The breakthrough of oncology, PD1-PDL1 axis inhibition.

2. 300 patients
DLBCL
200 Cured
with RCHOP
100 Relapse
Or refractory
50 Transplant
candidate
50 Transplant
ineligible
25 Chemo-refractory
25 Respond and ASCT
Friedberg 2011 ASH Educational Session
210 Cured
90 receive Palliation. Most likely die from DLBCL
15 patients relapse
10 Cured after ASCT

3. Immunotherapy
AntibodyCytokine
Adaptive cell
Therapy
Anti Idiotype
Vaccine
Immuno
Check point
Inhibitor
II
Pembrolizumab
Nivolumab
Ipilimumab
Urelumab
Durvalumab
III
Id
Vaccine
in FL
II
CD19
CART
therapy
CD30
CART
therapy
II
IL-12 in
CTCL
refractory
DLBCL
II
Anti-CD19
Ab
Anti-CD37
ab
Anti CD22
radioantibo
dy

4.  9p amplification
 EBV: PD-L1
overexpression

5. Ansell SM et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med
2015;372(4):311-9 UPDATED RESULT ASH 2015
 23 relapsed or refractory
Hodgkin's lymphoma
 78% post transplant
relapse
 78% post brentuximab
vedotin
 nivolumab (3 mg per kg)
every 2 weeks
 any grade and of grade 3
occurred in 78% and 22%
of
Response Patients (N = 23)
Objective response
rate
87%
Complete response 22%
Partial response 65%
Stable disease 13%
Median duration of
response
Not reached*
Median PFS Not reached*
1-year OS 91%
median follow-up of 101 weeks

6.  The median age was 37 years
(range, 18-72)
 The median number of prior
systemic regimens received was
5 (range, 3-15).
 98 %Auto HSCT,74 % Adcetris
 three mg/kg IV over 60 minutes
every two weeks until disease
progression or unacceptable
toxicity.
 The median duration of therapy
was 8.3 months (range, 1.9-24
 The ORR of 65 percent (7%CR).
 The median duration of response
was 8.7 months
 The median time to response
was 2.1 months
 AE fatigue (32 %), upper
respiratory tract infection (28%)
,pyrexia (24 %), diarrhea (23 %)
and cough (22%)

7.  nivolumab :Hodgkin lymphoma, human T cell leukemia
virus (HTLV)-associated leukemia/lymphoma
 nivolumab combined with brentuximab vedotin Hodgkin
lymphoma,non-Hodgkin lymphoma.
 • A phase I/II study of nivolumab combined with
urelumab (anti-4-1BB/CD137 antibody) B cell non-Hodgkin
lymphoma
 nivolumab combined with ipilimumab lymphoma who are
at high risk for recurrence
 nivolumab combined with ibrutinib,
 nivolumab +/- ipilimumab or lirilumab, an anti-KIR antibody
in lymphoma

8. Response
ASCT
failure
(n = 23)
ASCT
ineligible/re
fused
(n = 9)
All
patients
(N = 31)
Overall
response
73% 44% 65%
Complete
remission 14% 22% 16%
Partial
remission
59% 22% 48%
Stable disease 18% 33% 23%
Progressive
disease 9% 22% 13%
PFS at 24
weeks
– – 69%
Armand P, Shipp MA, Ribrag V et al. PD-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure:
Safety, efficacy, and biomarker assessment. Presented at the 57th American Society of Hematology (ASH) Annual Meeting. December 5-8, 2015; Orlando,
FL. Abstract 584
 31 patients (median age,
32 years)
 100% failed prior
brentuximab.
71% failed prior ASCT,
29% ineligible or refused
ASCT.
 pembrolizumab 10 mg/kg
every 2 weeks for up to 2
years
 most common AEs
diarrhea (16%) and
nausea (13%)

9.  pembrolizumab in relapsed or refractory B cell non-
Hodgkin lymphoma ,follicular lymphoma
 pembrolizumab after autologous stem cell
transplantation in patients with relapsed or
refractory Hodgkin lymphoma and diffuse large B
cell lymphoma
 pembrolizumab :relapsed or refractory T cell non-
Hodgkin lymphoma
 pembrolizumab :advanced primary mediastinal
large B cell lymphoma (NCT02576990).
 pembrolizumab : recurrent PCNSL

10.  Durvalumab + tremelimumab CTCL,DLBCL,
pediatric lymphoma
 Durvalumab +ibrutinib :relapsed or refractory
lymphoma

11.  Pidilizumab
 R/R DLBCL after ASCT:72 patients
 post-ASCT pidilizumab. # 3 Cycle
 response rate :51% ( 34% CR rate)
 The 18-month PFS: 72%
 Poor risk (PET+)18-month PFS was 70% vs
Historically controle 52%
Armand etal J Clin Oncol 2013;31(33):4199-4206.

12. • Idiotype of the Ig antigen of a
B-cell lymphoma can be used
as a tumor-specific
immunogen
• Keyhole lympet hemocyanin
(KLH) carrier serves as an
immune stimulant
• GM-CSF administered
concurrently at site of
injection as an adjuvant

13. CD4+
• Addition of GM-CSF Adjuvant improves
vaccine potency
CD8+
cytokines
Lymphoma
cell
Y
(Kwak et al. PNAS 1996)
Phase I/II Clinical Trial
(Nature Med 1999):
•Vaccine induces
molecular remissions
•
Tumor
protein
Phase III Controlled Clinical Trial
(J Clin Oncol 2011)
• Vaccine prolongs DFS in patients in a chemotherapy-
induced remission (n=117, p=0.045)
Preclinical
Isolate
antigen
Package in
Delivery system

14. LN
Bx
Assign CR
Stratify for IPI1, cycles of Chemotherapy2
2:1 Randomization
Chemo
• Primary endpoint: disease-free survival
• 14 sites enrolled patients from 2000-2007
6 - 12 months 6 months6 - 8 months
(Id Vaccine)
(Control)

15. Disease Free Survival from Randomization
log-rank
p=0.045
Median Follow-up
56.6 mo (range 12.6 – 89.3)
Median DFS
Id vaccine = 44.2 mo
Control vaccine = 30.6 mo
HR = 0.62; [95% CI:
0.39,0.99] (p=0.047)
Control vaccine (n=41)
Id vaccine( n=76)
Schuster , Neelapu et al. (Kwak) J Clin Oncol 29:2787, 2011

16.  Imprime PGG refractory non-Hodgkin
lymphoma
 CDX-301 (Flt3L plus Poly-ICLC (a Toll-like
receptor agonist B cell lymphoma
 Toll-like receptor 9 agonist: low grade
lymphomas (NCT02266147)
 immunotransplantation in MCL
 MCL cells are activated with TLR
 vaccine for patients in remission
 Transplant +Stimulated T cell

17. 100
10
1
0.1
0.01
T cell
expansion
ex vivo
Cancer
Vaccine
“Threshold
for cure”% Tumor
specific
T cells in
vivo
Hypothesis
Concepts of Adaptive Immunotherapy

20. Month +3 response
assessment
CD19+ Lymphoma
• Eligibility
determination
• Enrollment
Apheresis
• Baseline immune assays
Restaging and Lymphodepleting Chemotherapy
CT Scans and Bone Marrow. Therapy Physician Choice.
Ends 1-4 Days before CTL019 infusion
CTL019 Infusion, Monitoring and Response Assessments
Day
0
Month
+1
Month +2 and +3
evaluations
Quarterly f/u x 2 yr F/U 15 years
Adverse event
monitoring
CTL019
infusion
= Clinical evaluation; immune/CTL019 assays
Day -
1
Schuster et al. ASCO 2015, Abst 8516.

21. DLBCL: ORR at 3 Mo 50% (N = 13) Best Response 50% (N = 13)
- CR: 2
- PR: 4
- PD: 6
- Response not yet assessed: 1
- CR: 5
- PR: 1
- PD: 6
- Response not yet assessed: 1
• 3 PR at 3 mo converted to CR at 6; 1 PR at 3 mo had PD at 6
CAR-T Cells for CD19 Positive NHLs:
Response Rates for DLBCL and FL
FL: ORR at 3 Mo 100% (N = 7) Best Response 100% (N = 7)
- CR: 3
- PR: 4
- CR: 6
- PR: 1
• 3 PR at 3 mo converted to CR by 6 mo; 1 PR at 9 mo had PD at 12
Schuster et al. ASCO 2015, Abst 8516.

22.  CD19 CAR T cell : refractory DLBCL,
refractory PMBL, and transformed FL
 CD30 CAR T cell :CD30+ relapsed or
refractory Hodgkin and non-Hodgkin
lymphoma

23.  Immunotherapy addresses the unmet needs
 The breakthrough for Lymphoma treatment :
Nivolumab& Pembrolizumab