Immuntherapie bei malignen Lymphomen - omniamed.de · Immuntherapie bei malignen Lymphomen Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne German

Immuntherapie bei malignen

Lymphomen

Andreas Engert, MD

Chairman, German Hodgkin Study GroupUniversity Hospital of Cologne

German Hodgkin Study GroupDeutsche Hodgkin Studiengruppe

Andreas EngertTransparenzerklärung

• Honoraria: Takeda, BMS, Amgen

• Consulting/Advisory role: Takeda, BMS

• Research funding (institution): Takeda, BMS,

Affimed

Immuntherapiebei hämatologischen Tumoren

• Einleitung

• Brentuximab Vedotin

• PD1 Inhibition

• Ausblick

• Zusammenfassung

100BEACOPP (1993-99)

0

20

0 1 2 3 4 5 Jahre

Alkylantien(1965)

No therapy (1940)

40

60

80COPP+ABVD (1988-93)

COPP (1975)

Hodgkin LymphomProgress in advanced stages

• 2nd NPL AMLNHLSolid tumours

• Organ damage LungHeartThyroid

• Others FertilityOPSIFatiguePsycho-social

Hodgkin LymphomaLate side effects after treatment

NPL, neoplasias; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma; OPSI, overwhelming post-splenectomy infection

• Einleitung


• PD1 Inhibition

• Ausblick

• Zusammenfassung


Differentialdiagnose des cHLund verwandter Lymphome

NLPHL cHL* ALCL TCRBCL

CD30 - + + -

CD15 - + - -

CD20 + (+) - +

CD3 - - (+) -

EMA + - + -

*inklusive LRcHL

ALCL, anaplastisch-großzelliges Lymphom; cHL, klassisches Hodgkin-Lymphom; EMA, epitheliales Membranantigen; LRcHL, lymphozytenreichesklassisches Hodgkin-Lymphom; NLPHL, lymphozytenprädominantes Hodgkin-Lymphom; TCRBCL, T-Zell-reiches B-Zell-Lymphom

Mit freundlicher Genehmingung von H. Stein

Immunhistologie des klassischen HLCD30-Färbung

Brentuximab Vedotin (SGN-35)Wirkmechanismus

Brentuximab Vedotin (SGN-35) ADC

ADC bindet an CD30

MMAE zerstört die Vernetzung der Microtubuli

ADC-CD30-Komplex wandert in die Lysosomen

MMAE wird freigesetzt

Apoptose

G2/M-Zellzyklusarrest

Monoklonaler Anti-CD30-Antikörper

Durch Proteasen spaltbare Verbindung

Monomethyl-Auristatin E (MMAE), potenter antitubulärer Wirkstoff

Brentuximab VedotinPhase-II Pivotalstudie (PFS)

Chen et al, ASH 2015

n

Median(Mon.)Ereign.

n

Median(Mon.)Ereign.

Zeit (Monate) Zeit (Monate)

Patienten in der Studie in Remission

ITT Patienten

Ante

il P

atiente

n o

hne P

rogre

ssio

n o

der

Tod (

%)

Ante

il P

atiente

n o

hne P

rogre

ssio

n o

der

Tod (

%)

23 year old female

Diagnosis of HL in 01/09

Prior systemic chemo:

ABVD BEACOPP, ICE,

DHAP, BEAM+ auto-TX

09/09

Prior RT 12/09 to 02/10

6 cycles SGN35 5-8/10

Died after allo TX 3/11

Brentuximab VedotinCologne Case Study

Rothe et al, unpublished 2010

AETHERA PFS per Investigator

Pe

rce

nt

of

Su

bje

cts

Fre

e o

f P

D o

r D

ea

th

0

10

20

30

40

50

60

70

80

90

100

Time (Months)

0 4 8 12 16 20 24 28 32 36 40 44 48 52

N Events (Months)Median

StratifiedHazardRatio

Placebo+BSC 164 89 15.8BV+BSC 165 60 -- 0.50

164 (0) 113 (48) 92 (67) 83 (76) 77 (81) 71 (85) 61 (88) 45 (89) 28 (89) 23 (89) 13 (89) 3 (89) 3 (89) 0 (89)165 (0) 149 (12) 133 (27) 122 (36) 111 (45) 103 (52) 90 (55) 62 (58) 40 (59) 33 (60) 16 (60) 4 (60) 3 (60) 0 (60)

N at Risk (Events)Pla+BSCBV+BSC

HR = 0.50 [95% CI (0.36, 0.70)]

Median BV = NE (–, –); Placebo = 15.8m (8.5, –)

24-month PFS rate BV = 65%; Placebo = 45%

Moskowitz et al, Lancet 2015;385:1853-62

PFS, progression free survival; HR, hazard ratio; BV, brentuximab vedotin; NE,

non evaluable; BSC, best supportive care; Pla, placebo

Hodgkin LymphomECHELON-1: modifiziertes PFS

Connors et al, ASH 2017: A6

14

Side effects A+AVD ABVD

Neutropenia (%) 58 45

Infection grade ≥3 (%) 18 10

Peripheral neuropathy (all; %) 67 43

Peripheral neuropathy (PN; grade ≥3; %) 11 2

Lungtox grade ≥3 <1 3

Neutropenia related deaths(no G-CSF prophylaxis)

7 9

Lungtox related deaths 11 13

Connors et al, NEJM 2017

ECHELON-1: Phase III Trial BV + AVD vs. ABVD in Frontline Advanced cHL

HD18: 4xB.esc vs 6/8xB.escOverall Survival

504 476 438 363 298 207

501 479 459 370 292 227

Pts. at risk

╵╵ ╵╵╵╵ ╵ ╵╵╵ ╵╵╵╵╵╵ ╵╵ ╵ ╵ ╵╵ ╵ ╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵ ╵╵ ╵ ╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵ ╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵ ╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵ ╵ ╵╵ ╵ ╵╵╵ ╵ ╵

╵ ╵╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵ ╵ ╵╵╵ ╵╵ ╵ ╵╵╵╵╵╵╵╵╵ ╵ ╵ ╵╵╵╵╵ ╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵ ╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵╵ ╵╵╵ ╵╵ ╵ ╵╵╵ ╵╵╵╵ ╵ ╵╵╵ ╵╵

0 12 24 36 48 60

Time [months]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ov

era

ll S

urv

iva

l ra

te

PET-, 4x eBEACOPPPET-, 8/6x eBEACOPP

3-year estimate 5-year estimate

8/6x eBEACOPP: 95.9% [94.1-97-7] 95.4% [93.4-97.3]

4x eBEACOPP: 98.7% [97.6-99.7] 97.6% [96.0-99.2]

Difference: +2.7 [+0.6-+4.8] +2.2% [-0.3-+4.7]

Hazard Ratio 0.36 [0.17 to 0.76],

log-rank test p=0.006

Median observation time 56 months

Borchmann P et al, Lancet 2017

HD21: GHSG Perspective BV in advanced stage HL

2 x BEACOPP esc

End of therapy and residual nodes > 2.5 cm: PET positive: Rx PET negative: Follow up

Centrally reviewed PET

4xBEACOPP esc

4xBrECADD

2 x BrECADD

HL, Hodgkin Lymphoma; GHSG, German Hodgkin Study Group; BV, brentuximab vedotin; BEACOPPesc, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; BrECADD, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone; PET, positron emission tomography; RX, radiotherapy

• Einleitung


• PD1 Inhibition

• Ausblick

• Zusammenfassung


auto-HSCT = autologous hematopoietic stem cell transplant

Post-progression survival (years)

0.0

5 10 15 20

0.2

0.4

0.6

0.8

1.0

0

Months to relapse following auto-HSCT

Pro

bab

ility

of

surv

ival

>12 mo (n=214)

>6–12 mo (n=203)

>3–6 mo (n=169)

0–3 mo (n=170)

Survival in Hodgkin LymphomaRelapse After Autologous HSCT

Arai S et al, Leukemia & Lymphoma 2013;54:2531–2533. Reprinted by permission of Taylor & Francis Ltd (http://www.tandfonline.com)

http://www.tandfonline.com/

PD1 Inhibition in Classical HLMechanism of action

• Patients with cHL show high frequency of 9p24.1 alterations and

overexpression of PD-L1 and PD-L21

• Nivolumab is a fully human immunoglobulin G4 monoclonal antibody

targeting the programmed death-1 (PD-1) receptor immune checkpoint

pathway

cHL = classical Hodgkin lymphoma; MHC = major histocompatibility complex; NFκB = nuclear factor kappa B; PD-L1/2 = programmed death ligand 1/2; PI3K = phosphoinositide-3–kinase; Shp-2 = Src homology region 2-containing protein tyrosine phosphatase

Nivolumab blocks signaling through the PD-1 receptor

1. Roemer MGM et al, J Clin Oncol 2016;34:2690–7

Lymphoma n ORR (%) F´-up (w) Response (w)

Multiple Myeloma 27 4 46 12+

DLBCL 11 36 23 6-77+

Follicular NHL 10 40 91 27-82+

CTCL/MF 13 15 43 24-50+

PTCL 5 40 31 11-79+

HL 23 87 86 2-91+

Nivolumab in Lymphoma Patients Duration of Response Phase 1b*

*74 weeks median follow-up

Published 20161

Cohort Bn = 80

Cohort An = 63

Cohort Cn = 100

BV naïveBV

after auto-HSCT

Relapsed/refractory cHL after auto-HSCT Nivolumab monotherapy

Primary endpoint• ORR by IRC

Additional endpoints

• CR/PR rate

• Duration of CR/PR

• PFS by IRC

• OS

• Safety

Nivolumab 3 mg/kg IV Q2W

Treatment until disease progression or unacceptable toxicity

Extended follow-up (December 2016 lock)

Median: 23 mo

Median: 16 mo

Median: 19 mo

BV before and/or after auto-HSCT

1Younes A et al, Lancet Oncol 2016

Pts in CR for 1 year to

discontinue

Patients could elect to discontinue nivo and proceed

to (allo)-HSCT

Phase 2 CheckMate 205 Study Design

BV naïvea

(Cohort A)n = 63

BV after auto-HSCT

(Cohort B) n = 80

BV before and/orafter auto-HSCT

(Cohort C) n = 100

Overall

n = 243

Age, years 33 (18–65) 37 (18–72) 32 (19–69) 34 (18–72)

Male, % 54 64 56 58

ECOG PS, %01

6238

5348

5050

5446

Disease stage at study entry, %IV 38 68 61 57

Previous lines of therapyPrior radiotherapy, %

2 (2–8)59

4 (3–15)74

4 (2–9)69

4 (2–15)68

Diagnosis to first dose of nivolumab, years

3.1 (1.0–30.6) 6.2 (1.3–25.1) 3.5 (1.0–24.9) 4.5 (1.0–30.6)

Auto-HSCT to first dose of nivolumab, years

1.0 (0.3–18.2) 3.4 (0.2–19.0) 1.7 (0.2–17.0) 2.0 (0.2–19.0)

Phase 2 CheckMate 205 Demographics

Engert et al, EHA 2017

>95% of evaluable patients showed a reduction in tumor burden

100

75

50

25

0

–25

–50

–75

–100

Be

st

red

uc

tio

n f

rom

ba

se

lin

e in

ta

rge

t le

sio

n (

%)

Patients

BV naïve (Cohort A)

BV after auto-HSCT (Cohort B)

BV before and/or after auto-HSCT (Cohort C)

Asterisks (*) denote responders

Phase 2 CheckMate 205 Best Change in Target Lesion per IRC


Primary refractory

n = 142

Refractory to last line

n = 114

Refractory to BV after HSCT

n = 70

Response, % 73 68 69

Best Response %

CR

PR

18

55

13

54

6

63

Median DOR in PR,

months (95% CI)13 (9, 18) 17 (9, NE) 17 (8, NE)

Phase 2 CheckMate 205 Response According to Refractory Status


CR: 22 (19, NE) months

SD: 11 (6, 18) months

Number of patients at riskCRPRSD

16218

4012847

4012644

338925

327119

274611

20258

0.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

180 3 6 9 12 15

Pro

bab

ility

of

PFS

PFS (months)

0.2

0.1

PR: 15 (11, 19) months

Median (95% CI) PFS for overall patients (N = 243) was 15 (11, 19) months

Nivo for R/R cHL (CheckMate 205) PFS by Best Overall Response


Cohort C: NR (19, NE)

Cohort B: NR (NE, NE)

Cohort A : NR (NE, NE)

0.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18

Pro

bab

ility

of

surv

ival

OS (months)

0.2

0.1

BV naïve (Cohort A)

BV after auto-HSCT (Cohort B)

BV before and/or after auto-HSCT (Cohort C)

Number of patients at riskCohort ACohort BCohort C

366317

6380

100

617897

617593

597490

557183

546865

All values are medians (95% CI). NR = not reached

Phase 2 CheckMate 205 Overall Survival


Patients with drug-related AEs (≥10%), serious AEs (≥1%), or AEs leading to discontinuation (≥1%)

Overall population n = 243

Drug-related AEs, % Any grade Grade 3–4

Fatigue 23 1

Diarrhea 15 1

Infusion-related reaction 14 <1

Rash 12 1

Drug-related serious AEs, %

Infusion-related reaction 2 <1

Pneumonitis 1 0

Drug-related AEs leading to discontinuation, %

Pneumonitis 2 0

Autoimmune hepatitis 1 1

Phase 2 CheckMate 205 Safety Outcomes after Extended Follow-up


Table of

Contents

PD-1 Checkpoint

Inhibi tors: MOA

Pseudo-

Progression as

Response to

Immuno-Oncology

Therapies

Nivolumab:

Ongoing BMS-

Sponsored Clinical

Tr ials

CTLA-4

Checkpoint

Inhibi tors: MOA

Nivolumab: ISRs

Summary

CheckMate-205 Cohort B Patient-Reported QoL (EQ-5D VAS)

*Change from baseline exceeding MID (defined as change of at least 7 points from baseline)EQ-5D VAS, European Quality of life five dimensions questionaire visual analogue scale; MID, minimally important difference; QoL, quality of life. Engert A et al, ISHL 2016. A105

Januar 2015October 2014 August 2016

Patient D.P.; 48 yearsDiagnosed 2011 (6 prior therapies)

May 2015October 2014 February 2015

Patient M.M.; 39 yearsDiagnosed 2011 (5 prior therapies)

January 2015October 2014 April 2015

Patient S.G.; 27 years, maleDiagnosed 2011 (2 prior therapies, PD)

200

OS

fro

m s

ub

seq

uen

t al

lo-H

SCT

PFS from subsequent allo-HSCT (days)

Pts at risk:

0.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.2

0.1

44 32 21

0 50 100 150

Overall survival

OS: Cohort A+B+C NR (NE, NE)

100-day rate 87% (72, 95) 6-month rate

87% (72, 95)

Progression-free survival

PFS

fro

m s

ub

seq

ue

nt

allo

-HSC

T

PFS from subsequent allo-HSCT (days)

Pts at risk:

0.0

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.2

0.1

44 32 19

0 50 100 150 200

PFS: Cohort A+B+C: NR (NE, NE)

100-day rate 87% (72, 95)

6-month rate

82% (65, 91)

PD1 InhibitionOutcomes After Allo-HSCT (n=44)

Morschhauser ISHL10: 2016

Antibody Target Company

Nivolumab PD1 BMS

Pembrolizumab PD1 MSD

REGN2810 PD1 Regeneron

Durvalumab PD-L1 Celgene, AstraZeneca

Avelumab PD-L1 Pfizer

Ipilimumab CTLA-4 BMS

Immunomodifiers in LymphomaSelection

KEYNOTE-087: Study Design

Cohort 1 (N = 69)†

R/R cHL who progressed after ASCT and subsequent

BV therapy

Response assessed according to Revised Response Criteria for

Malignant Lymphomas (Cheson 2007)

Pembrolizumab 200 mg Q3W

Cohort 2 (N = 81)†

R/R cHL who failed salvage chemotherapy, ineligible

for ASCT‡

and failed BV therapy

Cohort 3 (N = 60)†

R/R cHL who failed ASCT and not treated with BV

post transplant

Survival Follow-Up

• Primary end point: Overall response rate (ORR, blinded independent central review)• Secondary end points: ORR (investigator review), DOR, PFS, OS

CT scans repeated Q12W

PET repeated at W12, W24, to confirm CR or PD, and as clinically indicated

†Patients in all cohorts had to have ECOG PS 0-1‡Unable to achieve a CR or PR to salvage chemotherapy

KEYNOTE-087: Study DesignPembro in r/r cHL

35

• Up to 16 total cycles of combination therapy

• Standard dosing of both drugs

• Staggered dosing for cycle 1 only

• Pts could go on to HDCT & ABMT

Nivo 3mg/kg

BV 1.8 mg/kg

Cycle 1

Weeks 0 3 6 9

C2 C3

12

C4

CT CT/PET*

C16

EOT

1 2

Phase 1/2 StudyBV and Nivolumab in Pts with R/R cHL

ASH 2017, Herrera et al, A649

Nivo-AVD in advanced-stage cHLEnd of Combotherapy

46/51 patients had available response data. Response assessed by IWG 2007 criteria

–50

–100

–75

–25

0

50

75

25

Re

du

ctio

n f

rom

bas

elin

e in

tar

get

lesi

on

(%

)

Patients

PET-negative

FDG-PET scan at end of therapy or last prior radiographic assessment

Ramchandren et al, ASH 2017: A651

HD20 Pilot Randomized trial in early unfavorable HL

Arm A:Restaging 2

Arm B:

AVD D1

AVD D15

AVD Cycle 1

PD1D1

PD1D15

AVD Cycle 2

AVD D1

AVD D15

PD1D1

PD1D15

AVD Cycle 3

AVD D1

AVD D15

PD1D1

PD1D15

AVD Cycle 4

AVD D1

AVD D15

PD1D1

PD1D15

Restaging 1

PD: biopsy + off-study

Restaging 2

PD1D1

PD1D15

PD1D1

PD1D15

AVDD1

AVD D15

PD1D1

AVD D1

AVD D15

PD1D1

Restaging 1


AVD Cycle 3

AVD D1

AVD D15

AVD Cycle 4

AVD D1

AVD D15

PD1D15

AVD Cycle 1 AVD Cycle 2

PD1D15

30Gy IS-RT

30Gy IS-RT



R

Scre

en

ing

AVD: Adriamycin, Vinblastin, Dacarbazine; PD1: Nivolumab

Ovarian Cancer3 Urothelial Cancer4 Hodgkin Lymphoma1

Esophageal Cancer7

Hepatocellular Carcinoma2

Small Cell Lung Cancer5

(Nivolumab 1 mg/kg BW + Ipilimumab 3 mg/kg BW)

Colorectal Cancer – MSI-H6 (Nivolumab 3 mg/kg BW)

Anal Cancer8

1.Younes ASCO 2016, A7535. 2. Sangro ASCO 2016, A4078. 3. Hamanishi JCO 2015. 4.Sharma ASCO 2016, A4501. 5.Antonia ASCO 2016, A100. 6.Overman ASCO-GI 2017. 7.Van Morris ASCO 2016 A503

PD1 Inhibition, klinische Studien Hohe Effektivität beim Hodgkin Lymphom

1.Younes ASCO 2016, A7535. 2. Sangro ASCO 2016, A4078. 3. Hamanishi JCO 2015. 4.Sharma ASCO 2016, A4501. 5.Antonia ASCO 2016, A100. 6.Overman ASCO-GI 2017. 7.Van Morris ASCO 2016 A503 8. Van Morris Lancet Oncology 18 – 4: 2017

• Einleitung


• PD1 Inhibition

• Ausblick

• Zusammenfassung


Challenges of adoptive immunotherapyin clinical practice

1. Kalos M, et al. Sci Transl Med. 2011;3(95):95ra73; 2. Porter DL, et al. J Cancer. 2011;2:331-332; 3. Porter DL, et al. New Engl J Med. 2011;365(8):725-733.

a Cellular reprogramming and ex vivo expansion are conducted at a cell processing facility.

CAR: Chimeric antigen receptor; CD: Cluster of differentiation

1. Leukapheresis:

Patient’s T-cells harvested1-3

2. T-cells activated on

antibody-coated beads, and

genetically transduced ex

vivo with a construct

encoding for the anti-CD19

CAR1-3

3. CTL019 cells undergo ex

vivo expansion on

antibody-coated beads1-3

4. Chemotherapy:

Patient receives preparative

lymphodepleting chemo

before T-cell infusion1-3

5. CTL019 cells reinfused 1-3

N AgePrior

auto %

Time to

infusion d

CR

%DOR

Neuro

tox ≥ 3

%

JULIET

Novartis141 56 51 ~ 100 (?) 43 79% at 6m 13

TRANSCEND

Juno/

Celgene

91 61 44 ~ 28 (?) 52 80% at 6m 16

ZUMA

Kyte111 58

21

(< 12 m)17 54 44% at 9m 28

Estimates for competing constructs Phase I/II trials in DLBCL

Borchmann Med1 2018

JULIET: Study Centers

• Global clinical trial with centralized manufacturing of tisagenlecleucel

• 27 sites in 10 countries across North America, Europe, Australia, and Asia

44

*

Manufacturing sites

*

*

Juliet: Study Centers

• Einleitung


• PD1 Inhibition

• Ausblick

• Zusammenfassung


Immuntherapie hämatolgischerTumoren - Zusammenfassung

• HL ist eine der am besten heilbaren malignen Erkrankungen; Zweitneoplasien, Organschäden und Fatigue relevant

• In frühen Stadien 2xABVD+20Gy ISRT; in mittleren Stadien 2+2+ISRT; nur 4xB.esc bei PET2- in fortgeschrittenen Stadien (3y OS 98,7%)

• Brentuximab Vedotin zugelassen beim r/r cHL, als Konsolidierung nach HDCT

• Checkmate 205 Kohortenstudie mit 243 Patienten: Ansprechen 69% (16% CR, 53% PR); gute Verträglichkeit

• PD1 Inhibition gerade beim cHL sehr effektiv; Studien mit Nivolumab in der 1. Linie beim cHL in mittleren (NIVAHL) und fortgeschrittenen Stadien

• Weitere neue GHSG Konzepte: Therapiedauer? Kombinationen?

• CAR-T Zellen: innovatives Konzept bei r/r hämatologischen Neoplasien

• Neue Immuntherapien wie Checkpoint Inhibitoren oder CAR-T Zellen werden zunehmend Chemo- und Strahlentherapie bei Lymphomen ersetzen

Documents

Immuntherapie bei malignen Lymphomen - omniamed.de · Immuntherapie bei malignen Lymphomen Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne German