Immunotherapy in Hemato-Oncology

Transcription

1 ESMO PRECEPTORSHIP PROGRAMME IMMUNO-ONCOLOGY ZURICH, SWITZERLAND, NOVEMBER 2-3, 2018 Immunotherapy in Hemato-Oncology Markus G. Manz Director Department of Hematology and Oncology, University Hospital Zurich

2 Markus G. Manz FINANCIAL CONFLICT OF INTEREST No pharma stocks/shares Education / Advisory fees last 3 years (each <CHF ) Amgen, Bristol-Myers Squibb, Celgene, Janssen Pharmaceutica, Novartis, Roche, Sanofi-Aventis, Teva Pharma Research Support (material) Novartis (CSF-1R inhibitors) Patents/Patent Aplications/Ownership on gene-modified humanized mice on definiton and use of spec hu hem progenitor cells co-founder hu-mouse company No financial COI regarding this pesentation

3 Hematopoiesis A Paradigmatic Stem-Cell Supported Organ

4 Hematopoietic Malignancies Cell Of Origin (COO) (almost always) Systemic Diseases AML MDS MPN T-ALL B-ALL Lymphoma LCH ECD Myeloma

5 Cancer Death Rates CH 2009 (6) (7) (5) (10) Leukemia and lymphoma about 10% of all neoplasias [Prozent] (Quellen für Zahlen: Zahlen Institut für Krebsepidemiologie und Registrierung NICER)

6 Hematopoietic Cancer Incidence ALL: ~1.5 / / year AML: ~2.5 / / year CLL: ~3 / / year CML: ~1 / / year Inzidenz pro Einwohner Zentraleuropa Diseases of an ageing population

7 Demographic Evolution in CH Expected scenario 2030: Doubling of population > 65 y Doubling of hematologic (and other neoplasias) in case of stable incidence and prevalance

8 Potential Immune-Mediated Mechanisms Against Cancer Mode of immune-action Mode of application T-cell mediated Antibody mediated NK-cell mediated Transfer of immune effectors Phagocyte mediated Activation of Artificial, intelligent «designerimmune» mediated endogenous immune effectors

9 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

10 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

11 Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + T cell CD3 T cell CD3 PD 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

12 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 PD PD1L tumor cell DON T KILL TC! (Tu)Surface Ag (CD..XY..) Dendritic cell / APC

13 Immune-mechanisms: T-cell mediated killing + Cytokine + + Cytokine + T cell CD3 T cell CD3 PD 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

14 Immune-mechanisms: Artificial designer (immune) killing Chimeric Antigen Receptor T 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

15 Immune-mechanisms: Macrophage/Innate Checkpoint Control don t eat me! CD47 SIRPa FcR tumor cell Macrophage eat me! (calreticulin +?) EAT and KILL TC!

16 Overview CD47-SIRPa «don t eat me» innate Immunity Checkpoint Control Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD, NHL) Optimized monoclonal Abs (CLL, FL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

17 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD, NHL) Optimized monoclonal Abs (CLL, FL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

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

19 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

20 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)

21 ESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD, NHL) Optimized monoclonal Abs (CLL, FL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

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

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

24 Checkpoint control - Hodgkin s Lymphoma

25 Checkpoint control - Hodgkin s Lymphoma 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 ORR of >80% in r/r HD

26 Hodgkin s Lymphoma Patho-Biology PD-L1/PD-L2 alterations (disomy, polysomy, copy gain, amplification) are a defining feature of chl Amplification of 9p24.1 is more common in patients with advanced stage disease and associated with shorter PFS

27 Checkpoint inhibition in other Lymphoma(s)+MM? Large B-cell lymphoma PD-L1 overexpression is not commonly seen on B NHL cells. ORR of 30-40% in heavily pretreated r/r DLBCL and also patients with r/r primary mediastinal large B- cell lymphoma Mantle cell lymphoma: no larger pt group data available Follicular lymphoma: Ten FL patients were included in a phase I study of nivolumab in a variety of r/r hematologic malignancies; the ORR was 40% and three responses were ongoing after a median follow-up of 91.4 weeks, which encouraged further clinical trials. Chronic lymphocytic leukemia: Richter syndrome, showed an ORR of 21% Other Lymphoma: T cell lymphoma and virus-related lymphomas (i.e. Epstein- Barr virus- or hepatitis C virus-related) might be susceptible, CNS Lymphoma, Testicular Lymphoma, Primary mediastinal B cell lymphoma MM: Trials ongoing

28 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD, NHL) Optimized monoclonal Abs (CLL, FL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

29 Antigen Expression in B Cell Maturation CD19 CD20 CD22 CD38 CD138 BCMA CD319 (SLAMF7) Expression outside of Blood / B-Cell Compartment - -(?)

30 mab acd20 in CLL CLL-8 FCR FC (p=0.0001) acd20 mab in all CD20+ B-cell NPL (ALL and NHL) in clinical use

31 Optimized mab Modes of action of GA101 (obinutuzumab): The first glycoengineered, type II anti-cd20 mab Antibody-dependent cellular cytotoxicity (ADCC) Complement-dependent cytotoxicity (CDC) Direct cell death Type I antibody (Rituximab) Glycoengineered Type II antibody (GA101) Glycoengineering Type I/II As a type II antibody, GA101 binds differently than type I mabs, leading to distinct modes of cytotoxic activity against B-cell malignancies 3-6 Roche

32 Optimized mab - CLL MabThera + Chlorambucil vs. GAZYVARO + Chlorambucil GAZYVARO + Clb MabThera + Clb Monate Goede V, et al. N Engl J Med 2014; 370: ) Study-Update EHA 2018: also significant OS benefit with longer FU 2.) FL first-line R-Chemo vs. O-Chemo (GALLIUM): longer PFS (NEJM 10/2017)

33 Antigen Expression in B Cell Maturation CD19 CD20 CD22 CD38 CD138 BCMA CD319 (SLAMF7) Expression outside of Blood / B-Cell Compartment - -(?)

34 Optimized mab Multiple Myeloma Daratumumab represents a landmark advance in the treatment of myeloma. It is likely to be incorporated into the treatment of all stages of the disease over the next several years.

35 Optimized mab Multiple Myeloma

36 CD38 Expression in MM vs normal Progenitors Multiple Myeloma HSPC (CD45 dim) Delta: Therapeutic Window for CD38 Targeting?

37 Optimized mab Relapsed/Refractory Multiple Myeloma CASTOR: DVd vs Vd POLLUX: DRd vs Rd Daratumumab: New Rituximab for r/r MM? Better with ImID?

38 Optimized mab first-line MM CONCLUSIONS Patients with newly diagnosed multiple myeloma, ineligible for stem cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections (pneumonia). anti-cd38 mab on way to first-line therapy in MM

39 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD) Optimized monoclonal Abs (CLL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

40 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 % of B-precursor ALL cases are CD19+ Amgen 1. Nagorsen D, Baeuerle PA. Exp Cell Res 2011;317: ; 2. Baeuerle PA, Reihnardt C. Cancer Res 2009;69:4941 4;

41 Bispecific Ab (BiTE) - ALL Amgen

42 Bispecific Ab (BiTE) - ALL TOWER-STUDY

43 Bispecific Ab (BiTE) - ALL TOWER-STUDY Now also in first-line MRD+: 78% MRD neg; Blood 2018

44 Engineering of Antibodies Engineering Reality Clinical Future

45 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD) Optimized monoclonal Abs (CLL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

46 New therapy for CD19+ B-ALL: CD19-CART cells Emma Whitehead 2012 NY Times

47 The principle of CAR T cell Therapy Chimeric Antigen Receptor T Cell Binder to Antigen on Cell CAR T cell Antigen on Cell Target Cell Target Cell

48 The principle of CAR T cell Therapy Chimeric Antigen Receptor T Cell Binder to Antigen on Cell CAR T cell Antigen on Cell Target Cell Target Cell

49 CART cells CAR T cell CD3

50 CD19 CART cells r/r ALL EFS OS

51 CD19 CART cells r/r ALL

52 CD19 CART cells r/r ALL First-in-class therapy showed an 83% (52/63) overall remission rate in B-cell ALL patient population with limited treatment options and historically poor outcomes FDA approved the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel for the treatment of pediatric and young adult patients with B-cell precursor acute lymphocytic leukemia (ALL) that is refractory or in second or later relapse. This is the first gene therapy available in the U.S. and is ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases, the FDA said. On the same day as the approval, the FDA expanded the indication for tocilizumab (ail-6r mab), a monoclonal antibody to treat CAR T-cell induced, severe or life-threatening CRS in patients 2 years of age. In clinical trials of patients treated with CAR T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of tocilizumab. Sources: U.S. Food and Drug Administration news release, August 30, 2017; Novartis news release, August 30, 2017.

53 CD19 CART cells r/r NHL

54 CD19 CART cells r/r NHL ZUMA-1 CTL019

55 CD19 CART cells r/r NHL Axicabtagene ciloleucel approved for adult patients whose disease failed to respond to at least two prior treatments, as well as for the following indications: diffuse large B-cell lymphoma (DLBCL) primary mediastinal large B-cell lymphoma (PMBCL) high grade B-cell lymphoma (hgbcl) DLBCL arising from follicular lymphoma (DLBCL from FL) Approval was based on data from the multicenter ZUMA-1 trial, which included 111 patients (median age = 58 years; range = years) with previously treated DLBCL, primary mediastinal large B-cell lymphoma, or transformed follicular lymphoma from 22 institutions. January 27, 2017, 101 patients (91%) had received axicabtagene ciloleucel cells/kg, following conditioning with lowdose cytarabine and fludarabine. ORR=72%, CR = 51% (95% CI 41-62).

56 CD19 CART cells r/r NHL

57 Antigen Expression in B Cell Maturation CD19 CD20 CD22 CD38 CD138 BCMA CD319 (SLAMF7) Expression outside of Blood / B-Cell Compartment - -(?)

58 BCMA CART cells Multiple Myeloma

59 BCMA CART cells Multiple Myeloma Results demonstrate for the first time that CAR T-cells targeting an antigen other than CD19 can induce complete remissions of a hematologic malignancy. Importantly, CAR-BCMA T cells have powerful activity against MM that was resistant to standard therapies.

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

61 CAR T cell modification and combination concepts Engineering Reality Clinical Future

62 CD19 CAR T cell Therapy associated Resistance Relapse B-ALL 7-25% Epitope escape Lineage switch Isoform switch/splice variants CD19 mutations Epitope masking Orlando EJ et al. Nat Med 2018 Ruella M et al. Nat Med 2018

63 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD) Optimized monoclonal Abs (CLL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis

64 CD47-SIRPa «don t eat me» innate Immunity Checkpoint Control SIRPa-CD47 interaction: don t eat me signal FcR-activation by tumor-bound mab: eat me signal Additional effect on APC adaptive immunity?

65 CD47-SIRPa «don t eat me» innate Immunity Checkpoint Control Phase 1b r/r DLBCL und FL (n=22) 2-10 prior therapies (Median=4) 95% refraktär auf Ritxumab 50% OR(CR + PR), 36% CR Most freq AE: anemia, infusion reactions The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study

66 CD47-SIRPa «don t eat me» innate Immunity Checkpoint Control

67 Overview Immunotherapy in Hemato-Oncology (examples) Allogeneic hematopoietic (stem) cell transplantation Checkpoint control (post-allo-hsct, HD) Optimized monoclonal Abs (CLL, MM) Bispecific Abs (BiTE; ALL) CART cells (CD19 CART, ALL, MM; BCMA CART, MM) Innate Immunity Checkpoint control CD47-SIRPa axis An ongoing (R)Evolution

68 Thank you for your attention