Will describe and detail the expanding role of immunotherapy / pd1 pathway inhibitors in the management of lymphoma

1. PD-1 PATHWAY INHIBITORS:
Mary Ondinee Manalo
13 Feb 2015
National Cancer Centre Singapore
Changing the Landscape of Cancer
Immunotherapy

2. OUTLINE
• Overview of Cancer Immune Surveillance
– Immunotherapy
– Immune Checkpoints : CTLA-4 and PD-1/PD-L1
• Review of PD-1 Inhibitors
– PD-1 / PD-L1 Pathway
– Mechanism of Action of PD-1 Inhibitors
– Studies in other Solid Tumors
– Patterns and Evaluation of Response
• Studies on PD-1 Inhibitors in Lymphoma
– Pidilizumab + Rituximab in Relapsed Follicular Lymphoma
– Pidilizumab after Autologous HSCT in DLBCL
– Nivolumab in Relapsed/Refractory Hodgkin’s Lymphoma
• Safety Profile of PD-1 Inhibitors

3. Immunotherapy
• Aims of immunotherapy are to:
1. Aid in the recognition of cancer as foreign by the
immune system
2. Stimulate immune responsiveness
3. Relieve inhibition of the immune system that allows
tolerance of tumor growth
• Differs from:
– Chemotherapy : targets rapidly dividing cells
– Targeted Therapies : interfere with key molecular events in
tumor cells that drive tumor growth and invasion

4. IMMUNE ACTIVATION AND
CHECKPOINT INHIBITION

5. Cytotoxic T Lymphocyte Antigen-4
• regulates early T cell
activity
• upregulated on T cells
after exposure to antigen
• competes with CD28 for
binding to B7.1 and B7.2
with much higher affinity,
– delivering a negative
signal to the T cell
– blocking the co-
stimulatory signal
resulting from B7/CD28
interaction needed for T
cell activation
LYMPH NODE

6. Programmed Death Receptor 1 and its Ligand
TUMOR
MICROENVIRONMENT
• PD-1 is expressed on
the surface of T-cells
upon activation
• Engaged by 2 ligands
both of which are in
the tumor
microenvironment:
– PD-L1 (aka: B7-H1 or
CD274)
– PD-L2 (aka: B7-DC or
CD273)
PD-1

7. Programmed Death Receptor 1 and its Ligand
TUMOR
MICROENVIRONMENT
• PD-1 engagement
with its ligand, PD-
L1 will lead to T-cell
inactivation
PD-1
Reduce cytokine production
Reduces proliferation of T cells
REDUCED KILLING OF CANCER
CELLS by cytotoxic T cells
== IMMUNOSTAT ==

8. REVIEW OF PD-1 INHIBITORS
SWITCHING OFF THE NEGATIVE SWITCH

10. PD-1 Blockade vs PD-L1 Blockade
- More
inflammatory
toxicity
- Less
inflammatory
toxicity
- Since this a
tumor targeting
Ab, will likely
require high levels
to be administered

12. Atypical Patterns of Response
• May differ from patterns of response
seen with standard chemotherapy:
1. Transient worsening of the disease,
manifested as progression of known
lesions or appearance of new lesions
before ultimate disease stabilization
or tumor regression
2. Responses can take an appreciably
long time to become apparent
3. Those who do not meet the criteria
for objective response can have
prolonged periods of stable disease
INCREASE D IMMUNE
CELL INFILTRATION
UP TO 6 MONTHS
AFTER TREATMENT
INITIATION
Kyi C and M Postow. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Letters 588 (2014) 368-376.
Pardoll. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews 2012;12:252-264.

14. PD-1 IN LYMPHOMAS
PROMISING PHASE II STUDIES

15. Background:
• PD-L1 is expressed in the tumor microenvironment of DLBCL and PMBCL
• The post-AHSCT is a fertile ground for PD-1 blockade
– Low volume disease
– Remodelling of the immune system
– Majority of the circulating leucocytes are targets of pidiluzumab
• No drug has been shown to extend survival immediately after AHSCT (CORAL: no benefit of
giving rituximab)
• PD-1 blockade early after ASHCT may prevent a tumor-dependent, PD-1 driven exhaustion
of anti-tumor lymphocytes >> Leading to eradication of residual disease >> Improvement
of PFS

16. PIDILIZUMAB after HSCT (Phase II)
Inclusion:
• ≥18 y
• Planned or had undergone
AHSCT for DLBCL, PMBCL, or
transformed indolent
lymphoma
• At least PR after salvage
therapy
Exclusion:
• CNS Disease
PIDILIZUMAB 1.5
mg/kg every 42 days
for 3 cycles
30-90 days after
AHSCT
Primary End Point: 16 mo progression free
proportion from the time of first pidiluzumab
administration
Secondary End Points: Safety and Toxicity, OS
30 centers from US,
Israel, Chile, India

18. RESULTS
SURVIVAL DATA
AFTER AHSCT
(1) AHSCT 
PIDILUZUMAB
(n=66, Phase II)
(2) AHSCT alone
(n=196, Phase III)
(3) Multi-
Institutional
Experience
(n=143,
Retrospective)
18 month PFS 72 % 47% -
18 month OS 85% 65% -
18 month PFS
among PET positive
patients after
AHSCT
70% - 52%
(1) Armand P et al. Disabling Immune Tolerance by Programmed Death-1 Blockade with Pidilizumab after AHSCT for DLBCL. JCO 2013; 31 (33):4199-4206.
(2) Gisselbrecht C et al. Salvage Regimens with Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era. JCO 2010; 28(27): 4184-
4190.
(3) Armand P et al. Prognostic Factors for Patients with DLBCL and Transformed Indolent Lymphoma undergoing ASCT in the PET era. Br J Haematol 2013; 160:
608-617 >> data from Dana-Farber Cancer Institute and Massachusetts General Hospital

20. Background:
• Rituximab partly acts via activation of Ab-dependent cellular
cytotoxicity, mediated by NK cells
• Pidilizumab works by inhibiting PD-1 therefore increasing T-cell
activation
• Therefore, the combination of rituximab + pidilizumab would
have additive or synergistic effects via activation of both INNATE
(NK cells/rituximab) and ADAPTIVE (T-cells/pidilizumab)
immunity.

21. PIDILIZUMAB + Rituximab in Relapsed
Follicular Lymphoma (Phase II)
Inclusion:
• ≥18 y
• FL grades 1-2, relapsing
after 1-4 previous
therapies
• Rituximab-sensitive
disease
• Measurable disease
Exclusion:
• CNS disease
• Prior transplant
PIDILIZUMAB 3 mg/kg every
4 weeks x 4 infusions
plus
RITUXIMAB 375 mg/m2
weekly x 4 weeks starting
17 days after infusion of
Pidiluzumab
SD or
better
Primary End Point: proportion of patients with
OR
Secondary End Points: Safety and Toxicity, PFS,
proportion of CR and PR
8 additional optional
doses of
PIDILIZUMAB 3
mg/kg every 4 weeks
x total of 12 infusions

22. PIDILIZUMAB +
Rituximab in Relapsed
Follicular Lymphoma

23. RESULTS compared to
other treatment options
DATA in the
RELAPSED /
REFRACTORY
Setting
(1)
PIDILUZUMAB +
Rituximab
(n=32, Phase 2)
(2)
BORTEZOMIB +
Rituximab
(n=336, Phase 3)
(3)
BENDAMUSTINE
+ Rituximab
(n=40, Phase II)
Has a subgroup of FL
(4)
BENDAMUSTINE
+ BORTEZOMIB +
Rituximab
(n=60, Phase II)
CR 52% 25% 41% 53%
PR 14% 38% 39% 35%
ORR 66% 63% 93% 88%
Median PFS 18.8 mo 12.8 mo 23.0 mo 14.9 mo
Median DOR 20.2 mo 16.0 mo 21.0 mo 11.7 mo
(1) Westin JR et al. Safety and activity of PD-1 blockade by pidilizumab in combination with rituximab in patients with relapsed FL. Lancet Oncology 2014; 15:69-
77.
(2) Coiffier B et al. Bortezomib plus Rituximab versus Rituximab Alone in Patients with Relapsed FL. Lancet Oncology 2011; 12:773-784.
(3) Robinson KS et al. Phase II Multicenter Study of Bendamustine plus Rituximab in Patients with Relapsed Indolent B-cell and Mantle Cell NHL. JCO 2008;
26:4473.
(4) Fowler N et al. Bortezomib, Bendamustine, and Rituximab in Patients With Relapsed or Refractory Follicular Lymphoma: The Phase II VERTICAL Study. JCO
Sep 1, 2011:3389-3395

24. PIDILIZUMAB +
Rituximab in Relapsed
Follicular Lymphoma

25. Background:
• Preclinical studies suggest that Reed-Sternberg cells exploit the PD-1 pathway
to evade immune detection.
• In classic Hodgkin’s lymphoma, alterations in 9p24.1 increase PD-1 ligands,
PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–
signal transducer and activator of transcription (STAT) signaling.
• Hypothesis: Nivolumab, a PD-1–blocking antibody, could inhibit tumor
immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma.

26. NIVOLUMAB in Relapsed / Refractory
Hodgkin’s Lymphoma (Phase I)
Inclusion:
• ≥18 y
• Relapsed or refractory
HL
• At least 1 lesion >1.5
cm
• ECOG 0-1
• At least 1
chemotherapy
• No ASCT within the
past 100 days
Exclusion:
• CNS disease
• Allogenic transplant
DOSE ESCALATION
COHORT:
Nivolumab 1 mg/kg with
escalation to 3 mg/kg
Primary End Point: safety and side effect profile
of nivolumab
Secondary End Points: efficacy, assessing PD-1
ligand loci integrity and expression of encoded
ligands
EXPANSION
COHORT:
Nivolumab 3 mg/kg

27. NIVOLUMAB in
Relapsed / Refractory
Hodgkin’s Lymphoma

28. RESULTS compared to
Brentuximab Vedotin
DATA in the RELAPSED /
REFRACTORY Setting
(1) NIVOLUMAB
(n=23, Phase 1)
(2) BRENTUXIMAB
(n=102, Phase 2)
CR 17% 34%
PR 70% 40%
ORR 87% 74%
Median PFS 86% at 24 weeks 5.6 mo
Median OS Not reached 22.4 mo
(1) Ansell SM et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. NEJM Jan 2015; 372(4):311-319.
(2) Younes A et al. Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients with Relapsedor Refractory Hodgkin’s Lymphoma. JCO 2012; 30(18):
2183-2189.

29. Heavily Pre-treated Population

31. Comparison of Grade ≥3 AEs
ADVERSE EVENTS
(Grade ≥3)
PIDILIZUMAB after
AHSCT in
DLBCL/PMBCL
(n=66)
PIDILIZUMAB +
RITUXIMAB in
Relapsed FL
(n=32)
NIVOLUMAB in
Relapsed /
Refractory
HODGKIN’S
(n=23)
Neutropenia 19% 0 4%
Thrombocytopenia 8% 0 0
Pancreatitis 0 0 4%
Stomatitis 0 0 4%
Myelodysplastic
Syndrome
0 0 4%
Deaths During
Treatment
Fatal disseminated
zoster infection
(reported as UNRELATED to
study drug)
None None

32. In a nutshell.
• When PD-1 integrates with PD-L1, an
IMMUNOSTAT is produced that leads to T-cell
inactivation and reduced tumor cell killing.
• Blocking this pathway will free the cytotoxic T-
lymphocytes and facilitate tumor cell killing.
• PD-1 inhibitors are effective and have a
favorable side effect profile.

33. OTHER SLIDES FOR LEARNING

34. How tumor is recognized by T cells
• T cells recognize
antigens by the
MHC on the
surface of cancer
cells through their
T-cell receptor

36. Chen D and I Mellman. Oncology meets Immunology. Immunity 39, July 2013, Elsevier.

37. Chen D and I Mellman. Oncology meets Immunology. Immunity 39, July 2013, Elsevier.

38. Programmed Death 1 (PD-1) Receptor and
its Ligands (PD-L1 and PD-L2)
• PD-1 is expressed on
the surface of T-cells
upon activation
• Engaged by 2 ligands
both of which are in
the tumor
microenvironment:
– PD-L1 (aka: B7-H1 or
CD274)
– PD-L2 (aka: B7-DC or
CD273)

39. Binding of PD-1 to PD-L1 delivers an
inhibitory signal
• Reduces cytokine
production
• Reduces
proliferation of T
cells
REDUCED KILLING OF
CANCER CELLS by
cytotoxic T cells

40. Targeting PD-1 in Cancer
• Antibodies against PD-1 would prevent binding of PD-1 to
PD-L1, thus freeing tumor antigen specific cytotoxic T cells
to mediate killing.
Activated
T cell
Tumor Cell