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Inmunoterapia aplicada al linfoma no Hodgkin

Andrés López Servicio de Hematología Hospital Universitario Vall d’Hebron 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 Antibodies, modified T-cells, and immune check points blockade Monoclonal antibodies 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% LY469298 I 13-20 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%) Monoclonal antibodies

Other antibodies Phase Lymphoma Response Epratuzumab I/II R/R FL ORR: 24% (anti-CD22) R/R DLBCL ORR: 15% Epratuzumab + II R/R B-NHL ORR: 67% Rituximab CR: (60% in FL, 50% in DLBCL)

1stLine FL ORR: 88% MEDI-551 I/II R/R B-NHL ORR: 24% (anti-CD19) Lucatumumab I/II R/R B-NHL ORR in FL: 33% (anti-CD40) ORR in DLBCL: 11% Dacetumumab II R/R DLBCL ORR: 47% (anti-CD40) + CR: 20% R-Gemcitabine Antibody-drug conjugates Conjugated monoclonal antibodies

Antibody Ph. Lymphoma N Response DoR (median) PFS (median) OS (median) (Target) Polatuzumab I/II R/R B-NHL 95 ORR: 19% - - - Vedotin CR: 7% (CD22) Inutuzumab I R/R B-NHL 79 ORR: 38% - FL: 317 days FL: NR Ozogamicin CR: 15% DLBCL: 49 days DLBCL: 193 d. (CD22) SAR3419 I/II R/R B-NHL 42 ORR: 30% 10 m (5-77) - - (CD19) CR: 15% +Maitensina Brentuximab II R/R ALTCL 58 ORR: 86% - 13.3 m. NR Vedotin CR: 57% (CD30) Monoclonal antibodies combinations

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

BiTE vs DART

Moore et al. Blood, 2011; 117: 4142-51 Blinatumumab (ant CD19 x CD3) in NHL: Final analysis

Disease Phase Dosing n Results Reference

R/R I Rapid infusion 22 No responses Nagorsen(1) NHL/CLL 13 µg/Kg 3 t/w

R/R NHL I CI: 0.5-90 µg/Kg 76 ORR: 69% Goebeler(2) for 4-8 w (DLBCL: 55%)

R/R DLBCL II CI: 112 µg/Kg for 25 ORR: 43% Viardot(3) 4-8 w CR: 19%

1. Nagorsen et al. Leuk lymphoma 2009. 2. Goebeler et al. JCO 2016. 3. Viardot et al. Blood 2016 Blinatumumab (ant CD19 x CD3) in NHL: Safety

AE Frequency (%) AE with a frequency < 20% Pyrexia 62 Pneumonia Headache 36 Tremor Peripheral edema 25 Device-related infections Febrile Neutropenia 25 Encephalopathy Nausea 25 Confusion Hypokalemia 23 Leukoencephalopathy: Rash 21 mainly in patients with Tremor 20 previous radiotherapy and Constipation 20 chemotherapy used to CNS Blinatumumab (BiTE: CD19xCD3) in R/R NHL

Phase I 76 patients mAge: 65 (20-80) years

Histology: DLBCL: 14 iNHL: 52 Other: 10

Medication with Prednisolone and/or Dexamethasone

n CR PR MTD: 60 mg/m2/day DLBCL 11 4 2 FL 15 6 6 MCL 7 3 2

Goebeler et al. JCO 2016; 34: 1104-11 CAR T-cells 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

TTR/P (Weeks) FL 2 Refractory No response 4 Relapsed 2 PR 7 - 18+

DLBCL 5 Relapsed No response SLL/CLL 15 Relapsed 3 CR 2+ - 15+ 5 PR CAR T-cell therapy in LPS Anti-CD19 CAR T-cells in R/R B-cell NHL

22 patients Lymphodepletion Histology: therapy with: - DLBCL: 19 Cyclophosphamide + - FL: 2 Fludarabine - MCL: 1 Response DLBCL (n=19) FL (n=2) MCL (n=1) CR 8 2 1 PR 5 ORR 13 2 1

DoR: 1-20 months (with 10 in ongoing CR)

Kochenderfer et al. Haematologica 2016; 101: s1 (#S792) Allogeneic Anti-CD19 CAR T-cells in R/R B-cell lymphoproliferative disease progressed after allo-SCT

20 patients One single Histology: No Lymphodepletion infusion of DLBCL: 5 therapy anti-CD19 MCL: 5 CAR T-cells CLL: 5 ALL: 5

Brudno et al. JCO 2016; 34: 1112-21 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): 1-30+

In ALL 4/5 cases CR with MRD neg.

NO new onset of GVHD in any case was seen

Brudno et al. JCO 2016; 34: 1112-21 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: 1112-21 Anti-CD19 CAR T-cells in R/R B-cell NHL

Lymphodepletion 28 patients therapy with: Cyclophosphamide or At least one Histology: Cyclophosphamide + infusion of DLBCL: 18 Fludarabine anti-CD19 FL: 6 (Fludarabine increase CAR T-cells MCL: 4 the CRR) Evaluable CR PR DLBCL (n=8) 3 3 FL (n=3) 2 0 Total (n=11) 5 3

Turtle et al. Blood 2015; 126 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: NHL2: mAge: 62 (50-75) years mAge: 58 (23-71) years m prior lines: 3 (2-4) m prior lines: 2 (1-3)

Histology: Histology: -DLBCL: 7 -DLBCL: 4 - MCL: 1 - MCL: 4

Popplewell et al. Blood 2015; 126 Central memory derived CD19 specific T-cell after ASCT in High-risk B-NHL

NHL1 CR PFS Progression DLBCL (n=7) 5 (62.5%) 50% @1 & 2 y. 4 (50%) MCL (mFU: > 2y.) (n=1)

NHL2 CR PFS Progression DLBCL 100% @ 6 m. 2 (25%) (n=4) 8 (100%) (mFU: > 1y.) @6.4 & 12.6 m. MCL (n=3)

Popplewell et al. Blood 2015; 126 Autologous CAR T-cell (CTL019) in R/R B-NHL

Phase II Preinfusion therapy (Lymphodepletion): 38 received CTL019 22 patients evaluable for response - EPOCH: 3 - Cyclophosphamide: 11 mAge: 56 (25-77) years - Bendamustine: 6 m prior therapies: 4 (1-10) - Cyclophosphamide + Fludarabine: 1 32% prior SCT: 11 auto, 1 allo - Cyclophosphamide + Radiotherapy: 3

Histologies: DLBCL (16), FL (7) Response:

- ORR at 3 months: 15 (68%) Neurological: 3 patients (1 fatal) - DLBCL: 54% - FL: 100% CRS: 16 patients (gr. 3-4: 2) - MCL: 50% - PFS (mFU: 11.7 m.): 62% (43% DLBCL, 100% FL) - DoR: DLBCL: 83%, FL: 100%

Schuster et al. Blood 2015; 126 High-dose chemotherapy à ASCTà 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)

-All in CR (2 with > 2 years) CRS in 2 patients

Schuster et al. Blood 2015; 126 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 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 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 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 Immune checkpoints inhibitors

Potential activity of anti-PD1 in lymphoma

B-cell lymphomas: T-cell lymphomas:

Ø PMBCL Ø FTH lymphomas (including AIBL) Ø THRBCL Ø Cutaneous T-cell Ø EBV-associated B-cell lymphoma Ø S. Sezary Ø Plasmablastic Ø Primary cutaneous CD4+ small-cell Ø Primary effussion Ø Double negative MF Ø Primary testicular Ø ALK+ anaplastic Ø Primary CNS Ø T/NK nasal type Ø PTLD Pidilizumab in relapsed Follicular Lymphomaa Patient’s characteristics Toxicity §Phase II trial §32 patients

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

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

FLIPI1

FLIPI2

Westing et al. Lancet Oncol, 2014; 15: 69-77 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: 4199-206 Pidilizumab after ASCT in R/R DLBCL

Overall (n=66) 16 months PFS after ASCT 16 months PFS 72% 24 PET + 70% 16 months OS 85% 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: 4199-206 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: 4199-206 Pidilizumab + Rituximab in R/R FL

Phase II N = 30

Toxicity

Westin et al. Lancet Oncol, 2014; 15: 69-77 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 Phase I studyies of Nivolumab in R/R lymphoid malignancies Dose: 1-3 mg/Kg w1/w4 and every 3w Tumor N Complete Partial Response Stable Disease Progression Free Response n (%) (SD) Survival Rate at 24 n (%) n (%) Weeks (%) Diffuse Large B 11 1 (9) 3 (27) 3 (27) (24) Cell Lymphoma (DLBCL) Follicular 10 1 (10) 3 (30) 6 (60) (68) Lymphoma (FL) Other B Cell 8 0 0 5 (63) (38) Lymphoma Primary 2 0 0 2 (100) (0) Mediastinal B Cell Lymphoma Mycosis Fungoides 13 0 2 (15) 9 (69) (39) (MF) Peripheral T Cell 5 0 2 (40) 0 (30) Lymphoma (PTCL) Other T Cell 5 0 0 1 (20) (0) Lymphoma

Lesokhin al. Blood, 2015; 126 (ASH) Pembrolizumab in R/R PMBCL

Phase I More frequent toxicity grade 1-2: 16 patients - Diarrhea mAge: 30 (22-62) years - Artralgia 44% ≥ 4 lines - Edema 75% Radiotherapy - 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) Mogamulizumab (anti-CCR4) in R/R ATLL

Response (n=14) After 4 cycles After 8 cycles Refractory ATLL (HTLV-1) Phase II CR 6 (43%) 6 (43%) 14 ptes (10 acute) PR 3 (21%) 0 Dose: 1 mg/Kg ORR 9 (64%) 6 (43%)

Kawano et al. Intern Med, 2016; 55: 1439-45 Mogamulizumab (anti-CCR4) in R/R ATLL

Refractory ATLL (HTLV-1) More frequent initial therapy: Phase II - VCAP-AMP-VECP: 41 77 patients - CHOP: 19 mAge: 65.6 (44-83) years Dose: 1 mg/Kg

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 Ipilimumab (anti-CCR4) in R/R B-NHL

18 patients 3à1 Mg/Kg x 3 doses

Response (n=14) % CR 5.6 ORR 11

Ansell et al. Clin Cancer Res, 2009; 15: 6446-53 Anti-CD137 stimulatory antibody

Houot et al. Oncoimmunology, 2012; 1: 957-8 Atezolizumab (anti-PD-L1) + Obinutumumab in R/R B-NHL

Phase I More frequent toxicity grade 1-2: 31 patients - Neutropenia: 13% mAge: 60 (26-90) years - Abdominal pain: 6% Death 4 (3 due to progression)

Median Duration of Treatment: - DLBCL: 43 days (2-389) - FL: 117 (2- 210)

- ORR: 15% (@ 4th cycle) - CR: 2 (FL) - PR: 1 (FL)

Palomba al. Haematologica, 2016; 101; s1 (#S314) Immune related response criteria (irRC) Immune-related response criteria Conventional criteria Bidimensional assessment50 Unidimensional assessment49 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) Changes contribute to defining best overall Non-index lesions Contribute to defining irRC (complete disappearance required) response of CR, PR, SD, and PD Longest diameter x longest perpendicular Measurement of each lesion Longest diameter (cm) Longest diameter (cm) diameter (cm2) ≥5 x 5 mm2 (longest diameter x longest “Measurable” lesions ≥10 mm in the longest diameter ≥10 mm in the longest diameter perpendicular diameter)/td> Sum of unidimensional measurements of all Sum of bidimensional measurements of all Sum of unidimensional measurements of all Sum of the measurements target lesions target lesions and any new lesions target lesions and any new lesions Response assessment: Increase in tumor volume ≥25% from nadir, and/or unequivocal progression of non-index “Progressive disease” (irPD) Increase in tumor volume ≥25% from nadir Increase in tumor volume ≥20% from nadir lesions, and/or appearance of new lesions at any single time point Not meeting criteria for CR or PR, in absence “Stable disease” (irSD) of new lesions or unequivocal progression of Not meeting criteria for CR or PR Not specified non-index lesions

Decrease in tumor volume ≥50% relative to Decrease in tumor volume ≥50% relative to Decrease in tumor volume ≥30% relative to “Partial response” (irPR) baseline, in absence of new lesions or baseline baseline unequivocal progression of non-index lesions

Complete disappearance of all index and new Complete disappearance of all index and new “Complete response” (irCR) Complete disappearance of all lesions measurable lesions measurable lesions Presence of new lesions alone defines Presence of new lesions alone does not define progression; measurement of new lesions New lesions progression; new lesions not included in sum included in sum of measurements of measurements

Confirmation at two consecutive timepoints at Confirmation at two consecutive time-points at least 4 weeks apart is required in the Confirmation least 4 weeks apart is required in the absence of absence of rapid clinical deterioration rapid clinical deterioration

Adapted from Clin Cancer Res. 2009;15(23):7412-7420 and Clin Cancer Res. 2013;19(14):3936-3943

Summary

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