2015. Abstract 183.

CTL019 in B-Cell Lymphomas: Pt Characteristics DLBCL (n = 19)

FL (n = 8)

MCL (n = 3)

56 (25-77)

60.5 (43-71)

55 (55-61)

68

38

66

4 (1-8)

5.5 (4-8)

4 (3-6)

Prior SCT, %

37

25

30

Stage III-IV, %

63

88

100

Elevated LDH, %

74

63

66

> 1 extranodal involvement, %

32

13

100

Median ECOG PS

1

0

1

Characteristic Median age, yrs (range) Male, % Median prior therapies, n (range)

Schuster S, et al. ASCO 2015. Abstract 8516.

CTL019 in B-Cell Lymphomas: PFS in DLBCL

DLBCL: PFS (days)

DLBCL: PFS 1.00

N = 13 Median PFS 90 days

0.75 0.50 0.25 0

0

100

200 Days

300

13413-01 13413-02 13413-05 13413-06 13413-09 13413-10 13413-12 13413-16 13413-17 13413-21 13413-22 13413-23 13413-28

400

0

100

200

300

400

Ongoing clinical responses Days to progressive disease

Schuster S, et al. ASCO 2015. Abstract 8516.

CTL019 in B-Cell Lymphomas: AEs Potentially Related to Treatment • No deaths from cytokine release syndrome; 1 death from

encephalopathy Grade ≥ 3 AE

Grade 3

Grade 4

Grade 5

Acute kidney injury

2

0

0

Cytokine release syndrome

1

1

0

Hypotension

1

1

0

Encephalopathy

0

0

1

Acidosis

1

0

0

Delirium

1

0

0

Fever

1

0

0

Hypertension

1

0

0

Infection

1

0

0

Schuster S, et al. ASCO 2015. Abstract 8516.

Phase 2a Study of CTL019 Cell Treatment in Extensively Pretreated CD19+ NHL: Safety Selected Adverse Events*, n

Grade 3

Grade 4

Grade 5

Total ≥ Grade 3

Agitation

1

-

-

-

Delirium

2

-

-

2

Encephalitis

-

-

1

1

Cytokine release syndrome (CRS) *at least possibly related.

2

2

-

4

•

The toxicity of this therapeutic approach appears acceptable

•

CRS was generally grade 2 and there were no deaths from CRS

Schuster et al. ASH 2015. Abstract 183.

Ongoing Complete Remissions in Phase 1 of ZUMA-1: A Phase 1-2 Multicenter Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Patients With Refractory Aggressive B Cell Non-Hodgkin Lymphoma (NHL) •

Locke, F1, Neelapu, S2, Bartlett, N3, Siddiqi, T4, Chavez, JC5, Hosing, C6, Cashen, A3, Budde, L4, Bot, A7, Rossi, J7, Navale, L7, Jiang, Y7, Aycock, J7, Elias, M7, Wiezorek, J7, Go, W7

•

1Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, US; 2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, US; 3Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, US; 4Department of Hematology andHematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, US; 5Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, US; 6Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, US; 7Kite Pharma, Santa Monica, CA, US

KTE-C19 Is an Autologous CD3ζ/CD28-Based CAR T Therapy Designed to Eliminate CD19-Expressing Cells • KTE-C19 is centrally manufactured in

a streamlined 6- to 8-day process • Upon recognition of CD19, KTE-C19

is designed to – Target – Activate – Proliferate – Systemically kill target cells throughout the body

90

ZUMA-1 Is a Multicenter Trial of KTE-C19 in Refractory Aggressive NHL (NCT02348216) Phase 2 Phase 1 Refractory DLBCL/PMBCL/TFL (cohort of n=6)

Eligibility criteria • Chemotherapy-refractory disease: PD or SD as best response to most recent chemotherapy or relapse ≤12 months of prior ASCT • Adequate prior therapy: anti-CD20 monoclonal antibody and an anthracycline-containing chemotherapy • ECOG PS 0-1

Cohort 1 Refractory DLBCL (n=72) Cohort 2 Refractory PMBCL/ TFL (n=~40) Primary endpoint • Phase 1: incidence of DLTs • Phase 2: ORR Key secondary endpoints • DOR • Progression-free/overall survival • Safety • Levels of CAR and cytokines

Neelapu SS, et al. ESMO 2016. Abstr 3222.

Abbreviations: DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PS, performance status; SD, stable disease.

91

Postinfusion Kinetics of CAR T Cells in Blood With KTE-C19a

Abbreviation: PBMC, peripheral blood mononuclear cell. aMeasurement by quantitative polymerase chain reaction; patient 7 was not evaluated. bLOD is 0.001% anti-CD19 CAR T cells/ PBMC.

92

Duration of Response and OS

93

d Combination therapy | Approaches to improve CAR-T-cell therapy.

Na

b

d| e| f|

cell-death protein 1 (PD-1) ligands or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) ligands. These inhibitory receptor–ligand interactions can be blocked with monoclonal antibodies that abrogate suppression of T cells; although this approach has shown encouraging results in some malignancies, the success of these therapies clearly relies on the presence of a pre-existing endogenous tumour-specific T-cell response149–152. Indeed, CAR T cells are susceptible to PD-1-mediated inhibition and, therefore, the combination of CAR T-cell therapy with monoclonal antibody immune-checkpoint inhibitors is an obvious progression to protect CAR-T-cell function within

the tumour microenvi ical trial at Baylor is in therapy in patients wit B-ALL (NCT00586391 with CD19-specific C combination with ipilu monoclonal antibody.

A potential reason for reduced persistence of C recognition of CAR-d subsequent immune-m

| CLINICAL ONCOLOGY ǟ ƐƎƏƖ !,(++ - 4 +(2'#12 (,(3#"ƥ ++ 1(%'32 1#2#15#"ƥ ɥ ɥ ɥ ɥ ɥ ɥ ɥ

Jackson et al. Nat Rev Clin Oncol 2016

trials at the University of Pennsylvania (Philadelphia, PA; NCT02624258, NCT01837602, NCT02277522, NCT02623582).

ization and T-cell depletion via the administ molecule AP1903 is a strategy that has been u graft-versus-host disease, demonstrating th approach (35).

CAR T cells may also be depleted through t protein for which a depleting antibody is alr that is, CD20 or EGFR (Fig. 2C). Administrat antibody is expected to deplete target-expre therapy-related toxicity arises or if "cure" has maintained (36). To our knowledge, neithe have been clinically tested as a CAR T-cellâ&#x20AC;&#x201C;d patients, but CARs containing an EGFR tran under clinical investigation at several cente NCT02159495, NCT01865617). Most inve ferred to manage toxicities with either cy corticosteroids, or both, rather than permane tially curative (and expensive) therapy.

A recent article demonstrated proof-of-c "ON-switch"-based CAR T cells; here, the sig the CAR was separated and each end was fu domain similar to the basis of iCasp9, wh

Regulating CAR CARs T-cell Persistence: Methods to regulate persistence Strategies on the Horizon

One of the beauties of CAR T cells is that they are "living drugs": once infused, physiologic mechanisms maintain T-cell homeostasis, memory formation, and antigen-driven expansion. However, imperfect human intervention may lead to T cells that target an undesired tissue or proliferate to greater levels than necessary and therapeutic. As CAR T cells become incorporated into standard therapies, it may be useful to design them with patient- or physician-controlled persistence mechanisms, either "ON" switches or "suicide" switches. For technical reasons, suicide switches are easier to incorporate into T cells. One of the fastest acting and clinically tested suicide gene strategies is the inducible caspase-9 (iCasp9) system (Fig. 2B; ref.33). Cells transduced with iCasp9 can be depleted by administration of a synthetic small molecule that dimerizes iCasp9 promolecules, triggering activation of the apoptotic pathway (34). Induction of iCasp9 dimer-

1878 Clin Cancer Res; 22(8) April 15, 2016

Clin

Maus et June. Clin Cancer Res 2016

Immunotherapy and Cellular Therapy (ICE-T) service at Moffitt Cancer Center • Objectives: – Develop expertise in the treatment of adoptive cellular therapies – Develop expertise in the treatment of complications of cellular therapies: neurotoxicity, cytokine release syndrome – Develop clinical trials to enhance the potency of cellular therapies • Multidisciplinary team: Collaboration – TILs – TCR (NY-ESO) – CART

ICE-T Team • Frederick Locke (Director): DLBCL and MCL • Javier Pinilla-Ibarz: CLL • Julio Chavez: FL and DLBCL • Bijal Shah: ALL and MCL • Mihaela Druta: TCR in sarcomas • Ben Creelan: TCR in lung cancer • Amod Sarnaik: TCR and TILs in melanoma • Jason Brayer: Myeloma

Concluding remarks • Monoclonal antibodies (MAbs)remain as important part of

the armamentarium of the treatment for B-cell malignancies with low toxicity profile • Conjugate antibodies (ADC) represent an effective and tolerable alternative for B-cell malignancies. Combination with chemotherapy studies are ongoing • Bi-specific antibodies (BiTE) are very effective.

Challenges with the management of toxicity • CART: Groundbreaking discovery. FDA approval

julio.c.chavez@moffitt.org