Inmunoterapia aplicada al linfoma no Hodgkin · Inmunoterapia aplicada al linfoma no Hodgkin...

Inmunoterapia aplicada al linfoma no Hodgkin

Andrés LópezServicio de Hematología

Hospital Universitario Vall d’Hebron

1. Monoclonal antibodies2. Antibody-drug conjugates3. Bispecific monoclonal antibodies:

Bispecific T-cell engager (BiTE), and Dual Affinity Re-Targeting (DART)

4. CAR T-cells5. Immune checkpoints inhibitors

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

Monoclonal antibodies

Anti-CD20 antibodies Type Comments

Rituximab I First in human

Ofatumumab I Approved by FDA in cases of CLL in whichFludarabine is not appropriate

Veltuzumab I Exibits a greatter CDCIn 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 thanRituximabIt is active in patients carrying FcyRIIIa alleleIn FL with this allele the ORR was 22-50% in a phase I trial

Obinutuzumab II In november 2013 FDA approved fortreatment of CLL in combination withChlorambucil (ORR:78%, CD 21%)


Other antibodies Phase Lymphoma Response

Epratuzumab(anti-CD22)

I/II R/R FLR/R DLBCL

ORR: 24%ORR: 15%

Epratuzumab + Rituximab

II R/R B-NHL

1stLine FL

ORR: 67% CR: (60% in FL, 50% in DLBCL)

ORR: 88%

MEDI-551(anti-CD19)

I/II R/R B-NHL ORR: 24%

Lucatumumab(anti-CD40)

I/II R/R B-NHL ORR in FL: 33%ORR in DLBCL: 11%

Dacetumumab(anti-CD40) + R-Gemcitabine

II R/R DLBCL ORR: 47%CR: 20%


Antibody-drug conjugates

Antibody(Target)

Ph. Lymphoma N Response DoR (median) PFS (median) OS (median)

PolatuzumabVedotin(CD22)

I/II R/R B-NHL 95 ORR: 19%CR: 7%

- - -

InutuzumabOzogamicin(CD22)

I R/R B-NHL 79 ORR: 38%CR: 15%

- FL: 317 daysDLBCL: 49 days

FL: NRDLBCL: 193 d.

SAR3419(CD19) +Maitensina


10 m (5-77) - -

BrentuximabVedotin(CD30)

II R/R ALTCL 58 ORR: 86%CR: 57%

- 13.3 m. NR

Conjugated monoclonal antibodies

Antibodies(Target)

Phase Lymphoma N Response PFS (median) OS (median)

InutuzumabOzogamicin(CD22) +Rituximab(CD20)

I/II R/R B-NHL 119 FL(ORR:87%, CR: 62%)DLBCL (ORR:74%, CR: 50%)Refr./Agrs.(ORR:20%, CR: 3%)

FL: NR

DLBCL: 17.1 m.

Refr./Agrs.: 1.9 m.

FL: NR

DLBCL: NR

Refr./Agrs.: 8.8 m.

Milatumumab(CD74) +Vetuzumab(CD20 type 2)


2 m. 16 m.

Monoclonal antibodies combinations

Bispecific monoclonal antibodies

BiTE vs DART

Moore et al. Blood, 2011; 117: 4142-51

Blinatumumab (ant CD19 x CD3) in NHL: Final analysis

1. Nagorsen et al. Leuk lymphoma 2009. 2. Goebeler et al. JCO 2016. 3. Viardot et al. Blood 2016

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: 0.5-90 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)

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

Phase I76 patientsmAge: 65 (20-80) years

Histology:DLBCL: 14iNHL: 52Other: 10

Blinatumumab (BiTE: CD19xCD3) in R/R NHL

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

Medication with Prednisolone and/or Dexamethasone

MTD: 60 mg/m2/day n CR PR

DLBCL 11 4 2

FL 15 6 6

MCL 7 3 2

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 Refractory4 Relapsed

No response2 PR 7 - 18+

DLBCL 5 Relapsed No response

SLL/CLL 15 Relapsed 3 CR5 PR

2+ - 15+

CAR T-cell therapy in LPS

Anti-CD19 CAR T-cells in R/R B-cell NHL

Kochenderfer et al. Haematologica 2016; 101: s1 (#S792)

22 patients

Histology:- DLBCL: 19- FL: 2- MCL: 1

Lymphodepletiontherapy with:Cyclophosphamide + Fludarabine

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)

20 patients

Histology:DLBCL: 5MCL: 5CLL: 5ALL: 5

No Lymphodepletiontherapy

One single infusion of anti-CD19 CAR T-cells

Allogeneic Anti-CD19 CAR T-cells in R/R B-cell lymphoproliferative disease progressed after allo-SCT

Brudno et al. JCO 2016; 34: 1112-21


CR: 6 (30%)PR: 2 (10%)SD: 7 (35%)

DoR (m): 1-30+

NO new onset of

GVHD in any case was

seen

Brudno et al. JCO 2016; 34: 1112-21

In ALL 4/5 cases CR with MRD neg.


Brudno et al. JCO 2016; 34: 1112-21

- CD8 CAR T-cells expressing PD1 increased form 12% at time of infusion to 82% at peak blood CAR T-cells

Anti-CD19 CAR T-cells in R/R B-cell NHL

Turtle et al. Blood 2015; 126

28 patients

Histology:DLBCL: 18FL: 6MCL: 4

Lymphodepletiontherapy 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

Central memory derived CD19 specific T-cell after ASCT in High-risk B-NHL

Popplewell et al. Blood 2015; 126

Phase I studyTwo 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) yearsm prior lines: 3 (2-4)

Histology:-DLBCL: 7- MCL: 1

NHL2:mAge: 58 (23-71) yearsm prior lines: 2 (1-3)

Histology:-DLBCL: 4- MCL: 4

Central memory derived CD19 specific T-cell after ASCT in High-risk B-NHL

Popplewell et al. Blood 2015; 126

NHL1 CR PFS Progression

DLBCL (n=7)MCL (n=1)

5 (62.5%) 50% @1 & 2 y.(mFU: > 2y.)

4 (50%)

NHL2 CR PFS Progression

DLBCL (n=4)MCL (n=3)

8 (100%)100% @ 6 m. (mFU: > 1y.)

2 (25%)@6.4 & 12.6 m.

Autologous CAR T-cell (CTL019) in R/R B-NHL

Schuster et al. Blood 2015; 126

Phase II38 received CTL01922 patients evaluable for response

mAge: 56 (25-77) yearsm 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)

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%

Preinfusion therapy (Lymphodepletion):

- EPOCH: 3- Cyclophosphamide: 11- Bendamustine: 6- Cyclophosphamide + Fludarabine: 1- Cyclophosphamide + Radiotherapy: 3

High-dose chemotherapy à ASCTà CAR (19-28z CAR T-cells) in R/R aggressive B-cell NHL

Schuster et al. Blood 2015; 126


Histologies: DLBCL (3), tFL (2 -1 DH-), tMZL (1)

CRS in 2 patients

Outcome:(@ mFU of 6 months)

-All in CR (2 with > 2 years)

Two syndromes:

- Cytokine release syndrome (CRS)- Macrophage activation syndrome (MAS)

It is possible that IL6 is produced by dying B-cells, dying tumor cells or activated macrophages

Two questions:

- Correlates with the antitumor activity?- The use of anti-IL6 and corticosteroids can affect the

antitumor response?

Reversible Neurotoxicity: Obtundation, seizures, aphasia, mental status changes

CAR T-cells toxicity

Challanges for CAR T-cells1. 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 burdenb) Neuropathy (encephalopathy, seizures, focal motors

deficits, aphasia) c) B-cell aplasia

5. Technical graft failure

Challanges for CAR T-cells6. 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

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

CAR T-cells challanges

Immune checkpoints inhibitors

Potential activity of anti-PD1 in lymphoma

B-cell lymphomas:

Ø PMBCLØ THRBCLØ EBV-associated B-cell lymphomaØ PlasmablasticØ Primary effussionØ Primary testicularØ Primary CNSØ PTLD

T-cell lymphomas:

Ø FTH lymphomas (including AIBL)Ø Cutaneous T-cellØ S. SezaryØ Primary cutaneous CD4+ small-cellØ Double negative MFØ ALK+ anaplasticØ T/NK nasal type

Pidilizumab in relapsed Follicular Lymphomaa

Westing et al. Lancet Oncol, 2014; 15: 69-77

Patient’s characteristics Toxicity

§Phase II trial§32 patients


Response



FLIPI1

FLIPI2

Outcome


Pidilizumab after ASCT in R/R DLBCL

Armand et al. JCO 2013; 31: 4199-206

Phase IIR/R DLBCL66 patientsmAge: 57 (19-80)

Histologies:- DLBCL: 49- tFL: 13- PMLBCL: 4

Toxicity


Armand et al. JCO 2013; 31: 4199-206

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%)

All patients (n=97) Patients who remain PET positive after salvage treatment (n=24)

Armand et al. JCO 2013; 31: 4199-206


Westin et al. Lancet Oncol, 2014; 15: 69-77

Phase IIN = 30

Toxicity

Pidilizumab + Rituximab in R/R FL

Westin et al. Lancet Oncol, 2014; 15: 69-77

Responses (n=29)

CR 15 (52%)

PR 4 (14%)FLIPI1

FLIPI2

Pidilizumab + Rituximab in R/R FL

Lesokhin al. Blood, 2015; 126 (ASH)

Phase I studyies of Nivolumab in R/R lymphoid malignancies

Tumor N Complete Response

n (%)

Partial Responsen (%)

Stable Disease(SD)n (%)

Progression Free Survival Rate at 24

Weeks (%)Diffuse Large B Cell Lymphoma (DLBCL)

11 1 (9) 3 (27) 3 (27) (24)

Follicular Lymphoma (FL)

10 1 (10) 3 (30) 6 (60) (68)

Other B Cell Lymphoma

8 0 0 5 (63) (38)

Primary Mediastinal B Cell Lymphoma

2 0 0 2 (100) (0)

Mycosis Fungoides (MF)

13 0 2 (15) 9 (69) (39)

Peripheral T Cell Lymphoma (PTCL)

5 0 2 (40) 0 (30)

Other T Cell Lymphoma

5 0 0 1 (20) (0)

Dose: 1-3 mg/Kg w1/w4 and every 3w

Zinzani al. Haematologica, 2016; 101; s1 (#S797)

Phase I16 patientsmAge: 30 (22-62) years44% ≥ 4 lines75% Radiotherapy

Outcome (n=10) Results

CR 6%

ORR 37.5%

More frequent toxicity grade 1-2:- Diarrhea- Artralgia- Edema- PyrexiaNo grade 3-5 AEs

With a median FU of 5 months (0.8-22) 5 patients continue on response (0.03+ to 17+ months)

Pembrolizumab in R/R PMBCL

Kawano et al. Intern Med, 2016; 55: 1439-45

Refractory ATLL (HTLV-1)Phase II14 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%)

Mogamulizumab (anti-CCR4) in R/R ATLL

Tokunaga et al. Blood, 2015; 126

Refractory ATLL (HTLV-1)Phase II77 patientsmAge: 65.6 (44-83) yearsDose: 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%

More frequent initial therapy:- VCAP-AMP-VECP: 41- CHOP: 19

Mogamulizumab (anti-CCR4) in R/R ATLL

Ansell et al. Clin Cancer Res, 2009; 15: 6446-53

18 patients3à1 Mg/Kg x 3 doses

Response (n=14) %

CR 5.6

ORR 11

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

Houot et al. Oncoimmunology, 2012; 1: 957-8

Anti-CD137 stimulatory antibody

Palomba al. Haematologica, 2016; 101; s1 (#S314)


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

Atezolizumab (anti-PD-L1) + Obinutumumab in R/R B-NHL

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)

Non-index lesionsChanges contribute to defining best overall

response of CR, PR, SD, and PDContribute to defining irRC (complete disappearance required)

Measurement of each lesion Longest diameter (cm)Longest diameter x longest perpendicular

diameter (cm2)Longest diameter (cm)

“Measurable” lesions ≥10 mm in the longest diameter≥5 x 5 mm2 (longest diameter x longest

perpendicular diameter)/td>≥10 mm in the longest diameter

Sum of the measurementsSum of unidimensional measurements of all

target lesionsSum of bidimensional measurements of all

target lesions and any new lesionsSum of unidimensional measurements of all

target lesions and any new lesions

Response assessment:

“Progressive disease” (irPD)

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

Increase in tumor volume ≥25% from nadir Increase in tumor volume ≥20% from nadir

“Stable disease” (irSD)Not meeting criteria for CR or PR, in absence of new lesions or unequivocal progression of

non-index lesionsNot meeting criteria for CR or PR 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) Complete disappearance of all lesionsComplete disappearance of all index and new

measurable lesionsComplete disappearance of all index and new

measurable lesions

New lesionsPresence of new lesions alone defines

progression; new lesions not included in sum of measurements

Presence of new lesions alone does not define progression; measurement of new lesions included in sum of measurements

ConfirmationConfirmation at two consecutive timepoints at least 4 weeks apart is required in the absence of

rapid clinical deterioration

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):7412-7420 and Clin Cancer Res. 2013;19(14):3936-3943

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