CAR T-Cell Therapy for Lymphoma: Assessing Long-Term DurabilityJulie M. Vose, MD, MBA

Relevant Disclosures

Research Funding: Kite Pharma/Gilead, JUNO/Celgene, Novartis

Honorarium/Ad Boards: Novartis, Kite Pharma/Gilead, JUNO/Celgene, Legend, Janssen

(A) Progression-free survival (PFS)according to prior rituximab (ITT)

Gisselbrecht et al. J Clin Oncol 2010 28:27;4184-4190.

What does AutoSCT achieve in r/r DLBCL in the rituximab era? CORAL Study

(B) PFS according to time to failure from diagnosis (ITT)

3-year PFS ≈ 29%

3-year PFS ≈ 29%

100 Relapsed or Refractory DLBCL

50 Transplant-Ineligible

Potential Deaths from Lymphoma

50 Transplant Eligible

25 Respond to

Salvage Therapy and ASCT

10 Patients Cured

What does AutoSCT achieve in r/r DLBCL in the rituximab era*?

* Estimates based on Gisselbrecht et al. J Clin Oncol 2010 28:27;4184-4190.* Assumes all patients received rituximab as part of primary therapy.

What can CD19-directed CAR T-Cells achieve in r/r DLBCL in the rituximab

era?

CD19-directed CAR T-CellsKTE-C19

axicabtagene ciloleucel(axi-cel)

CTL019tisagenlecleucel

(CTL019)

JCAR017lisocabtagene maraleucel

(liso-cel)

Kite Pharma Novartis Juno Therapeutics

scFv = anti-CD19 scFv = anti-CD19 scFv = anti-CD19

CD28-CD3ζ 4-1BB-CD3ζ 4-1BB-CD3ζ

FDA approved FDA approved investigational

CD19-directed CAR T-Cells:What is the Response Rate in r/r DLBCL?

auto-SCT, autologous stem cell transplant; CNS, central nervous system; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; IRC, Independent Review Committee; ORR,

overall response rate; OS, overall survival; PD, progressive disease; PR, partial response.

JULIET Trial: Eligibility and endpoints• tisagenlecleucel (CTL019)

• ≥ 18 years of age

• Central confirmation of histology

• ≥ 2 prior lines of therapy for DLBCL

• PD after or ineligible for auto-SCT

• No prior anti-CD19 therapy

• No active CNS involvement

• Primary endpoint: best

overall response rate

(ORR: CR + PR)

– Lugano criteria used for response assessment by IRC1

• Secondary endpoints: DOR,

OS, safety

Key eligibility criteria Endpoints

N = 111; Median follow-up, 14 mo (max, 23 mo)

1. Cheson BD, et al. J Clin Oncol. 2014;32(27):3059-3068.

JULIET: Patient characteristicsPatients (N = 111)

Age, median (range), years 56 (22-76)

≥ 65 years, % 23

ECOG performance status 0/1, % 55/45

Central histology review

Diffuse large B-cell lymphoma, % 79

Transformed follicular lymphoma, % 19

Double/triple hits in CMYC/BCL2/BCL6 genes, % 17

Cell of origin

Germinal/Nongerminal center B-cell type, % 57/41

# of prior lines of antineoplastic therapy, %

2/3 / 4-6 44/31 / 21

IPI ≥ 2 at study entry, % 72

Refractory/relapsed to last therapy, % 55/45

Prior auto-SCT, % 49

Bridging chemotherapy, n 102

Lymphodepleting chemotherapy, n 103

* from Borchmann et al. EHA 2018.

JULIET: Response ratesBest ORR w/in 3 months of infusion, 52% (95% CI, 41%-62%): 40% CR, 12% PR

*Borchmann et al. EHA 2018.

ZUMA-1 Trial: Eligibility and endpoints

Locke, et al. ASCO 2018.

• ZUMA-1 phase 2 portion

– Cohort 1: patients with refractory DLBCL (n = 77)

– Cohort 2: patients with refractory PMBCL or transformed FL (n = 24)

• Key inclusion criteria

– No response to last CT or relapsed within 12 mos of ASCT

– Prior treatment with anthracycline and anti-CD20 monoclonal antibody

Key eligibility criteria Secondary Endpoints

• Assess TTR for patients with both objective response and CR

• Assess PR and CR at Month 3 as PFS prognostic factor

TTR, time to response

• axicabtagene ciloleucel (KTE-C19)

ZUMA-1: Patient Characteristics

Locke, et al. ASCO 2018.

CharacteristicOverallN=101

Median age, yrs (range) 58 (23-76)

Male, n (%) 68 (67)

ECOG PS 1, n (%) 59 (58)

Disease stage III/IV, n (%) 86 (85)

IPI score 3-4, n (%) 46 (46)

3 prior therapies, n (%) 70 (69)

Median SPD of index lesions, mm2 (range) 3721 (171-23, 297)

Refractory to 2 lines of therapy, n (%) 77 (76)

Best response as PD to last therapy, n (%) 67 (66)

Relapse post-ASCT, n (%) 21 (21)

ZUMA-1: Response rates

Phase 2 (Primary Analysis)N = 101

Median follow-up, mo 8.7

ORR CR

Best objective response, % 82 54

Ongoing, % 44 39

Neelapu, et al. ASH 2017

Neelapu, et al. ASH 2017.

SCT, stem cell transplant; CNS, central nervous system; CR, complete response;DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; ORR, overall response rate;

OS, overall survival; PR, partial response.

TRANSCEND NHL 001 Trial: Eligibility and endpoints• lisocabtagene maraleucel (liso-cel; JCAR017)

• DLBCL after 2 lines of therapy:

– DLBCL, NOS (de novo or transformed FL)

– High-grade B-cell lymphoma

(double/triple hit)

▪ Prior SCT allowed

▪ Secondary CNS involvement allowed

▪ ECOG 0-2

▪ No minimum lymphocyte count

requirement for apheresis

• Response rates

- ORR, CR, PR

• DOR, OS, safety

Key eligibility criteria* Endpoints

N = 73*; Median follow-up, 8 mo (CORE cohort)

*CORE cohort

TRANSCEND: Response rates

ORR* at 3 months from infusion, 59% (95% CI, 47%-70%): 45% CR, 14% PR

*Abramson, et al. ASCO 2018.*Includes 2 dose levels in CORE cohort

CD19-directed CAR T-Cells:Are Responses Durable?

JULIET: TisagenlecleucelResponse Duration by Best ORR w/in 3 months of infusion (JULIET)

* from Borchmann et al. EHA 2018.

• Median DOR not reached at 14-mo median follow-up

• 12-mo relapse-free survival rate

CR = 78.5% (95% CI, 60%-89%)

CR + PR = 65% (95% CI, 49%-78%)

ZUMA-1: Axicabtagene Ciloleucel Response Duration by Best Objective Response (ZUMA-1)

Neelapu SS, et al. NEJM. 2017;377:2531; Locke FL, et al. ASCO 2018.

• More than one half of patients with PR progressed by Month 3• 12 mo PFS for CR or PR at 3 mos: CR = 79% (95% CI, 63-88); PR = 78% (95% CI, 36-94)

TRANSCEND: lisocabtagene maraleucel Response Duration (TRANSCEND)

* from Abramson et al. ASCO 2018.

• Median DOR not reached at 8-mo median follow-up

* Borchmann et al. EHA 2018; ** Locke, et al. ASCO 2018; Neelapau, et al. NEJM. 2017;*** Abramson et al. ASCO 2018.

CTL019 *tisagenlecleucel

KTE-C19 **axicabtagene ciloleucel

JCAR017 ***lisocabtagene maraleucel

Disease state r/r DLBCL r/r tFL r/r DLBCL r/r tFL/PMBCL r/r DLBCL r/r tFL

Response evaluable pts, n 89 22 77 24 53 20

Follow-up, median 14 months 15.4 months 8 months

Efficacy n = 111 n = 101 N = 73

ORR / CR 52% / 40% [w/in 3 mo] 82% / 54% [best] 59% / 45% [at 3 mo]

% PFS for CR @ 12 mos 78.5% 79% [88% 3 mo-CR in CR @ 6 mo]

DOR (CR + PR; median) not reached 11.1 months not reached

DOR (CR; median) not reached not reached not reached

Safety n = 111 n = 101 n = 73

CRS 22% grade 3/4* 13% grade > 3** 1% grade > 3**

Neurotoxicity 12% grade 3/4 28% grade > 3 15% grade 3/4

* Penn scale; ** Lee scale

CD19-directed CAR T-Cell Therapy Summary

22

Factors That Influence Treatment Success and Failure to CAR T Cell Therapy: A Hypothesized Model

T cell expansion capability

T cell polyfunctionality

CAR functional avidity

Number of‘specialized’T cellsinfused

Tumor burden

Tumor cell biology

Tumor immunemicroenvironment

Conditioning and concomitant medications

PK/PD profile

Clinical efficacy and toxicity

Infl

amm

ato

ry s

tate

Manufacturing starting material

Product fitness:

CAR, chimeric antigen receptor; PD, pharmacodynamics; PK, pharmacokinetics.Adapted from Locke et al SITC 2018 #P212

• CAR expansion was significantly associated with response (P < .001), with an AUCDay0-28 that was 5.4 times as high among patients with a response as among those who did not have a response

23

In ZUMA-1 CAR T Cell Expansion Associated With Response

Objective Response Rate (ORR)

• CAR AUCDay0-28 is defined as cumulative levels of CAR+ cells/μL of blood over the first 28 days post axi-cel

• AUC fold change is shown for patients with vs. without response Locke et al ASCO 2017 #3023

24

CAR Peak Levels In Vivo and Polyfunctional Strength Index Associated With Objective Response

aMann-Whitney U Test.CAR, chimeric antigen receptor; NR, nonresponder; PSI, polyfunctional strength index; R, responder.

CAR PeakP = .0326a

CAR Peak + PSIP = .0046a

PSIP = .0119a

No

rmal

ized

CA

R P

eak

+ P

SI

NR R

Pre

-In

fusi

on

Po

lyfu

nct

ion

al S

tren

gth

NR R

Post

-In

fusi

on

CA

R P

eak

Leve

ls

NR R

Rossi et al AACR 2017 #2990

Association Between Immunosign 21 Score Measured Before CAR T Cell Treatment and Clinical Outcomea

• A high Immunosign 21 score was associated with objective response at a minimum follow-up of 9 months (P = .012)

• In a sensitivity analysis, which included the delayed responder, the association between a high Immunosign 21 score and objective response had a P = .053

25

aThis analysis was performed on samples from 25 patients treated with axi-cel with a minimum follow-up of 9 months. One patient subsequently converted from a “nonresponder” to a “responder” at 12-month follow-up.bCutoff was arbitrarily defined as the 25th percentile of the observed scores among samples.

Rossi et al AACR 2018 #LB-016

Differences in Expression of Immunosign 21 Genes Measured Before CAR T Cell Treatment in Responders vs Nonrespondersa

26

aThis analysis was performed on samples from 25 patients treated with axi-cel with a minimum follow-up of 9 months. One patient subsequently converted from a “nonresponder” to a “responder” at 12-month follow-up.

Rossi et al AACR 2018 #LB-016

Treatment with Axi-Cel Results in Rapid and Dramatic Changes in the Tumor Immune Microenvironment

27

Top transcripts from a pre-specified 43 immune gene panel upregulated in tumor 7-21 days after treatment. IDO1 and other genes not in the 43 panel are pending.

Galon et al, ASCO 2017

Checkpoints IFN related Effectors Proliferative Chemokines

PD-L1

IRF1

CTLA4

STAT1

CD8A

IL15

GNLY

GZMACXCL9

CCL2

CCL5

STAT4

LAG3

TNFRSF18

GZMM

GZMB

IFNg

GZMH

ICOS

Galon et al ASCO 2017 #3025

Analysis of B Cell and Immune-Related Molecules at Progression Identifies Relapse with CD19+ or CD19- Tumor cells

28

Post-progression tumor biopsies (21 evaluable patients)

- 33% were CD19-

- 62% were PD-L1+

At Baseline, 94% (16/17) of evaluable patients were CD19+

Baseline and post-progression samples not

obtained from the same lesions.

PD-L1, programmed death ligand 1.28

PD-L1 (n=19)

CD19 (n=21)

Progression Biopsies N=21

CD19+

14/21 (67)

PD-L1+

9/14 (64)

PD-L1-

4/14 (29)

PD-L1 N/E

1/14 (7)

CD19-

7/21 (33)

PD-L1+

4/7 (57)

PD-L1-

2/7 (29)

PD-L1 N/E

1/7 (14)

Example CD19+ relapse Example CD19- relapse

CD19 RNA splice variants identifiedIn DLBCL relapse biopsies

Adapted from Neelapu et al ASH 2018 #578

• In ZUMA-1 ~20% of treated patients were primary refractory to anti-CD19 CAR T cell therapy

– Mechanisms of primary treatment related failure ascribable to:o Product T cell fitness

o CAR T cell function in product

o Immune exclusionary tumor microenvironment

• In ZUMA-1 ~35% of treated patients experienced a secondary treatment-related failure

– Mechanisms of secondary treatment-related failure ascribable to:o High tumor burden

o Rapid upregulation of immune checkpoints

o CD19 target antigen loss

29

Conclusions

Peak Cytokine Levels Correlate with Response to Anti-CD19 CAR T Therapy

30

Kochenderfer JN et al. J Clin Oncol. 2017;35(16):1803-1813.

JCAR017 (lisocabtagene maraleucel; liso-cel): CD19-Targeted CAR T-cell

scFv

Signaling sequenceT cell

Intracellular costimulatory domain

SpacerTransmembrane domain

EpitopeTumor antigen

Tumor cell

3’

LTR

VL linker VH CD28tm 4-1BB CD3ζ T2A

CD19 scFv murine monoclonal FMC63

Signaling domain

Spacer

Transductionmarker

EF1p

huEGFRt

Transmembrane domain

• Immunomagnetic selection

• Lentivirus transduction

• Expansion

• Formulated at specified composition of CD4+ and CD8+ CAR+ T cells

• Administered at precise doses of CD4+

and CD8+ CAR+ T cells

Patient’s

PBMCs

Other PBMC Cell Types

CD4+ (targets tumor, supports persistence)

CD8+ (targets tumor)

CAR+CD8+

CAR+CD4+

Siddiqi, ASH 2017

Tumor Burden, Baseline Markers of Inflammation, and Inflammatory Cytokines May Trend Lower in Patients with Durable Response

a Similar result seen when analyzed at DL2 alone.

Un

its

10000

1000

100

10

1

0.1

Pre-LD Parametera

No Response

at 3 Months

Response

(CR/PR) at 3

Months

Ferritin and D-dimer measured in μg/L, CRP and SAA-1 measured in mg/L; all cytokines measured in pg/mLp < 0.05 for all parameters except SPD (p = 0.12)

Data as of October 9, 2017

Siddiqi, ASH 2017

Preliminary Logistic Modeling Data Suggest a Therapeutic Window Exists that Could Limit Toxicity and Optimize Efficacy

Any CRS

Any NT

ORR

M3 Response

Gr 3-4 NT

Increasing Maximum CAR T Cell Expansion

High expansion• High tumor burden and inflammatory cytokines

• Potential product and/or patient characteristics

• Identify at risk population and investigate strategies to limit expansion

Low expansion• Potential tumor-mediated suppression

• Potential product and/or patient characteristics

• Identify at risk population and investigate strategies to enhance expansion

Target Expansion

Esti

mate

d P

rob

ab

ilit

ies

0.2

0.4

0.6

0.8

1.0

0

CRS, cytokine release syndrome; NT, neurotoxicity; ORR, overall response rate; M3, month 3 Data as of October 9, 2017

Siddiqi, ASH 2017

Conclusions

• CD 19+ CAR-T cell for DLBCL – CR rates 30-50%

• If patients in CR at 6 months post-CAR-T – many maintain response

• Long term responders – some understanding:– Lower tumor volume– Lower CRP and ferritin – less inflammation– Cytokine profile in responders– Hi PD-1 may decrease the response rates and/or increase early relapse.

• Combinations during or after CAR-T may help to decrease relapse rates