Mariano Provencio Servicio de Oncología Médica Hospital Universitario Puerta de Hierro Immune checkpoint inhibition in DLBCL
Immunotherapy: The Cure is Inside Us Our immune system prevents or limit infections by foreign antigens expressed in microorganisms (bacteria, viruses, etc.) Our immune system can also recognize and destroy cancer cells.. However, cancer cells have developed escape mechanisms to avoid their destruction by immune cells put the brakes on Immuno-Oncology: Find ways of unleashing the power of our body s immune system to treat or prevent cancer T-lymphocytes (Tcells)
Detectives Dendritic cells Killer T cells Microenvironment antigen (flags)
Detectives Dendritic cells Killer T cells Tumor infiltranting T cell recognizable ags Cor e Margin Algorithms Neo-antigens antigen (flags)
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Scott DW et al. Nature Rev 2014 6
Strategy approach Effective immune response: barriers microenviroment Activate anti-tumor immune response inhibitory receptors: blocking antibodies Nivo, Pembro, Ipi, (anti PD 1) (CTLA4) combining 2 checkpoint inhibitors combining with chemotherapy activate receptors: agonist Urelumab Utumilumab Varlilumab
Strategy approach Effective immune response: barriers microenviroment
Inactivated effector T cell angiogenesis metabolism PDL-1 Lymphoma CTLA-4 PDL-1 Strategy approach Effective immune response: barriers PD-1 PDL-1 TIM-3 PDL-1 PDL-1 mtor LAG-3 OXPHOS MHC1 Interferon gamma EB virus T cell activation antigen presenting cells Aerobic glycolysis
Strategy approach Effective immune response: barries microenviroment Activate anti-tumor immune response inhibitory receptors: blocking antibodies Nivo, Pembro, Ipi, combining 2 checkpoint inhibitors combining with chemotherapy activate receptors: agonist Urelumab Utumilumab Varlilumab
Atezolizumab Inhibitory receptors Durvalumab Ipilimumab Tremelimumab PDL-1 Avelumab Lymphoma CTLA-4 PDL-1 Nivolumab Pembrolizumab Pidilizumab PD-1 PDL-1 TIM-3 PDL-1 PDL-1 LAG-3 Interferon gamma EB virus T cell activation MBG453 TSR-022 IMP321
Atezolizumab Inhibitory receptors Durvalumab Avelumab PDL-1 Ipilimumab Tremelimumab Lymphoma PDL-1 CTLA-4 PD-1 Nivolumab Pembrolizumab Pidilizumab PDL-1 PDL-1 TIM-3 MBG453 TSR-022 LAG-3 IMP321 Varlilumab CD27 CD40L 4-1BB Dacetuzumab Utumilumab Activating receptors
PD-L1 expression in lymphomas PD-L1 expression was found to be abundant in agressive B- cell lymphoma viral associated, and immunodeficiencyrelated lymphomas Similar to chl, primary mediastinal B cell lymphoma, T- cell/histiocyte rich large B cell lymphoma : 90% PDL1/2 expression NK-T cell lymphoma (80%), primary effusion lymphoma (75%), plasmablastic (44%) and DLCBL NOS: 14%
Development of Immune checkpoints Early trials Anti CTLA 4 Ipilimumab Anti PD 1 Pidilizumab Nivolumab Pembrolizumab Combination Ipilimumab + nivolumab Phase II Anti PD 1
Development of Immune checkpoints Early trials Anti CTLA 4 Ipilimumab Anti PD 1 Pidilizumab Nivolumab Pembrolizumab Combination Ipilimumab + nivolumab Phase II Anti PD 1
Ipilimumab CTLA-4 blockade (ipilimumab) APC T-cell interaction Tumor microenvironment MHC DendriticB7 cell B7 TCR +++ Activation (cytokine secretion, lysis, proliferation, migration to tumor) CD28 +++ T cell CTLA-4 --- CTLA-4 is expressed on T cells and inhibits T-cell activation Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity Blockade of CTLA-4 has been shown to enhance T-cell responses and anti-tumor responses
First trial: Ipilimumab in lymphoma 18 patients: 2 responses (11%), were durable, lasting over 31 m in DLCBL
Development of Immune checkpoints Early trials Anti CTLA 4 Ipilimumab Anti PD 1 Pidilizumab Nivolumab Combination Ipilimumab + nivolumab Phase II Anti PD 1
Ipilimumab and PD1 blockade CTLA-4 blockade (ipilimumab) PD-1 blockade APC T-cell interaction Tumor microenvironment MHC DendriticB7 cell B7 TCR +++ Activation (cytokine secretion, lysis, proliferation, migration to tumor) CD28 +++ T cell CTLA-4 --- anti-ctla-4 TCR +++ T cell PD-1 --- PD-1 --- MHC Tumor cell PD-L1 anti-pd-1 PD-L2 CTLA-4 is expressed on T cells and inhibits T-cell activation5 PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity Anti PD-1 disrupts PD-1 pathway signaling and restores anti-tumor T-cell function
Sixty-six eligible patients were treated. At 16 months, PFS was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point Treatment was associated with an apparent CR rate of 34% and overall response rate of 51% among patients with measurable disease after transplant
Nivolumab Efficay results Kinetics response Drug-Related AEs Biomarker assessment IHC for PD-L1 positive >20% of nonmalignant cells and no staining of malignant cells
Durability of response Armand P EHA 20 th 2015, updated results phase I
7 lines of treatments including TASPE
Post Nivolumab
immunotherapy in lymphomas Hodgkin s Lymphomas Copy number of 9p24.2, a genomic region that includes CD274 (encoding PD-L1), PDCD1LG2 (encoding PD- L2), and JAK2 correlates with cell surface PD-L1 protein expression more? Whole-exome sequencing of RS cells from chl revealed a median of only 244 mutations per case But, PD-L1 blockade therapy us extraordinarily effective in chl, suggesting at least in this disease, that antigenic quality is an important as quantity,» in some cases, HRS specific antigens may derived from immunogenic EBV antigens
Development of Immune checkpoints Early trials Anti CTLA 4 Ipilimumab Anti PD 1 Pidilizumab Nivolumab Pembrolizumab Combination Ipilimumab + nivolumab Phase II Anti PD 1
Nivolumab and Ipilimumab CTLA-4 blockade (ipilimumab) PD-1 blockade (nivolumab) APC T-cell interaction Tumor microenvironment MHC DendriticB7 cell B7 TCR +++ Activation (cytokine secretion, lysis, proliferation, migration to tumor) CD28 +++ T cell CTLA-4 --- anti-ctla-4 TCR +++ T cell PD-1 --- PD-1 --- MHC Tumor cell PD-L1 anti-pd-1 PD-L2 CTLA-4 is expressed on T cells and inhibits T-cell activation5 PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity Nivolumab disrupts PD-1 pathway signaling and restores anti-tumor T-cell function
CheckMate 039 Study Design: Nivolumab and Ipilimumab Combination Cohort Phase 1, non-randomized, non-comparative, sequential cohort pilot study Inclusion Criteria Relapsed/refractory lymphoid malignancies: Hodgkin lymphoma B-cell lymphoma a T-cell lymphoma b Multiple myeloma No prior organ or allogeneic bone marrow transplantation No prior immune checkpoint blockade therapy Combination phase Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Q3W x 4 doses Treatment Monotherapy phase Nivolumab 3 mg/kg IV Q2W 2 years Treatment until disease progression, toxicity, or maximum duration of 2 years Primary Endpoints Safety and tolerability Secondary INV-assessed best overall response Duration of response Progression-free survival Biomarker analyses a Includes follicular B-cell lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). b Includes cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) INV, investigator; IV, intravenously; Q2W, every 2 weeks; Q3W, every 3 weeks Ansell AHS 2016 ASH 2016 30
Baseline Characteristics Disposition HL (N = 31) B-cell NHL a (N = 15) T-cell NHL b (N = 11) MM (N = 7) (DLBCL + FL) (CTCL + PTCL) Male, % 42 73 55 86 ECOG 1, % 52 80 73 71 Prior systemic therapies, median (range) 4 (2 10) 3 (1 16) 4 (1 11) 5 (2 20) Prior ASCT, % 42 7 0 57 Median time from prior therapy to first nivolumab dose, months (range) 2.2 (0.5 103.5) 2.0 (0.5 43.6) 1.4 (0.4 8.7) 1.0 (0.0 28.3) a B-cell NHL: DLBCL, n = 10; FL, n = 5; b T-cell NHL: CTCL, n = 7; PTCL, n = 4 ASCT, autologous stem cell transplantation; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FL, follicular B-cell lymphoma; HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non-hodgkin lymphoma; PTCL, peripheral T-cell lymphoma For HL cohort, transplant naïve, n = 18 Chemoresistant, n = 13 Ineligible for ASCT, n = 3 Declined procedure, n = 2 ASH 2016 31 31
Dosage Summary HL (N = 31) B-cell NHL (N = 15) T-cell NHL (N = 11) MM (N = 7) Median number of doses received (range) Nivolumab 12 (2 43) 2 (1 34) 5 (1 24) 2 (1 4) Ipilimumab 4 (2 4) 2 (1 4) 4 (1 4) 2 (1 4) Patients receiving 90% of intended dose, n (%) Nivolumab (combination phase) 21 (68) 14 (93) 9 (82) 5 (71) Ipilimumab (combination phase) 20 (65) 14 (93) 9 (82) 5 (71) Nivolumab (monotherapy phase) a 21 (81) 3 (75) 5 (83) 0 a Total number of patients included in the nivolumab monotherapy for whom dose intensity was reported: HL, n = 26; B-cell NHL, n = 4; T-cell NHL, n = 6; MM, n = 0 HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non-hodgkin lymphoma The reason for patients receiving <90% of the intended dose was dose delays 32 ASH 2016 32
Safety Overview Drug-related AEs All AEs Grade 3 4 Serious AEs AE leading to discontinuation All patients (N = 65), n (%) a 51 (78) 19 (29) 14 (22) 5 (8) HL (N = 31) 28 (90) 8 (26) 6 (19) 2 (6) B-cell NHL (N = 15) 8 (53) 3 (20) 2 (13) 0 T-cell NHL (N = 11) 11 (100) 5 (45) 4 (36) 2 (18) MM (N = 7) 4 (57) 3 (43) 2 (29) 1 (14) a Total includes 1 patient with primary mediastinal B cell lymphoma HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non-hodgkin lymphoma Adverse events (AEs) leading to discontinuation: Pneumonitis (grade 1 in a patient with HL; grade 3 in a patient with T-cell NHL; grade 3 in a patient with MM) Pneumonia and pneumonitis (both grade 4, both AEs occurred in a single patient with T-cell NHL) Diabetic ketoacidosis (grade 4 in a patient with HL) No drug-related deaths occurred; most deaths were due to disease progression ASH 2016 33
Drug-Related AEs AEs by preferred term, n (%) Nivolumab + ipilimumab (N = 65) Any grade a Grade 3 4 Fatigue 17 (26) 1 (2) Pyrexia 15 (23) 0 Rash 7 (11) 0 Diarrhea 12 (18) 1 (2) Nausea 9 (14) 1 (2) Pneumonitis 9 (14) 4 (6) Cough 9 (14) 0 Infusion-related reaction 9 (14) 2 (3) Select AEs b by category, n (%) Any grade c Grade 3 4 Gastrointestinal 14 (22) 2 (3) Skin 14 (22) 0 Hypersensitivity/infusion reaction 11 (17) 2 (3) Pulmonary 10 (15) 4 (6) Hepatic 6 (9) 2 (3) Renal 2 (3) 0 a AEs occurring in 10% of patients. b Select AEs = AEs with potential immunologic etiology that require frequent monitoring/intervention that occurred between first nivolumab dose and up to 30 days after last nivolumab dose. c All drug-related select AEs AE, adverse event ASH 2016 34
B-Cell NHL: Best Overall Response B-cell NHL (N = 15) ORR, n (%) a 3 (20) Complete response 0 Partial response 3 (20) Stable disease 1 (7) Relapsed or progressive disease Median duration of PR, months (range) 8 (53) NR (11.0+, 12.7+) a Response was not reported or unable to be determined for 3 (20%) patients with B- cell NHL Change from baseline in target lesions tumor burden (%) 100 75 50 25 0 25 50 75 100 Change in tumor burden, B-cell NHL 0 12 24 36 48 60 72 84 96 1st occurrence of new lesion Off treatment DLBCL responders (n = 2) DLBCL non-responders (n = 8) FL responders (n = 1) FL non-responders (n = 4) Time since first treatment date (weeks) % change truncated to 100 +, censored value; DLBCL, diffuse large B-cell lymphoma; FL, follicular B-cell lymphoma; NHL, non-hodgkin lymphoma; NR, not reached; ORR, overall response rate; PR, partial response ASH 2016 35
Change in Tumor Burden by PD-L1 H-Score Nivolumab and Ipilimumab Combination Non-Hodgkin lymphoma A diverse group of tumors, characterized by variable PD-L1 expression Immune-mediated AEs consistent in frequency and severity with known safety profile of this combination In NHL, activity in a small H proportion H H of DLBCL H H H H H H H H H H H H H Change from baseline in tumor size (%) 100 50 0 50 100 D F C D D P F P P M C P D D 5 10 Patients PD-L1 H-score quartile: 0 0.5 and <150 150 and <250 250 and 300 ASH 2016 36
Development of Immune checkpoints Early trials Anti CTLA 4 Ipilimumab Anti PD 1 Pidilizumab Nivolumab Pembrolizumab Combination Ipilimumab + nivolumab Phase II Anti PD 1
CheckMate 139, phase II, Nivo in DLBCL refractory after ASCT 121 patients were evaluated 87 after ASCT and 34 ASCT ineligible (ASCT-i) ORR. 10.3% (95% CI, 4.8 to 18.7) 3.4% CR in ASCT and 2.9% ASCT-i Duration of response was: 11.4 m PFS: 1.87 m (ASCT) and 1.4m (ASCT-i) This study is ongoing, but not recruiting participants https://clinicaltrials.gov/ct2/show/nct02038933. Accessed december, 12, 2017.
ASH 2017
Early combinations
Dec 2017
Conclusions Anti PD1: Highly tumor-dependent very active in Hodgkin Lymphoma Modest activity in Non-Hodgkin Lymphoma Combinations Modest activity IPI+ Nivo Incorporing promising agentsinto combination approaches Optimizing new terapeutics agents and immune fuction
Merci!! mprovencio.hpth@salud.madrid.org