Checkpoint Inhibition in Hodgkin’s Lymphoma John Kuruvilla, MD & Rob Laister, PhD
Research Support Leukemia and Lymphoma Society US, Rasch Foundation, CCSRI
Employee N/A
Consultant N/A
Major Stockholder N/A
Speakers Bureau N/A
Honoraria Celgene, Janssen, Jazz Pharmaceuticals, Seattle Genetics,
Scientific Advisory Board N/A
Disclosures for Rob Laister
Research Support Leukemia and Lymphoma Society US, Rasch Foundation Roche,
Employee N/A
Consultant Abbvie, BMS, Gilead, Janssen, Roche
Major Stockholder N/A
Speakers Bureau N/A
Honoraria Abbvie, Amgen, BMS, Celgene, Gilead, Roche, Janssen, Lundbeck, Merck Seattle Genetics,
Scientific Advisory Board Lymphoma Canada (Chair)
I don’t understand the purpose of the World Cup of Hockey
I will likely discuss all sorts of off-label use of agents as well as investigational agents
Disclosures for John Kuruvilla
The Cancer Immunity Cycle
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
- To understand the genesis of immune checkpoint inhibitors, it behooves us to understand the process by which immune cells target cancer cells.
The Cancer Immunity Cycle
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
1) Tumour cell turnover/ death results in the release of tumour antigens that are captured, taken up and processed by dendritic cells.
The Cancer Immunity Cycle
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
2) These dendritic cells migrate to lymph nodes where they prime naïve T-cells to have anti-cancer activity.
The Cancer Immunity Cycle
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
3) These activated effector T-cells travel to and infiltrate into the tumour where they kill cancer cells.
What are Immune Checkpoints?
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476 and Pardoll , 2012, Nat Rev Can, 5, 252-265
What are Immune Checkpoints?
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476 and Pardoll , 2012, Nat Rev Can, 5, 252-265
What are Immune Checkpoints?
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476 and Pardoll , 2012, Nat Rev Can, 5, 252-265
- Oncogenic pathways in HL cells express cell surface ligands that bind to and shut down T-cell function
What are Immune Checkpoints?
Adapted from Pardoll , 2012, Nat Rev Can, 5, 252-265
-there are numerous ligand/receptor interactions between T-cells and tumour cells that can positively or negatively regulate T-cell function -these interactions are used in normal T-cell biology to control the duration and amplitude of immune responses -cancer cells can express inhibitory ligands to evade the immune system
Surface of Cancer Cell (Ligand)
Surface of T-cell (Receptor)
What are Immune Checkpoints?
Adapted from Pardoll , 2012, Nat Rev Can, 5, 252-265
Cancer Cell T-cell
-upon binding there respective ligands, PD-1 and CTLA4 transmit negative regulatory signals into the T-cell thereby compromising its anti-tumour activity.
Regulation of PD-1 Ligands in Hodgkin Lymphoma
Adapted from Green, et al., 2010, Blood, 116, 3268-3277
-what drives PD-L1 expression in Hodgkin lymphoma ?
- 9p copy gain has been reported in HL and MLBCL - the PD-L1 and PD-L2 genes are located in close proximity to each other on chromosome 9p24
9p24 amplified
Regulation of PD-1 Ligands in Hodgkin Lymphoma
Adapted from Green, et al., 2010, Blood, 116, 3268-3277
-there is an association between 9p24 amplification and increased levels of PD-L1 in HL
Regulation of PD-1 Ligands in Hodgkin Lymphoma
Adapted from Green, et al., 2010, Blood, 116, 3268-3277
-9p24 amplification also increases JAK2 levels which drive PD-L1 expression through JAK/STAT signaling.
Regulation of PD-1 Ligands in Hodgkin Lymphoma
Adapted from Green, et al., 2010, Blood, 116, 3268-3277 and Roemer, et al., 2016 JCO, 34, 2690-2697
-with a limited number of cases, 9p24 amplification appears to results in a trend towards worse outcome in patients with early stage unfavourable(ES-U) and advanced stage(AS) HL
Regulation of PD-1 Ligands in Hodgkin Lymphoma
Adapted from Green, et al., 2010, Blood, 116, 3268-3277 and Green et al., 2012, Clin Can Res, 18, 1611-1618
-EBV can also promote PD-L1 expression through JAK/STAT singnaling and the transcription factor AP1
EBV AP-1
Adapted from Pardoll , 2012, Nat Rev Can, 5, 252-265
Cancer Cell T-cell
- Several mechanisms have been identified by which Hodgkin lymphoma cells up-regulate factors that result in immune system evasion. - What can we do about it?
Immune Checkpoint Inhibitors
Immune Checkpoint Inhibitors
Adapted from Pardoll , 2012, Nat Rev Can, 5, 252-265
Cancer Cell T-cell
Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab
Tremelimumab
PD1 Inhibitory Receptor Nivolumab Pembrolizumab
PD-L1 Inhibitory Ligand Durvalumab Avelumab
PD-1 PD-L1
PDB ID: 4ZQK
Immune Checkpoint Inhibitors
Adapted from Pardoll , 2012, Nat Rev Can, 5, 252-265
Cancer Cell T-cell
PD-1 PD-L1
PDB ID: 4ZQK
PDB ID: 5JXE
PD-1
Fab fragment of Pembrolizumab
Immune Checkpoint Inhibitors
Immune Checkpoint Inhibitors
-the current immune checkpoint inhibitors are antibodies targeting either the inhibitory ligands or their receptors thus blocking their interaction and preventing the transmission of a negative regulatory signal into the T-cell.
Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab
Tremelimumab
PD1 Inhibitory Receptor Nivolumab Pembrolizumab
PD-L1 Inhibitory Ligand Durvalumab Avelumab
Fab fragment of Pembrolizumab
PD-1
Immune Checkpoint Inhibitors
-some potential downsides to the use of therapeutic antibodies in the clinic are their limited tumour penetration, lack of oral bioavailability, immunogenicity and cumbersome production.
PD-1
PD-L1
PDB ID: 4ZQK
Immune Checkpoint Inhibitors
-the development of small molecules inhibiting PD-1/PD-L1 interactions is currently underway.
PD-1
PD-L1
PDB ID: 4ZQK
Next Steps: Immune Checkpoint Combinations
Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab
Tremelimumab
PD1 Inhibitory Receptor Nivolumab Pembrolizumab
PD-L1 Inhibitory Ligand Durvalumab Avelumab
- checkpoint inhibitors have impressive clinical activity (Nivolumab, 87% ORR in rrHL; Ansell et al., NEJM, 2015)
- what are the strategies to combine them with other agents to turn some of those PRs into CRs?
Next Steps: Immune Checkpoint Combinations
Checkpoint Inhibitors + ?
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
Next Steps: Immune Checkpoint Combinations
Checkpoint Inhibitors
Checkpoint Inhibitors +
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
Next Steps: Immune Checkpoint Combinations
Direct on-target HL inhibition ADC (Vedotin) JAK2 inhibitors Chemotherapy
Radiation
Checkpoint Inhibitors
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
+
Next Steps: Immune Checkpoint Combinations
Cytokines IL-2
IL-12
Checkpoint Inhibitors
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
+
Next Steps: Immune Checkpoint Combinations
Checkpoint Inhibitors
Cell-Cell Interactions BiTEs CARs
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
+
Next Steps: Immune Checkpoint Combinations
Immune modulators Lenalidomide
CC-122
Checkpoint Inhibitors
Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10
+
Next Steps: Immune Checkpoint Combinations
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
- Activated T-cells need the appropriate vasculature to enter the tumour micro-environment and carry out their cytotoxic activities. -VEGFR signalling can contribute to aberrant tumour vascularization
Next Steps: Immune Checkpoint Combinations
Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476
- VEGFR inhibitors in combination with checkpoint inhibitors, may allow greater numbers of effector T-cells into the tumour micro-environment.
Checkpoint Inhibitors Question #1
• Which of the following mechanisms have been associated with enhanced expression of the PD-1 ligands ?
1. 9p24 amplification 2. CHK1 and CHK2 activation 3. JAK/STAT signalling 4. T-cell ambivalence 5. Answers 1 and 3
Ready for prime time in 2014?
Nivo phase 1: Treatment-Related Serious Adverse Events
Adverse Event, n (%) cHL (n = 23)
Any Grade Grade 3–4
Any event 3 (13) 2 (9)
Lymph node pain 1 (4) 0 (0)
Pancreatitis 1 (4) 1 (4)
Myelodysplastic syndrome 1 (4) 1 (4)
• 3 patients discontinued due to adverse events – 2 discontinuations were study drug related (pancreatitis, myelodysplastic syndrome)
Ansell ASH 2015
Response Rates
Best Objective Response cHL (n = 23)
n (%) 95% CI
Objective response rate 20 (87) 66.4–97.2
CR 5 (22) 7.5–43.7
PR 15 (65) 42.7–83.6
SD 3 (13)
Ansell ASH 2015
Progression-Free Survival
Median PFS (95% CI): NA (18.6–NA)
Time, Months
Prop
ortio
n of
Pat
ient
s With
out P
rogr
essi
on
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 21 27 18 No. Patients at Risk
24
23 20 13 12 11 8 1 0 5 11
• Median follow-up: 101 wks, Median PFS not reached Ansell ASH 2015
Question #2 • Early signals from PD1 inhibition look promising (safe
and effective). How would you proceed if you were in charge of development?
1. I’m in it to win it – who needs a phase II trial? Fire up a phase 3 in the relapsed/refractory setting (palliative)
2. Let’s generate some revenue – I love single arm phase 2 trials. Pathway to a quick approval and I’ll figure out a phase 3 later…
3. Split the difference? Maybe an adaptive design phase 2-3 or a randomized phase 2 design is the way to go?
4. I can’t believe these drugs work RR-H. We need to build studies with heavy biology.
5. Combo combo combo. CR rate is low and I want to build a more effective regimen. What else is in the pipeline?
Keynote 13
Moskowitz JCO 2016
K13: Baseline Characteristics
Moskowitz JCO 2016
K13: Overall Response and Waterfall Plot
Moskowitz JCO 2016
K13: PFS
Median F/U of surviving patients 17.6m
Moskowitz JCO 2016
K13: AEs (Any grade in ≥ 3 patients) ASH 2015
Checkmate 205 – cohort B Prior ASCT and post-ASCT BV
Younes Lancet Oncol 2016
C205:Baseline Characteristics
Younes Lancet Oncol 2016
C205: Overall Response rate IRRC Waterfall Plot of best response
Younes Lancet Oncol 2016
C205: Change in tumour burden in patients treated beyond PD
Younes Lancet Oncol 2016
C205: PFS by IRRC
Younes Lancet Oncol 2016
C205: Drug-related AEs in ≥ 10% of patients
Younes Lancet Oncol 2016
Summary: Nivolumab and Pembrolizumab in RR-cHL
• Safe and active • Profile of both drugs appears remarkably similar • Differences may relate to patient populations, trial
design and assessment along with length of follow-up
• ROLE TODAY: post ASCT and BV failure • Post ASCT failure or in ASCT ineligible?
• What’s next? • Combinations • Registration trials
Nivolumab Trials in HL
• Checkmate 205 – other cohorts not yet published • Ipilimumab, Brentuximab Vedotin and Nivolumab • Brentuximab and Nivolumab (older or RR HL, NHL) • Ibrutinib and Nivolumab • Ipilimumab and Nivolumab post ASCT (high risk,
NHL)
Pembrolizumab Trials in HL
• Keynote 087 (the bigger phase 2) – presented, not published
• AFM13 (bispecific anti-CD30/CD16) and Pembrolizumab
• Lenalidomide and Pembrolizumab • Post ASCT Pembrolizumab • Pembrolizumab with ibrutinib or idelalisib (iNHL)
Keynote 204 in RR-HL
Question #3 • PD1 inhibition is a standard therapy in RR-cHL.
Where do you see the best fit for these therapies? 1. First line localized “higher risk” 2. First line advanced stage 3. RR potentially curative (peri-ASCT) 4. RR non-curative 5. Special groups (ie. elderly)
Summary – anti-PD1 antibodies in RR-cHL
• Significant activity with favourable toxicity profile • Various strategies being evaluated
• Combinations • Earlier in the disease course
• Best use of these agents remains unknown • Biology not well defined
• ?