Immuun Checkpoint blockade bij lymfomen - KU Leuven · through expression of the PD-1 ligands,...

Immuun Checkpoint blockade bij lymfomen

Gregor Verhoef

Prize motivation: "for their discovery of cancer therapy by inhibition of negative immune regulation."

James P. Allison Tasuku Honjo

Lymphoma immune evasion mechanisms.

Marie de Charette, and Roch Houot Haematologica 2018;103:1256-1268

Overview of lymphoma immune escape mechanisms

Lymphoma immune escape mechanisms

Type of immune escape

HL GC-DLBCL ABC-DLBCL PMBCL PTCL-NOS

PDL1 expression 97% 36% 4% 71% 60%

PDL2 expression 60% 26%

6

In Advanced tumors, the PD-1 Pathway May Be Exploited to Evade the Immune Response

APC = antigen-presenting cell; MHC = major histocompatibility complex; NSCLC = non‒small cell lung cancer; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor.

Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.

•SPC Keytruda®, 09/2018

•Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.

• Emerging research has identified PD-1 as a key immune checkpoint pathway involved in inhibiting the T-cell–mediated immune response

• Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD‐L1 and PD‐L2

• PD-L1 and PD-L2 engage the PD-1 receptor on T cells to inactivate them, which may allow tumor cells to evade the immune response

Antigen

MHCTCR

Activated cytotoxicT cell Tumor cell/APC

PD-L2

PD-L1PD-1

Antigen

MHCTCR

Inactivated cytotoxicT cell

PD-1

PD-L2

PD-L1

Tumor cell/APC

7

PD-1 Receptor Blockade With Pembrolizumab

• By inhibiting the PD-1 receptor from binding to its ligands, pembrolizumab/nivolumab reactivates tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and reactivates antitumor immunity1

APC = antigen-presenting cell; MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor.Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.

• SPC Keytruda®, 09/2018 • 2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.

Antigen

MHCTCR

Activated cytotoxicT cell

PD-1

KEYTRUDA

PD-L2

PD-L1

Tumor cell/APC

Antigen

MHCTCR

Inactivated cytotoxicT cell

PD-1

PD-L2

PD-L1

Tumor cell/APC

KEYTRUDA

Ribas A. N Engl J Med 2015;373:1490-1492.

T-cell Activation in the Lymph Node.

MA Postow et al. N Engl J Med 2018;378:158-168.

Immune Checkpoint–Blocking Antibodies Approved by the Food and Drug Administration.*

PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma

Ansell et al, N Engl Med 2015;372:311-9

Ansell SM et al. N Engl J Med 2015;372:311-319.

15

Checkpoint inhibitor therapy: a new spectrum of adverse events

Champiat et al. Annals of Oncology, 2016;27:559-74.

Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell

transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial

Younes et al, Lancet Oncol 2016; 17:1283-94

Baseline characteristics

All patients (n=80)Previous lines of therapy

median 4(4-7)Previous autologous 80 (100%)

One 74 (93%)Two or more 6 (8%)

Previous brentuximab vedotin 80 (100%)


Objective response and best overall response

IRRC assessed(n=80)

Investigator assessed(n=80)

Objective response 53 (66,3%) 58 (72.5%)Best overall response

CR 7 (9%) 22 (28%)PR 46 (58%) 36 (45%)Stable disease 18 (23%) 18 (23%)

Progressive disease 6 (8%) 3 (4%)Unable to determine 3 (4%) 1 (1%)


Figure 1

The Lancet Oncology 2016 17, 1283-1294DOI: (10.1016/S1470-2045(16)30167-X) Younes et al, Lancet Oncol 2016; 17:1283-94

Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended

follow-up of the multicohort single-arm phase II CheckMate 205 trial

Armand et all, J Clin Oncol 36:1428-1439, 2018

Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology

Fig 1. CONSORT diagram. (*) Includes seven patients who discontinued nivolumab because of persistent complete remission for 1 year. AE, adverse event.


Table 2. Objective and Best Overall Response per IRC


Fig A2. Duration of response in cohorts A, B, and C. All values are median (95% CI).


Fig A3. Progression-free survival (PFS) in cohorts A, B, and C. All values are median (95% CI).


Fig 4. Cumulative incidence of (A) transplant-related mortality (TRM) and disease progression, (B) acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD), and (C) overall survival (OS) and progression-free survival (PFS) after allogeneic hematopoietic cell transplantation (allo-HCT). Cumulative incidence (95% CI) at 100 days and 6 months for TRM, disease progression, and GVHD, and median (95% CI) PFS and OS are shown. Death was considered a competing risk to GVHD, and post-transplant disease progression was considered a competing event to TRM. G, grade; NA, not available; NE, not estimable. Journal of Clinical Oncology 2018, 36, 1428-1439

Programmed Death-1 blockade with Pembrolizumab in patients with classical

Hodgkin lymphoma after Brentuximab vedotin failure (phase 1b Keynote-013 study)

Armand et al, J Clinic Oncol 34:3733-39, 2016

Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology

Fig 1. Response to treatment. (A) Maximum percentage change from baseline in target lesions. (B) Change from baseline in target lesions. (C) Treatment exposure and response duration. Three patients had a formal response assessment before the protocol-required time point of 12 weeks. One patient only received one dose of pembrolizumab, discontinued treatment because of toxicity at 4 weeks, and had nonprotocol scans to assess response, which showed CR. The other two patients had nonprotocol scans to confirm the clinical impression of progressive disease before the 12-week time point. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.


Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic

Hodgkin lymphoma

Chen et al, J Clin Oncol 35:2125-32, 2017

Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology

Fig 3. Distribution of programmed death-ligand 1 expression scores and response to pembrolizumab across all cohorts. A total of 177 patients across all cohorts had evaluable pretreatment tumor tissue and best evaluable response per central review. Three scores were reported separately: (A) staining intensity score (0-3); (B) membrane staining score (percentage of tumor cells with membrane staining 0%, > 0 to < 50%, ≥ 50 to < 100%, or 100%); and (C) histiocyte score (1-3; semiquantitative assessment of histiocytes/macrophages staining positive for programmed death-ligand 1). CR, complete remission; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.


Nivolumab in patients with relapsed or refractory hematologic malignancies: preliminary results of

a phase Ib study

Lesokhin et al, J Clin Oncol 34:2698-2704, 2016

Lesokhin et al, J Clin Oncol 34:2698-2704, 2016

Lymphoma immune escape mechanisms

Type of immune escape

HL GC-DLBCL ABC-DLBCL PMBCL PTCL-NOS

PDL1 expression

97% 36% 4% 71% 60%

PDL2 expression

60% 26%

Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell

lymphoma

by Pier Luigi Zinzani, Vincent Ribrag, Craig H. Moskowitz, Jean-Marie Michot, John Kuruvilla, Arun Balakumaran, Yayan Zhang, Sabine Chlosta, Margaret A. Shipp, and

Philippe Armand

BloodVolume 130(3):267-270

July 20, 2017

Clinical outcome

N(%) (N=17)ORR 7 (41.2%)

CR 2 (11.8%)PR 5 (29.4%)

Stable disease 6 (35.3%)Progressive disease 3 (17.6%)No assessment 1 (5.9%)

Pier Luigi Zinzani et al. Blood 2017;130:267-270

Treatment response in the 16 pembrolizumab-treated patients with rrPMBCL who were evaluable (by imaging) for efficacy at the time of data cutoff.

Pier Luigi Zinzani et al. Blood 2017;130:267-270

PD1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma

(Nayak et al, Blood, 2017;129:3071-73

• Frequent 9p24.1/PD-L1/PD-L2 copy-number alterations and increased expression of the PD-1 ligands in PCNSZL and PTL

• N=5• 100% responses, 4 CR, 1 PR • Progression-free survival: 13+, 17, 17+, 14, 14+

Pre- and posttreatment head CTs with contrast in a patient with primary refractory PCNSL. (Left) The contrast-enhancing lesion before treatment with nivolumab.

Lakshmi Nayak et al. Blood 2017;129:3071-3073

PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase (Kwong

et al, Blood, 2017;129:2437-2442

• N=7• 100% responses, • After median follow up of 6 months: 5 patients remain in CR• Strong PDL1 expreesion on lymphoma cells in 4/5 patients tested

Actively recruiting trials of immunotherapy in lymphoma

MA Postow et al. N Engl J Med 2018;378:158-168.

Organs Affected by Immune Checkpoint Blockade.

54

Pembrolizumab:Immune-mediated Adverse Reactions1

Adverse ReactionPEMBROLIZUMAB

N=3830Grade 1-2 (%) Grade 3-5 (%) Total (%)

Pneumonitis 2,3 1,3 3,6Colitis 0,6 1,1 1,7Hepatitis 0,3 0,4 0,7Nephritis 0,1 0,2 0,3Hypophysitis 0,2 0,3 0,5Hyperthyroidism 3,2 0,1 3,3Hypothyroidism 9,6 0,2 9,8Cutaneous irAE 0,3 1,4 1,7

1. Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018

• Evaluation based on 4,439 patients with advanced melanoma, NSCLC, cHL urothelial carcinoma and HNSCC.

Grafiek1

PneumonitisPneumonitis

ColitisColitis

HepatitisHepatitis

NephritisNephritis

HypophysitisHypophysitis

HyperthyroidismHyperthyroidism

HypothyroidismHypothyroidism

Cutaneous irAECutaneous irAE

Grade 1-2

Grade 3-5

2.3

1.3

0.6

1.1

0.3

0.4

0.1

0.2

0.2

0.3

3.2

0.1

9.6

0.2

0.3

1.4

Sheet1

Fatigue21%

Pruritus16%

Rash13%

Diarrhoea12%

Nausea10%

G1-2G3-5Total

Pneumonitis2.31.33.6

Colitis0.61.11.7

Hepatitis0.30.40.7

Nephritis0.10.20.3

Hypophysitis0.20.30.5

Hyperthyroidism3.20.13.3

Hypothyroidism9.60.29.8

Cutaneous irAE0.31.41.7

Sheet1

Grade 1-2

Grade 3-5

Sheet2

Sheet3

55

Pembrolizumab: Immune-mediated Adverse Reactions Median Time to Onset and Median Duration1

• mo = months; NR = not reached; NSCLC = non‒small cell lung cancer; cHL: classical Hodgkin lymphoma; HNSCC: head and neck squamous cell carcinoma

• Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018

• Median time to onset and median duration of immune-mediated adverse reactions are presented based on 4,439 patients with advanced melanoma, NSCLC, cHLurothelial carcinoma and HNSCC.

Months

Median Time to Onset

Months

Median Duration

NR

(2 days–21.3 mo)

(7 days–16.2 mo)

(8 days–21.4 mo)

(1 day–17.7 mo)

(1 day–21.9 mo)

(1 day–18.9 mo)

(12 days–21.4 mo)

(1 day–17.2+ mo)

(1 day–8.7+ mo)

(8 days–20.9+ mo)

(4 days–12.7+ mo)

(10 days–15.5+ mo)

(2 days–29.9+ mo)

(10 days–10.5+ mo)

Grafiek1

Nephritis

Hypothyroidism

Hyperthyroidism

Hypophysitis

Hepatitis

Colitis

Pneumonitis

Series 1

4.9

3.5

1.4

3.7

2.0

3.6

3.4

4.9

3.5

1.4

3.7

2

3.6

3.4

Sheet1

Series 1

Nephritis4.9

Hypothyroidism3.5

Hyperthyroidism1.4

Hypophysitis3.7

Hepatitis2

Colitis3.6

Pneumonitis3.4

mTollulmDllul

Pneumonitis3.70.066666666721.32.10.033333333317.2

Colitis3.60.233333333316.21.30.03333333338.7

Hepatitis1.30.266666666721.41.50.266666666720.9

Nephritis4.90.412.81.80.333333333310.5

Hypophysitis3.70.033333333317.73.30.133333333312.7

Hyperthyroidism1.40.033333333321.92.10.333333333315.5

Hypothyroidism3.50.033333333318.90.066666666729.9

Cutaneous irAE2.50.133333333321.520.117.8

Grafiek1

Nephritis

Hypothyroidism

Hyperthyroidism

Hypophysitis

Hepatitis

Colitis

Pneumonitis

Series 1

1.8

2.0

3.3

1.7

1.2

2.0

1.8

2

3.3

1.7

1.2

2

Sheet1

Series 1

Nephritis1.8

Hypothyroidism

Hyperthyroidism2

Hypophysitis3.3

Hepatitis1.7

Colitis1.2

Pneumonitis2

56

Pembrolizumab: Immune-mediated Adverse ReactionsRate of Discontinuation1

• NSCLC = non‒small cell lung cancer; cHL= classical Hodgkin lymphoma; HNSCC: head and neck squamous cell carcinoma

• Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018

Patients, %

• Rate of discontinuation from treatment due to immune-mediated adverse reactions is presented based on 4,439 patients with advanced melanoma, NSCLC, cHL urothelial carcinoma and HNSCC.

Rate of Discontinuation

Open questions checkpoint blocking in lymphoma

• Duration of therapy?• Bridge to allo-transplant?• Treatment option for other types of lymphoma?• Combination therapy?• Second or first line therapy?• Biological markers for predicting response?

Immuun Checkpoint blockade bij lymfomenSlide Number 2Slide Number 3Overview of lymphoma immune escape mechanismsLymphoma immune escape mechanismsIn Advanced tumors, the PD-1 Pathway May Be Exploited to Evade the Immune ResponsePD-1 Receptor Blockade With PembrolizumabRibas A. N Engl J Med 2015;373:1490-1492.MA Postow et al. N Engl J Med 2018;378:158-168.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphomaSlide Number 12Slide Number 13Ansell SM et al. N Engl J Med 2015;372:311-319.Checkpoint inhibitor therapy: a new spectrum of adverse eventsSlide Number 16Slide Number 17Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trialBaseline characteristicsObjective response and best overall responseSlide Number 21Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trialSlide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Programmed Death-1 blockade with Pembrolizumab in patients with classical Hodgkin lymphoma after Brentuximab vedotin failure (phase 1b Keynote-013 study)Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphomaSlide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Nivolumab in patients with relapsed or refractory hematologic malignancies: preliminary results of a phase Ib studySlide Number 43Slide Number 44Lymphoma immune escape mechanismsSlide Number 46Clinical outcomeSlide Number 48PD1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma�(Nayak et al, Blood, 2017;129:3071-73Slide Number 50PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase (Kwong et al, Blood, 2017;129:2437-2442Slide Number 52MA Postow et al. N Engl J Med 2018;378:158-168.Pembrolizumab:�Immune-mediated Adverse Reactions1Pembrolizumab: �Immune-mediated Adverse Reactions �Median Time to Onset and Median Duration1Pembrolizumab: �Immune-mediated Adverse Reactions�Rate of Discontinuation1Open questions checkpoint blocking in lymphoma

Immuun Checkpoint blockade bij lymfomen - KU Leuven · through expression of the PD-1 ligands,...

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