Immune Checkpoint Inhibitors in Lymphoma
Transcript of Immune Checkpoint Inhibitors in Lymphoma
Immune Checkpoint Inhibitors in Lymphoma
Stephen M. Ansell, MD, PhDProfessor of Medicine
Chair, Lymphoma Group
Mayo Clinic
Conflicts of Interest
• Research Funding from –– Bristol Myers Squibb
– Celldex Therapeutics
– Seattle Genetics
H+E CD3 CD21
What’s Wrong with the Anti-Tumor Immune Response in Lymphoma?
CD8CD4H+E
A. B.
C. D.
PD-1+ T-cells in Lymphoma are Functionally Exhausted
Yang et al. J Clin Invest 2012;122(4):1271-82.
Intratumoral TGF-β upregulates CD70 andInduces an exhausted T-cell phenotype
Yang ZZ et al. Leukemia. 2014 Sep;28(9):1872-84.
Alterations in chromosome 9p24.1 increase PD-L1 and PD-L2 expression in classical
Hodgkin Lymphoma
Ansell et al. N Engl J Med. 2015;372:311-319Roemer et al. J Clin Oncol. 2016 Apr 11. [Epub ahead of print]
PD-L1+ Expression on malignant and non-malignant cells in Diffuse Large B-cell
Lymphoma is associated with Outcome
Kiyasu et al. Blood 2015;126:2193-2201
How could we activate the exhausted anti-tumor immune response?
Yao et al. Nature Reviews Drug Discovery 2013; 12:130-146.
Immune Checkpoints are Targets for Immune Modulation
How does blocking inhibitory signals work?
Okazaki et al. Nature Immunol 14:1212–1218 (2013)
PD-1
CTLA4
Does Immune Checkpoint Blockade work? Blocking CTLA4
Ansell et al. Clin Cancer Res 2009;15:6446-6453
•Treated 18 patients with ipilimumab 3mg/kg•2 patients responded; 1 CR (>31 months), 1 PR (19 months)•In 5 of 16 cases (31%), T-cell proliferation to recall antigens was increased (>2-fold)
Ipilimumab to treat relapse after allogeneic hematopoietic cell transplantation
• 29 patients with relapsed hematologic disease.
• Three patients with lymphoid malignancy developed objective disease responses following ipilimumab:
– CR in 2 patients with Hodgkin disease
– PR in a patient with refractory mantle cell lymphoma.
• Ipilimumab did not induce or exacerbate clinical GVHD
Bashey et al. Blood. 2009;113(7):1581-8.
• PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response via PD-1 on immune effector cells.1
• PD-L1 expressed on malignant cells and/or in the tumor microenvironment suppresses tumor infiltrating lymphocyte activity.2
MHC
PD-L1
PD-1
PD-1
T-cellreceptor
PD-L2
T cell
NFκBOther
PI3K
IFNγ
IFNγR
Shp-2
Anti-PD-1
Tumor cell
1Francisco LM et al. J Exp Med 2009;206:3015-29.2Andorsky DJ et al. Clin Cancer Res 2011;17:4232-44
Does Immune Checkpoint Blockade work? Blocking PD-1
Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for DLBCL
• Pidilizumab is an anti–PD-1 humanized IgG1 monoclonal antibody
• Sixty-six eligible patients were treated.
• PFS at 16 months was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point.
• Among the 24 high-risk patients who remained positive on PET after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82).
• Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%.
Armand et al. JCO 2013;31:4199-4206
Pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma
Westin et al. Lancet Oncol. 2014;15(1):69-77.
• 32 patients enrolled. • The combination was
well tolerated. • Of 29 evaluable
patients, 19 (66%) achieved an objective response: CRs in 15 (52%) patients and PRs in four (14%).
Relapsed or Refractory HM
(N=105)
• No autoimmune disease
• No prior organ or stem cell
allografting• No prior checkpoint blockade
Endpoints
Primary• Safety and Tolerability
Secondary• Best Overall Response• Investigator assessed• Objective Response• Duration of Response
• PFS• Biomarker studies
Nivolumab – Phase I/II Study Design
Dose Expansion (3mg/kg)
Hodgkin Lymphoma (n=23)
Dose Escalation
Nivolumab 1mg/kg→3mg/kg
Wks 1,4 then q2w
(N=69)• B-Cell Lymphoma
(n=23)• T-Cell Lymphoma
(n=23)• Multiple Myeloma
(n=23)
(N=13)• B-Cell Lymphoma
(n=8)• CML (n=1)
• Multiple Myeloma (n=4)
Lesokhin et al. ASH 2014, abstract 291
Nivolumab - Drug-related Adverse Events Overview
• Safety profile similar to other nivolumab trials
• The majority of pneumonitis cases were Grade 1 or 2
• No clear association between pneumonitis and prior radiation
(28 patients), brentuximabvedotin (9 patients) or
gemcitabine
Nivolumab (N=82) n (%)
Any Grade Related AE 51 (62)
Any Grade Drug-related AE Occurring in ≥ 5% of Patients
n (%)
Fatigue 11 (13)
Pneumonitis 9 (11)
Pruritus 7 (9)
Rash 7 (9)
Pyrexia 6 (7)
Anemia 5 (6)
Diarrhea 5 (6)
Decreased appetite 5 (6)
Hypocalcemia 5 (6)
Lesokhin et al. ASH 2014, abstract 291
Multiple Myeloma (n=27) 0 (0) 0 (0) 0 (0) 18 (67)
Nivolumab - Best Overall ResponseObjective
Response Rate, n (%)
Complete Responses,
n (%)
Partial Responses,
n (%)Stable Disease
n (%)
B-Cell Lymphoma* (n=29) 8 (28) 2 (7) 6 (21) 14 (48)
Follicular Lymphoma (n=10) 4 (40) 1 (10) 3 (30) 6 (60)
Diffuse Large B-Cell Lymphoma (n=11)
4 (36) 1 (9) 3 (27) 3 (27)
†includes other cutaneous T-cell lymphoma (n=3) and other non-cutaneous T-cell lymphoma (n=2)
T-Cell Lymphoma† (n=23)
Mycosis Fungoides (n=13)
Peripheral T-Cell Lymphoma (n=5)
4 (17) 0 (0) 4 (17) 10 (43)
2 (15) 0 (0) 2 (15) 9 (69)
2 (40) 0 (0) 2 (40) 0 (0)
*includes other B-cell lymphoma (n=8)
Primary Mediastinal B-Cell Lymphoma (n=2)
0 (0) 0 (0) 0 (0) 2 (100)
Lesokhin et al. ASH 2014, abstract 291
Hodgkin Lymphoma - Response to Nivolumab
PR (70%) CR (17%)SD (13%)
Ansell et al. N Engl J Med. 2015;372(4):311-9.
Response Duration - NivolumabP
ati
en
ts
Ansell et al. N Engl J Med. 2015;372(4):311-9.
Nivolumab - Durability of Response
–100
–50
0
50
100
Time Since First Treatment Date, Weeks
Pe
rce
nt
Ch
ange
Fro
m B
ase
line
in
Tar
get
Lesi
on
s/Tu
mo
r B
urd
en
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114
On treatment, ongoing response
Off treatment without progression
Progressive disease, following response or stable disease
First occurrence of new lesion Ansell et al. ASH 2015, abstract 583
• Red=PD-L1
• Green=PD-L2
• Yellow= Red + Green
• Cyan=Centromere
• PD-L1 (brown)PAX-5 (red)
• PD-L2 (brown)pSTAT3 (red)
Immunohistochemistry
PD-L1/2 locus integrity
9p24.1/PD-L1/PD-L2 Locus Integrity and Protein Expression
Hodgkin Lymphoma - Response to Pembrolizumab (n=29)
*Patient became PET negative and was therefore declared to be in complete remission.Analysis cut-off date: November 17, 2014.
*
Moskowitz et al. ASH 2014, abstract 290
Treatment Exposure and Response Duration
Treatment ongoing
Treatment discontinued
Complete remission
Partial remission
Stable disease
Progressive disease
Transplant ineligible at baseline
• Median time to response:
12 weeks
• 89% (17 of 19) of
responses were ongoing as
of November 17
• Duration of response
– Median: not reached
– Range: 1+ to 185+
days
Moskowitz et al. ASH 2014, abstract 290
Treatment-Related Adverse Events of Any GradeObserved in ≥2 Patients
Analysis cut-off date: November 17, 2014.
• 16 (55%) patients experienced ≥1 treatment-related AE of any grade
Adverse Event, n (%) N = 29
Hypothyroidism 3 (10)
Pneumonitis 3 (10)
Constipation 2 (7)
Diarrhea 2 (7)
Nausea 2 (7)
Hypercholesterolemia 2 (7)
Hypertriglyceridemia 2 (7)
Hematuria 2 (7)
Moskowitz et al. ASH 2014, abstract 290
PD-L1 Expression
• Among the 10 enrolled patients who provided samples evaluable for PD-L1 expression, 100% were PD-L1 positive
• Best overall response in these 10 patients was CR in 1 patient, PR in 2 patients, SD in 4 patients, and PD in 3 patients
PD-L1 expression was assessed using a prototype immunohistochemistry assay and the 22C3 antibody. PD-L1 positivity was defined as Reed-Sternberg cell membrane staining with 2+ or greater intensity.
Analysis cut-off date: November 17, 2014.
PD-L1 Negative PD-L1 Positive
Moskowitz et al. ASH 2014, abstract 290
All B-Cell Lymphoma Patient ResponsesP
erce
nt
Ch
ange
fro
m B
asel
ine
0 8 16 24 32 40 48 56 64 72 80 88 96
Time since First Dose (Weeks)
Diffuse Large B-Cell lymphoma
Follicular B-Cell Lymphoma
Other B-Cell Lymphoma
-30
-20
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
-40
-50
-60
-70
-80
-90
-100
* ***
Lesokhin et al. ASH 2014, abstract 291
Time since First Dose (Weeks)
All T-Cell Lymphoma Patient Responses
-30
-20
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
130
0 8 16 24 32 40 48
-40
-50
-60
-70
-80
-90
-100
Pe
rce
nt
Ch
ange
fro
m B
asel
ine
Other Non-cutaneousT-Cell Lymphoma
Peripheral T-Cell Lymphoma
Mycosis Fungoides CutaneousT-Cell Lymphoma
Other Cutaneous T-Cell Lymphoma
Median ResponseDuration
wks (range)
Ongoing Responders/
Total Responders
MedianFollow-upwks (range)
MF (n=13)Not Reached(0.1+, 13.0+)
2/2Not Reached(2.9+, 41.9+)
PTCL (n=5)Not Reached(10.6, 32.0+))
1/235
(4.9+, 39.9+)
Lesokhin et al. ASH 2014, abstract 291
Does activating immune stimulatory signals work? – CD27 and CD40
Kurts et al. Nature Reviews Immunology 10, 403-414 (2010)
●24 patients enrolled
●No significant depletion in absolute lymphocyte counts, T cells or B cells
●Evidence of increased immunologic activity, consistent with expected mechanism of action:
‒ Increased soluble CD27
‒ Reduction of circulating Tregs
‒ Induction of pro-inflammatory cytokines
●Anti-lymphoma activity – 1 CR in a patient with Hodgkin Lymphoma
Phase I trial of an agonist anti-CD27 antibody (Varlilumab /CDX-1127) in lymphoma patients
Ansell et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 3024)
Phase I study of humanized anti-CD40 monoclonal antibody dacetuzumab in recurrent non-Hodgkin's lymphoma.
Advani et al. JCO 2009;27:4371-4377
• 50 patients treated.• Two DLTs: conjunctivitis
and ALT elevation. • Six objective responses
(one complete response, five partial responses).
• Tumor size decreased in approximately one third of patients.
Conclusions
• Optimizing immune function is the new therapeutic “frontier” in lymphoma
• Immune checkpoint inhibitors hold real promise in Hodgkin and non-Hodgkin lymphoma.
• Multiple new agents (anti-PDL1, anti-LAG3, anti-TIM3) are in development to block immune suppression or induce immune stimulation.
• Incorporating promising immunologic agents into combination approaches will be the next clinical challenge.
Acknowledgements
Lab members -
Zhi-Zhang Yang
Steve Ziesmer
Denny Grote
Tammy Price Troska
Jacob Smeltzer
Anne Novak
Grant funding –
National Institutes of Health, Leukemia & Lymphoma Society, Lymphoma Research Foundation, Predolin Foundation.