Inmunoterapia aplicada al linfoma no Hodgkin. Andrés López Servicio de Hematología Hospital Universitario Vall d Hebron

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2 Inmunoterapia aplicada al linfoma no Hodgkin Andrés López Servicio de Hematología Hospital Universitario Vall d Hebron

3 1. Monoclonal antibodies 2. Antibody-drug conjugates 3. Bispecific monoclonal antibodies: Bispecific T-cell engager (BiTE), and Dual Affinity Re-Targeting (DART) 4. CAR T-cells 5. Immune checkpoints inhibitors

4 Antibodies, modified T-cells, and immune check points blockade

5 Monoclonal antibodies

6 Monoclonal antibodies Anti-CD20 antibodies Type Comments Rituximab I First in human Ofatumumab I Approved by FDA in cases of CLL in which Fludarabine is not appropriate Veltuzumab I Exibits a greatter CDC In FL previously exposed to Rituximab, ORR of 44% and CR of 27% In FL no previously exposed to Rituximab, ORR of 57% and CR of 43% LY I fold higher affinity to CD20 than Rituximab It is active in patients carrying FcyRIIIa allele In FL with this allele the ORR was 22-50% in a phase I trial Obinutuzumab II In november 2013 FDA approved for treatment of CLL in combination with Chlorambucil (ORR:78%, CD 21%)

7 Monoclonal antibodies Other antibodies Phase Lymphoma Response Epratuzumab (anti-cd22) Epratuzumab + Rituximab I/II II R/R FL R/R DLBCL R/R B-NHL ORR: 24% ORR: 15% ORR: 67% CR: (60% in FL, 50% in DLBCL) MEDI-551 (anti-cd19) Lucatumumab (anti-cd40) Dacetumumab (anti-cd40) + R-Gemcitabine 1stLine FL ORR: 88% I/II R/R B-NHL ORR: 24% I/II R/R B-NHL ORR in FL: 33% ORR in DLBCL: 11% II R/R DLBCL ORR: 47% CR: 20%

8 Antibody-drug conjugates

9 Conjugated monoclonal antibodies Antibody (Target) Polatuzumab Vedotin (CD22) Inutuzumab Ozogamicin (CD22) SAR3419 (CD19) +Maitensina Brentuximab Vedotin (CD30) Ph. Lymphoma N Response DoR (median) PFS (median) OS (median) I/II R/R B-NHL 95 ORR: 19% CR: 7% I R/R B-NHL 79 ORR: 38% CR: 15% I/II R/R B-NHL 42 ORR: 30% CR: 15% II R/R ALTCL 58 ORR: 86% CR: 57% FL: 317 days DLBCL: 49 days 10 m (5-77) m. NR FL: NR DLBCL: 193 d.

10 Monoclonal antibodies combinations Antibodies (Target) Inutuzumab Ozogamicin (CD22) + Rituximab (CD20) Milatumumab (CD74) + Vetuzumab (CD20 type 2) Phase Lymphoma N Response PFS (median) OS (median) I/II R/R B-NHL 119 FL (ORR:87%, CR: 62%) DLBCL (ORR:74%, CR: 50%) Refr./Agrs. (ORR:20%, CR: 3%) I/II R/R B-NHL 34 ORR: 24% CR: 6% FL: NR DLBCL: 17.1 m. Refr./Agrs.: 1.9 m. FL: NR DLBCL: NR 2 m. 16 m. Refr./Agrs.: 8.8 m.

11 Bispecific monoclonal antibodies

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13 BiTE vs DART Moore et al. Blood, 2011; 117:

14 Blinatumumab (ant CD19 x CD3) in NHL: Final analysis Disease Phase Dosing n Results Reference R/R NHL/CLL I Rapid infusion 13 µg/kg 3 t/w 22 No responses Nagorsen (1) R/R NHL I CI: µg/kg for 4-8 w 76 ORR: 69% (DLBCL: 55%) Goebeler (2) R/R DLBCL II CI: 112 µg/kg for 4-8 w 25 ORR: 43% CR: 19% Viardot (3) 1. Nagorsen et al. Leuk lymphoma Goebeler et al. JCO Viardot et al. Blood 2016

15 Blinatumumab (ant CD19 x CD3) in NHL: Safety AE Frequency (%) Pyrexia 62 Headache 36 Peripheral edema 25 Febrile Neutropenia 25 Nausea 25 Hypokalemia 23 Rash 21 Tremor 20 Constipation 20 AE with a frequency < 20% Pneumonia Tremor Device-related infections Encephalopathy Confusion Leukoencephalopathy: mainly in patients with previous radiotherapy and chemotherapy used to CNS

16 Phase I 76 patients mage: 65 (20-80) years Histology: DLBCL: 14 inhl: 52 Other: 10 Blinatumumab (BiTE: CD19xCD3) in R/R NHL Medication with Prednisolone and/or Dexamethasone MTD: 60 mg/m2/day n CR PR DLBCL FL MCL Goebeler et al. JCO 2016; 34:

17 CAR T-cells

18 CAR T-cell therapy (ant CD19). First reported on the road Centers: City of Hope, Baylor, Pennsylvania University, MSKCC, NCI, Children Hospital Philadelphia, Fred Hutchinson, BMC, Beijing, MDACC FL 2 Refractory 4 Relapsed TTR/P (Weeks) No response 2 PR DLBCL 5 Relapsed No response SLL/CLL 15 Relapsed 3 CR 5 PR

19 CAR T-cell therapy in LPS

20 Anti-CD19 CAR T-cells in R/R B-cell NHL 22 patients Histology: - DLBCL: 19 - FL: 2 - MCL: 1 Lymphodepletion therapy with: Cyclophosphamide + Fludarabine Response DLBCL (n=19) FL (n=2) MCL (n=1) CR PR 5 ORR DoR: 1-20 months (with 10 in ongoing CR) Kochenderfer et al. Haematologica 2016; 101: s1 (#S792)

21 Allogeneic Anti-CD19 CAR T-cells in R/R B-cell lymphoproliferative disease progressed after allo-sct 20 patients Histology: DLBCL: 5 MCL: 5 CLL: 5 ALL: 5 No Lymphodepletion therapy One single infusion of anti-cd19 CAR T-cells Brudno et al. JCO 2016; 34:

22 Allogeneic Anti-CD19 CAR T-cells in R/R B-cell lymphoproliferative disease progressed after allo-sct CR: 6 (30%) PR: 2 (10%) SD: 7 (35%) DoR (m): In ALL 4/5 cases CR with MRD neg. Brudno et al. JCO 2016; 34: NO new onset of GVHD in any case was seen

23 Allogeneic Anti-CD19 CAR T-cells in R/R B-cell lymphoproliferative disease progressed after allo-sct - CD8 CAR T-cells expressing PD1 increased form 12% at time of infusion to 82% at peak blood CAR T-cells Brudno et al. JCO 2016; 34:

24 Anti-CD19 CAR T-cells in R/R B-cell NHL 28 patients Histology: DLBCL: 18 FL: 6 MCL: 4 Lymphodepletion therapy with: Cyclophosphamide or Cyclophosphamide + Fludarabine (Fludarabine increase the CRR) At least one infusion of anti-cd19 CAR T-cells Evaluable CR PR DLBCL (n=8) 3 3 FL (n=3) 2 0 Total (n=11) 5 3 Turtle et al. Blood 2015; 126

25 Central memory derived CD19 specific T-cell after ASCT in High-risk B-NHL Phase I study Two types: NHL1: CD8pos. Tcm (derived CD19;zeta T-cells) NHL2: CD4/CD8 pos.tcm (derived CD19R;zeta/EGFR pos. T-cells) NHL1: mage: 62 (50-75) years m prior lines: 3 (2-4) Histology: -DLBCL: 7 - MCL: 1 NHL2: mage: 58 (23-71) years m prior lines: 2 (1-3) Histology: -DLBCL: 4 - MCL: 4 Popplewell et al. Blood 2015; 126

26 Central memory derived CD19 specific T-cell after ASCT in High-risk B-NHL NHL1 CR PFS Progression DLBCL (n=7) MCL (n=1) 5 (62.5%) & 2 y. (mfu: > 2y.) 4 (50%) NHL2 CR PFS Progression DLBCL (n=4) MCL (n=3) 8 (100%) 6 m. (mfu: > 1y.) 2 & 12.6 m. Popplewell et al. Blood 2015; 126

27 Autologous CAR T-cell (CTL019) in R/R B-NHL Phase II 38 received CTL patients evaluable for response mage: 56 (25-77) years m prior therapies: 4 (1-10) 32% prior SCT: 11 auto, 1 allo Histologies: DLBCL (16), FL (7) Neurological: 3 patients (1 fatal) CRS: 16 patients (gr. 3-4: 2) Preinfusion therapy (Lymphodepletion): - EPOCH: 3 - Cyclophosphamide: 11 - Bendamustine: 6 - Cyclophosphamide + Fludarabine: 1 - Cyclophosphamide + Radiotherapy: 3 Response: - ORR at 3 months: 15 (68%) - DLBCL: 54% - FL: 100% - MCL: 50% - PFS (mfu: 11.7 m.): 62% (43% DLBCL, 100% FL) - DoR: DLBCL: 83%, FL: 100% Schuster et al. Blood 2015; 126

28 High-dose chemotherapy ASCT CAR (19-28z CAR T-cells) in R/R aggressive B-cell NHL Phase I 6 patients mage: 61 (34-68) years Histologies: DLBCL (3), tfl (2-1 DH-), tmzl (1) Outcome: (@ mfu of 6 months) CRS in 2 patients -All in CR (2 with > 2 years) Schuster et al. Blood 2015; 126

29 CAR T-cells toxicity Two syndromes: - Cytokine release syndrome (CRS) - Macrophage activation syndrome (MAS) Reversible Neurotoxicity: Obtundation, seizures, aphasia, mental status changes Two questions: - Correlates with the antitumor activity? - The use of anti-il6 and corticosteroids can affect the antitumor response? It is possible that IL6 is produced by dying B-cells, dying tumor cells or activated macrophages

30 Challanges for CAR T-cells 1. Exhaustion due to excessive TCR signaling 2. 20% of ALL develops resistance due to loss of CD19 epitope 3. Immuneresponse induced by CAR s can lead to a rejection of CD19 CAR s 4. Side effects: a) CRS, associated with tumor burden b) Neuropathy (encephalopathy, seizures, focal motors deficits, aphasia) c) B-cell aplasia 5. Technical graft failure

31 Challanges for CAR T-cells 6. CD-19 z-4-1bb CARs (CD19,zeta-28) have more persistence 7. Development of other targets (CD22, CD30) when appropriate 8. Lymphodepletion by chemotherapeutic agents 9. Use of IL6 inhibitors and corticosteroids 10. Avoid as much as possible myeliod contamination 11. Engineering suicide genetic elements to turn off the activated cells when toxicity is observed

32 CAR T-cells challanges A. CARs are susceptible to PD1-PDL1 interactions. So, CARs in combination with PD1 blockade is testing together in clinical trials B. Need for universal CARs (UCAR): allogeneic donors based on knockdown of the HLA genes coupled with enforced expression of non-classical HLA molecules to avoid NK recognition and lysis

33 Immune checkpoints inhibitors

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35 Potential activity of anti-pd1 in lymphoma B-cell lymphomas: PMBCL THRBCL EBV-associated B-cell lymphoma Plasmablastic Primary effussion Primary testicular Primary CNS PTLD T-cell lymphomas: FTH lymphomas (including AIBL) Cutaneous T-cell S. Sezary Primary cutaneous CD4+ small-cell Double negative MF ALK+ anaplastic T/NK nasal type

36 Patient s characteristics Pidilizumab in relapsed Follicular Lymphomaa Phase II trial 32 patients Toxicity Westing et al. Lancet Oncol, 2014; 15: 69-77

37 Pidilizumab in relapsed Follicular Lymphomaa Response Westing et al. Lancet Oncol, 2014; 15: 69-77

38 Pidilizumab in relapsed Follicular Lymphomaa Outcome FLIPI1 FLIPI2 Westing et al. Lancet Oncol, 2014; 15: 69-77

39 Pidilizumab after ASCT in R/R DLBCL Phase II R/R DLBCL 66 patients mage: 57 (19-80) Histologies: - DLBCL: 49 - tfl: 13 - PMLBCL: 4 Toxicity Armand et al. JCO 2013; 31:

40 Pidilizumab after ASCT in R/R DLBCL Overall (n=66) 16 months PFS 72% 16 months OS 85% 16 months PFS after ASCT 24 PET + 70% 31 PET - 72% 11 no PET performed 72% 35 ptes with measurable disease after ASCT After PD1i achieved a CR 12 (34%) After PD1i achieved a PR 6 (17%) Armand et al. JCO 2013; 31:

41 Pidilizumab after ASCT in R/R DLBCL All patients (n=97) Patients who remain PET positive after salvage treatment (n=24) Armand et al. JCO 2013; 31:

42 Pidilizumab + Rituximab in R/R FL Phase II N = 30 Toxicity Westin et al. Lancet Oncol, 2014; 15: 69-77

43 Pidilizumab + Rituximab in R/R FL Responses (n=29) CR 15 (52%) PR 4 (14%) FLIPI1 FLIPI2 Westin et al. Lancet Oncol, 2014; 15: 69-77

44 Phase I studyies of Nivolumab in R/R lymphoid malignancies Dose: 1-3 mg/kg w1/w4 and every 3w Tumor N Complete Response n (%) Diffuse Large B Cell Lymphoma (DLBCL) Follicular Lymphoma (FL) Other B Cell Lymphoma Primary Mediastinal B Cell Lymphoma Mycosis Fungoides (MF) Peripheral T Cell Lymphoma (PTCL) Other T Cell Lymphoma Partial Response n (%) Stable Disease (SD) n (%) Lesokhin al. Blood, 2015; 126 (ASH) Progression Free Survival Rate at 24 Weeks (%) 11 1 (9) 3 (27) 3 (27) (24) 10 1 (10) 3 (30) 6 (60) (68) (63) (38) (100) (0) (15) 9 (69) (39) (40) 0 (30) (20) (0)

45 Pembrolizumab in R/R PMBCL Phase I 16 patients mage: 30 (22-62) years 44% 4 lines 75% Radiotherapy More frequent toxicity grade 1-2: - Diarrhea - Artralgia - Edema - Pyrexia No grade 3-5 AEs Outcome (n=10) Results CR 6% ORR 37.5% With a median FU of 5 months (0.8-22) 5 patients continue on response (0.03+ to 17+ months) Zinzani al. Haematologica, 2016; 101; s1 (#S797)

46 Mogamulizumab (anti-ccr4) in R/R ATLL Refractory ATLL (HTLV-1) Phase II 14 ptes (10 acute) Dose: 1 mg/kg Response (n=14) After 4 cycles After 8 cycles CR 6 (43%) 6 (43%) PR 3 (21%) 0 ORR 9 (64%) 6 (43%) Kawano et al. Intern Med, 2016; 55:

47 Mogamulizumab (anti-ccr4) in R/R ATLL Refractory ATLL (HTLV-1) Phase II 77 patients mage: 65.6 (44-83) years Dose: 1 mg/kg More frequent initial therapy: - VCAP-AMP-VECP: 41 - CHOP: 19 Outcome (n=77) Results CR 18 (23%) PR 15 (19%) ORR 33 (43%) mos 7.7 months (5-11) 3 y. OS 18% Tokunaga et al. Blood, 2015; 126

48 Ipilimumab (anti-ccr4) in R/R B-NHL 18 patients 3 1 Mg/Kg x 3 doses Response (n=14) % CR 5.6 ORR 11 Ansell et al. Clin Cancer Res, 2009; 15:

49 Anti-CD137 stimulatory antibody Houot et al. Oncoimmunology, 2012; 1: 957-8

50 Atezolizumab (anti-pd-l1) + Obinutumumab in R/R B-NHL Phase I 31 patients mage: 60 (26-90) years More frequent toxicity grade 1-2: - Neutropenia: 13% - Abdominal pain: 6% Death 4 (3 due to progression) Median Duration of Treatment: - DLBCL: 43 days (2-389) - FL: 117 (2-210) - ORR: 15% (@ 4 th cycle) - CR: 2 (FL) - PR: 1 (FL) Palomba al. Haematologica, 2016; 101; s1 (#S314)

51 Immune related response criteria (irrc) Immune-related response criteria Conventional criteria Bidimensional assessment 50 Unidimensional assessment 49 New measurable lesions Always represent progressive disease Incorporated into tumor burden New non-measurable lesions Always represent progressive disease Do not define progression (but preclude irrc) Non-index lesions Measurement of each lesion Measurable lesions Sum of the measurements Response assessment: Progressive disease (irpd) Stable disease (irsd) Changes contribute to defining best overall response of CR, PR, SD, and PD Longest diameter (cm) 10 mm in the longest diameter Sum of unidimensional measurements of all target lesions Increase in tumor volume 25% from nadir, and/or unequivocal progression of non-index lesions, and/or appearance of new lesions at any single time point Not meeting criteria for CR or PR, in absence of new lesions or unequivocal progression of non-index lesions Contribute to defining irrc (complete disappearance required) Longest diameter x longest perpendicular diameter (cm 2 ) 5 x 5 mm 2 (longest diameter x longest perpendicular diameter)/td> Sum of bidimensional measurements of all target lesions and any new lesions Increase in tumor volume 25% from nadir Not meeting criteria for CR or PR Longest diameter (cm) 10 mm in the longest diameter Sum of unidimensional measurements of all target lesions and any new lesions Increase in tumor volume 20% from nadir Not specified Partial response (irpr) Decrease in tumor volume 50% relative to baseline, in absence of new lesions or unequivocal progression of non-index lesions Decrease in tumor volume 50% relative to baseline Decrease in tumor volume 30% relative to baseline Complete response (ircr) New lesions Confirmation Complete disappearance of all lesions Presence of new lesions alone defines progression; new lesions not included in sum of measurements Confirmation at two consecutive timepoints at least 4 weeks apart is required in the absence of rapid clinical deterioration Complete disappearance of all index and new measurable lesions Complete disappearance of all index and new measurable lesions Presence of new lesions alone does not define progression; measurement of new lesions included in sum of measurements Confirmation at two consecutive time-points at least 4 weeks apart is required in the absence of rapid clinical deterioration Adapted from Clin Cancer Res. 2009;15(23): and Clin Cancer Res. 2013;19(14):

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