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 (T- cells) Detectives Dendritic cells Killer –T cells Microenvironment antigen (flags) Detectives Dendritic cells Killer –T cells Tumor infiltranting T cell recognizable ags Cor e Algorithms Margin Neo-antigens antigen (flags) 5 6 Scott DW et al. Nature Rev 2014 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 Strategy approach PDL-1 Effective immune CTLA-4 response: barriers Lymphoma PDL-1 PD-1 PDL-1 TIM-3 PDL-1 PDL-1 mTOR LAG-3 OXPHOS MHC1 Aerobic glycolysis Interferon gamma EB virus T cell activation antigen presenting cells 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 PDL-1 Avelumab Tremelimumab CTLA-4 Lymphoma PDL-1 Nivolumab PD-1 Pembrolizumab Pidilizumab PDL-1 MBG453 TIM-3 PDL-1 TSR-022 PDL-1 LAG-3 IMP321 Interferon gamma EB virus T cell activation Atezolizumab Inhibitory receptors Durvalumab Ipilimumab PDL-1 Avelumab Tremelimumab Lymphoma PDL-1 CTLA-4 Nivolumab Pembrolizumab PD-1 Pidilizumab PDL-1 MBG453 TIM-3 TSR-022 PDL-1 LAG-3 IMP321 CD27 Varlilumab 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 immunodeficiency- related 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 Tumor interaction microenvironment Activation (cytokine secretion, lysis, proliferation, MHC TCR migration to tumor) +++ DendriticB7 CD28 cell +++ T cell B7 CTLA-4 --- Blockade of CTLA-4 has been shown to enhance T-cell CTLA-4 is expressed on T cells and responses and anti-tumor responses inhibits T-cell activation Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity 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 Tumor interaction microenvironment Activation (cytokine secretion, lysis, proliferation, MHC TCR migration to tumor) +++ TCR MHC DendriticB7 +++ CD28 Tum or cell cell +++ T cell T PD-1 PD-L1 B7 CTLA-4 cell --- --- anti-PD-1 PD-1 anti-CTLA-4 --- PD-L2 CTLA-4 is expressed on T cells and PD-1 expression on tumor-infiltrating lymphocytes is inhibits T-cell activation5 associated with decreased cytokine production and effector function Ipilimumab disrupts the CTLA-4 pathway, Anti PD-1 disrupts PD-1 pathway signaling and thus inducing anti-tumor immunity 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 20th 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 Tumor interaction microenvironment Activation (cytokine secretion, lysis, proliferation, MHC TCR migration to tumor) +++ TCR MHC DendriticB7 +++ CD28 Tum or cell cell +++ T cell T PD-1 PD-L1 B7 CTLA-4 cell --- --- anti-PD-1 PD-1 anti-CTLA-4 --- PD-L2 CTLA-4 is expressed on T cells and PD-1 expression on tumor-infiltrating lymphocytes is inhibits T-cell activation5 associated with decreased cytokine production and effector function Ipilimumab disrupts the CTLA-4 pathway, Nivolumab disrupts PD-1 pathway signaling thus inducing anti-tumor immunity 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 Treatment Inclusion Criteria Endpoints Combination Monotherapy Relapsed/refractory phase phase Primary lymphoid malignancies: Nivolumab • Safety and tolerability • Hodgkin lymphoma 3 mg/kg IV Nivolumab Secondary • B-cell lymphomaa + 3 mg/kg IV • T-cell lymphomab Ipilimumab • INV-assessed best overall response • Multiple myeloma 1 mg/kg IV • No prior organ or Q3W Q2W • Duration of response allogeneic bone marrow x 4 doses 2 years • Progression-free transplantation survival Treatment until disease • No prior immune progression, toxicity, or • Biomarker analyses checkpoint blockade maximum duration of 2 years therapy aIncludes follicular B-cell lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). bIncludes cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) INV, investigator; IV, intravenously; Q2W, every 2 weeks; Q3W, every 3 weeks ASH 2016 Ansell AHS 2016 30 Baseline Characteristics Disposition HL B-cell NHLa T-cell NHLb MM (N = 31) (N = 15) (N = 11) (N = 7) (DLBCL + FL) (CTCL + PTCL) Male, % 42 73 55 86 ECOG 1, % 52 80 73 71 Prior systemic therapies, median 4 3 4 5 (range) (2–10) (1–16) (1–11) (2–20) Prior ASCT, % 42 7 0 57 Median time from prior therapy to 2.2 2.0 1.4 1.0 first nivolumab dose, months (0.5–103.5) (0.5–43.6) (0.4–8.7) (0.0–28.3) (range) aB-cell NHL: DLBCL, n = 10; FL, n = 5; bT-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 B-cell NHL T-cell NHL MM (N = 31) (N = 15) (N = 11) (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 aTotal 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 ASH 2016 32 32 Safety Overview Drug-related AEs AE leading to All AEs Grade 3–4 Serious AEs 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) aTotal includes 1 patient with primary mediastinal