Immunotherapy in Hemato-Oncology

ESMO Preceptorship Programme Immuno-Oncology From tumor immunology to clinical application 2-3 November 2016 Zurich - CH Immunotherapy in Hemato-Oncology Markus G. Manz Klinikdirektor Hämatologie USZ Leiter Hämato-Onkologisches Zentrum USZ

Two fundamentally different approaches: A) Exogenuous application of active therapeutics against cancer Advantage: patient s own immune system not essential Disadvantage: specific therapeutic approach to each cancer Examples: monoclonal Abs (+/-conjugates), CART cells B) Activation of patients own immune system against cancer Advantage: broader therapeutical approach for different cancers? Disadvantage/Risk: non-specific immune activation and response Example: vaccination/adjuvant, «checkpoint inhibitors»

Are there natural immune responses against cancer? Cancer is mostly «own tissue» and therefor not a primary target of immunity (in contrast to infection) Evidence of continuous elimination of «minimal, non-infection driven cancer» by adaptive immunity is still under debate If cancer is clincally manifest, immunity has not been achieved Particular problem if cancer is arising from elements of immune system? But Cancer with (adaptive) immune cell infiltration often has better prognosis Immunostimulation can lead to regression of some cancers In preclinical models, cancer immuno-control has been firmly established Immune cells in cancer leasions appear «paralyzed»

Potential immune mechanisms against cancer? T-cell mediated NK-cell mediated Antibody mediated Phagocyte mediated Artificial, intelligent «designer-immune» mediated

Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + PD1 T cell CD3 T cell CD3 CD28 TCR TCR - PD1L (Tu)Surface Ag (CD..XY..) + + + CD86 MHC I MHC II KILL TC! MHC I tumor cell Dendritic cell / APC

Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + T cell CD3 T cell CD3 PD1 - - - - DON T KILL TC! CD28 TCR TCR - PD1L (Tu)Surface Ag (CD..XY..) + + + CD86 MHC I MHC II MHC I tumor cell Dendritic cell / APC

Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + + + + CD86 T cell CD28 T cell «Enhance CD3the Enhancers!» -Adjuvant / Co-Stimulation TCR -Cytokines MHC I -Vaccination (Peptides, DCs) MHC II CD3 MHC I TCR PD1 - - - - - PD1L tumor cell DON T KILL TC! (Tu)Surface Ag (CD..XY..) Dendritic cell / APC

Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + T cell CD3 T cell CD3 PD1 - - - - DON T KILL TC! «Inhibit the Inhibitors!!» CD28 TCR -mab interference TCR - PD1L (Tu)Surface Ag (CD..XY..) + + + CD86 MHC I MHC II MHC I tumor cell Dendritic cell / APC

Immune-mechanisms: T-cell mediated killing Multiple immuno-receptors guide an adequate T cell response An over-reaction of the immune system generates self-destruction and has to be limited Effector-Cell (T cell) Regulator cell (APC) (or target cell - TC) Nat Rev Immunol

Immune-mechanisms: T-cell mediated killing Multiple immuno-receptors guide an adequate T cell response An over-reaction of the immune system generates self-destruction and has to be limited Effector-Cell (T cell) Nivolumab - a PD-1 blocking mab Ipilimumab a CTLA4-blocking mab Regulator cell (APC) (or target cell - TC) Nat Rev Immunol

Immune-mechanisms: Antibody-mediated killing Antibody-dependent cellular cytotoxicity NK cell Complement-dependent cytotoxicity FcR Antibody-dependent cellular phagocytosis FcR Surface Ag (e.g. CD..XY..) tumor cell Macrophage Direct antibodydependent toxicity

Immune-mechanisms: Artificial designer (immune) killing CART cell Super-armed single chain mab (MHC independent) T cell CD3 CAR T cell BiTE Bispecific T cell Engager (MHC independent) TCR Surface Ag (CD..XY..) tumor cell CD3 Optimized Super -mab (enhanced mab function or drug targeting) + Conjugate or modification

Immune-mechanisms: Artificial designer (immune) killing CART cell Super-armed single chain mab (MHC independent) T cell CD3 CAR T cell BiTE Bispecific T cell Engager (MHC independent) TCR Surface Ag (CD..XY..) tumor cell CD3 Maus et al., 2014. Blood Optimized Super-mAb (enhanced mab function or drug targeting) + Conjugate or modification

Immune-mechanisms: Macrophage activation and killing don t eat me! CD47 SIRPa FcR tumor cell Macrophage eat me! (calreticulin +?) EAT and KILL TC!

Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Optimized monoclonal Abs (CLL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM) Checkpoint control (PD1-PD1/2L, HD, NHL) «eat me» control CD47-SIRPa

Allogeneic hematopoietic (stem) cell transplantation Nobel-Price Medicine Since >50y Bench-Mark for any future SC therapy in regenerative medicine

Allogeneic hematopoietic (stem) cell transplantation Donor HSC Reconstruction of hematopoiesis T NK Infection-Protection GvL (GvHD against hematopoiesis) GvHD HD-Chemo-/RT-Therapie GvL Patient therapeutic activity Time Day 0 Day 14 agvhd Day 100+ cgvhd Active Tumor-Therapy Causes of death -GvHD -Infection -Relapse

Allogeneic hematopoietic (stem) cell transplantation Allo-HSCT: currently only routinely applied CELLULAR immunotherapy and only clinical SC therapy GvL is GvHD against Hematopoiesis (+hematologic malignancy)

Allogeneic hematopoietic (stem) cell transplantation Ipilimumab a CTLA4-blocking mab

Allogeneic hematopoietic (stem) cell transplantation Best Response Examples Ipilimumab post allo-hsct relapse Leukemia Cutis Hodgkin s Lymphoma Bone Marrow

Allogeneic hematopoietic (stem) cell transplantation Adverse Events and Outcomes All seven patients (of 28) with CR or PR, as compared to patients that did not have a response, had some prior GvHD (p=0.08)

mab acd20 in CLL CLL-8 FCR FC (p=0.0001)

Optimized mab - CLL

Optimized mab - CLL Untreated CLL With Co-Morbidity (N=781) R A N D O M I s I E R T 2:1:2 GAZYVARO + Chlorambucil MabThera + Chlorambucil 1a Chlorambucil 2 1b Goede V, et al. N Engl J Med 2014; 370:1101 1110,

Optimized mab - CLL MabThera + Chlorambucil vs. GAZYVARO + Chlorambucil GAZYVARO + Clb MabThera + Clb Monate Goede V, et al. N Engl J Med 2014; 370:1101 1110,

Optimized mab - MM

Optimized mab - MM Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7),

Optimized mab - MM RR MM randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group) First mab in MM: Significant relative reduction of 30% in the risk of disease progression or death. Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT- 2 ClinicalTrials.gov number, NCT01239797.

Optimized mab - MM

Optimized mab - MM Multiple Myeloma HSPC (CD45 dim) Delta: Therapeutic Window for CD38 Targeting?

Optimized mab - MM Daratumumab showed single agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options. Its target and mechanisms of action differentiate it from existing therapies. Supported by Janssen Research and Development and Genmab

Optimized mab - MM Two randomized trials in RR multiple myeloma presented: CASTOR: DaraVd vs Vd POLLUX: DaraRd vs Rd

Optimized mab - MM CASTOR: DVd vs Vd POLLUX: DRd vs Rd Daratumumab: New Rituximab for MM?

Bispecific Ab (BiTE) - ALL α-cd19 Blinatumomab 1,2 Single-chain antibody V H α-cd3 Single-chain antibody V L Linker 55 kda Very short distance between arms allows T cells and tumour cells to come into close proximity 95 100% of B-precursor ALL cases are CD19+ Amgen 1. Nagorsen D, Baeuerle PA. Exp Cell Res 2011;317:1255 60; 2. Baeuerle PA, Reihnardt C. Cancer Res 2009;69:4941 4;

Bispecific Ab (BiTE) - ALL Amgen

Bispecific Ab (BiTE) - ALL

Bispecific Ab (BiTE) - ALL TOWER-STUDY CONCLUSIONS First study to show improved survival with bi-specific T-cell engaging mab immunotherapy vs SOC in Ph- R/R ALL Trial stopped early by DMC because OS endpoint was reached Similar difference in survival after censoring for allohsct Secondary efficacy endpoints (hematologic and molecular remission; EFS) favored blinatumomab vs SOC Grade 3 neutropenia and infection appeared less frequently with blinatumomab, while neurologic events appeared at a similar rate

CD19 CART cells - ALL CAR T cell CD3

CD19 CART cells - ALL

CD19 CART cells - ALL EFS OS

CD19 CART cells - ALL

CD19 CART cells - MM

CD19 CART cells - MM Ten patients, including the patient described in detail here, have been treated (for details, see Table S1 in the Supplementary Appendix, available at NEJM.org) Six of the 10 patients remain progression-free The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis In summary, this is a case of advanced, refractory multiple myeloma in which a durable complete response has been attained with CTL019 infusion after treatment with high-dose melphalan and autologous transplantation, despite the absence of CD19 expression in the vast majority of neoplastic cells.

CD19 CART cells off-the-shelf the future? Great Ormond Street Hospital (GOSH) and University College London: Used cells from a healthy donor DNA added (+CD19 CAR) two genes erased (-TCR, -CD52) CD52 CD19 CAR CAR T cell TCR

Checkpoint control - HD

Checkpoint control - HD 23 patients with relapsed or refractory Hodgkin s lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight hu monoclonal IgtG4 Ab against PD-1) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. n=20 responding pt

Checkpoint control HD+NHL extention Methods: - Patients (pts) were treated using a dose-escalation design (1 and 3 mg/kg) of NIVO administered every 2 weeks (wks) for 2 years - Responses were assessed using standard criteria - Primary endpoint was safety - The secondary endpoint was efficacy Results: - 105 pts were enrolled (23 chl, 31 B-NHL, 23 T-NHL, 27 MM and 1 CML) - Pts were heavily pretreated: Previous ASCT was reported for 75% of pts with chl, 56% of MM, 13% of B-NHL and 9% of T-NHL - As of 1/8/2015, median duration of FU was 62 wks (range: 2 to 106+ wks)

Checkpoint control HD+NHL extention Results continued: - The rate of stable disease in MM (n = 27) was 63%. - Among responding B- and T-NHL pts, 1/4 DLBCL, 3/4 FL and 3/4 T-NHL pts remain in response Conclusions: - Encouraging, durable objective responses were observed - NIVO treatment remains safe and tolerable - further analysis is warranted in chl and selected B- and T-NHLs

Hodgkin s Lymphoma Patho-Biology PD-L1/PD-L2 alterations are a defining feature of chl. Amplification of 9p24.1 is more common in patients with advanced stage disease and associated with shorter PFS

«Don t eat me!» CD47-SIRPa (studies ongoing)

ESMO Preceptorship Programme Immuno-Oncology From tumor immunology to clinical application 2-3 November 2016 Zurich - CH Thank you for your attention