car t-cell therapy for lymphoma: assessing long-term...
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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