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 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) ASH 2016 • No drug-related deaths occurred; most deaths were due to disease progression 33 Drug-Related AEs

Nivolumab + ipilimumab (N = 65) AEs by preferred term, n (%) Any gradea 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 AEsb by category, n (%) Any gradec 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 aAEs occurring in ≥10% of patients. bSelect 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. cAll drug-related select AEs AE, adverse event ASH 2016 34 B-Cell NHL: Best Overall Response

Change in tumor burden, B-cell B-cell NHL (N = 100 NHL 15) DLBCL responders (n = 2) 75 DLBCL non-responders (n = 8) a ORR, n (%) 3 (20) FL responders (n = 1) 50 FL non-responders (n = 4) Complete response 0 25 Partial response 3 (20) 0 Stable disease 1 (7) −25

Relapsed or progressive target from in baseline 8 (53) disease −50 lesions lesions tumor burden (%) Median duration of PR, NR −75 Change Change months (range) (11.0+, 12.7+) 100

aResponse was not reported or unable to be determined for 3 (20%) patients with B- 0 12 24 36 48 60 72 84 96 cell NHL Time since first treatment date 1st occurrence of new(weeks) lesion % change truncated to Off treatment 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

100 • Immune-mediated AEs D F C consistent in frequency and 50 D severity with known safety D profile of this combination baseline 0 P F P P • In NHL, activity in a small M C H −50 proportionH H of DLBCL

H H H in tumor size (%) H H H P H H H H H D

Change from from Change D H H −100 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 agents into combination approaches § Optimizing new terapeutics agents and immune fuction Merci !! [email protected]