Immunotherapy in Hemato-Oncology

Transcription

1 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

2 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»

3 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»

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

5 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

6 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

7 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

8 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

9 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

10 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

11 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

12 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

13 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., Blood Optimized Super-mAb (enhanced mab function or drug targeting) + Conjugate or modification

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

15 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

16 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

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

18 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

19 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)

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

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

22 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)

23 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

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

25 Optimized mab - CLL

26 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: ,

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

28 Optimized mab - MM

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

30 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, NCT

31 Optimized mab - MM

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

33 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

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

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

36 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

37 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;

38 Bispecific Ab (BiTE) - ALL Amgen

39 Bispecific Ab (BiTE) - ALL

40 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

41 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

42 CD19 CART cells - ALL CAR T cell CD3

43 CD19 CART cells - ALL

44 CD19 CART cells - ALL

45 CD19 CART cells - ALL

46 CD19 CART cells - ALL EFS OS

47 CD19 CART cells - ALL

48 CD19 CART cells - MM

49 CD19 CART cells - MM

50 CD19 CART cells - MM

51 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.

52 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

53 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-PD1L, HD, NHL) «eat me» control CD47-SIRPa (studies initiated)

54 Checkpoint control - HD

55 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

56 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: 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)

57 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

58 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

59 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

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

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

62 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

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