Has immunotherapykept its promises

in malignant lymphomas?

Franco Cavalli M.D., F.R.C.P.

President

Institute of Oncology Research (IOR)

President WOF and Scientific Committee ESO

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Lymphomas and immunotherapy

Notwithstanding the “natural correlation” for many

years only adoptive immunotherapy through allogeneic SCT was

“sometimes” efficacious.

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What do we mean today by ‘immunotherapy’?

• MONOCLONAL ANTIBODIES

– ‘Naked’

– Radio-immunotherapy

– Immuno-toxins

• ENGAGING T-CELLS

– Interferon

– Vaccination

– Immune checkpoint inhibition

– CAR T cells

– Bispecific antibodies

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Rituximab: mechanisms of action

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Patients usually respond to upfront R

Colombat 2001 (n= 50) 73%

Hainsworth 2002 (n= 60) 73%

Witzig 2005 (n= 37) 72%

Ghielmini 2005 (n= 202) 75%

Kimby 2008 (n= 123) 78%

Ardeshna 2010 (n= 192) 85%

RR of prolonged rituximab in first-line FL

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FL: the response to upfront rituximab (RR 70%) can be long lasting if maintained

1. Martinelli G, et al. J Clin Oncol 2010;28:4480–842. Taverna C, et al. ASH 2013; Abstract 508

PFS2

Median EFS = 4.4 years

Median EFS = 2.5 years

P=0.04

1 year

5 years

Years since start of treatment

0.0

0.4

0.6

0.8

1.0

0.2

2 4 6 8 101 3 5 7 9

p = 0.045

1 month

1 year

Prolonged

Standard

Time from randomisation (years)

0.0

0.4

0.6

0.8

1.0

0.2

2 4 6 8 91 3 5 70

Pro

bab

ility

EFS1

Median PFS = 7.4 years

Median PFS = 3.5 years

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R2 in FL patients in need of treatment

10% 13%25%

36%

35%

62% 36%

45%

0

10

20

30

40

50

60

70

80

90

Rituximab (N=77) Rituximab +Lenalidomide (N=77)

Rituximab (N=77) Rituximab +Lenalidomide (N=77)

PR

CR/CRu

Week 10 Week 23

45%

75%

61%

82%

Pro

po

rtio

n o

f p

atie

nts

(%

)

p<0.0001 p=0.002

Kimby E, et al. ASH 2014; Abstract 7995th

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RELEVANCE trial

Morschhauser F, et al.NEJM, 2018;379:934-947 5th

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Improvement in lymphoma treatment: DLBCL

1st phase

Chemo

Survival improvement

2nd phase

Some are cured

Doxo

3rd phase

More are cured

Rituximab

4th phase

New drugs?

All are cured, no side effects

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131I

Targeted irradiation: radio-immuno-therapy

Properties

90Yttrium

(Zevalin)

131Iodine

(Bexxar)

Half-life 64 hours 192 hours

Energy emitter Beta

(2.3 MeV)

Gamma (0.36 MeV)

Beta (0.6 MeV)

Path length 90 5 mm 90 0.8 mm

Urinary excretion Minimal

7% in 7 days

Extensive/variable

46 - 90% in 2 days

Dosing

Based on weight

and platelet

count

Clearance based dosing

using whole body

dosimetry

Administration Outpatient Inpatient or restrictions to

protect family/public

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Radio-immunotherapy as initial therapy for indolent NHL

GELF, Groupe d'Etude des Lymphomes Folliculaires1. Kaminski MS, et al. N Engl J Med 2005;352:441–49

2. Ibatici A, et al. Br J Haematol 2014;164:710–16

I-131 Tositumomab1

n=76 patients, 95% OR, 75% CR

90-Y Ibritumomab2

n=50 patients, 94% OR, 86% CR

Years after dosimetric dose

0

40

60

80

100

20

2 4 60 81 3 5 7

Progression-free survival

Overall survival

Su

rviv

al (%

)

0.0

0.4

0.6

0.8

1.0

0.2

24 48 8412 36 60 720

Progression-free survival (months)

Cu

mu

lati

ve

su

rviv

al

GELF criteria

GELF criteria not met

GELF criteria met

Global

Censored data

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Brentuximab vedotin (SGN35) Anti-CD30 conjugated to an antitubulin agent

MMAE – microtubule-disrupting agent

ADC binds to CD30

MMAE disruptsmicrotubule network

Internalised in lysosome

MMAE is released

anti-CD30 monoclonal antibody

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Brentuximab vedotin in HL

80% of patients respond to the treatment even in relapses after

autologous/allogeneic SCT

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Brentuximab vedotin within chemotherapy for stage III or IV Hodgkin’s lymphoma

N = 670 ABVD= 664 A-AVD

Fu = 25 months

A-AVD5% lower combined risk of PD, death or non-CR requiring alternative treatment

J.M. Connors et al. NEJM 2018; 378:331-3445th

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ECHELON-1 trial

HL Stage III-IV untreated

670 ABVDR

664 AVD + A (Adcetris = Brentuximab)

4.9% less modified PFS (including non CR requesting new treatment)

P = 0.04

J.M. Connors et al. NEJM 2018; 378:331-3445th

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NativeT cell

Malignant B Cell

PD1

PD-L1PD-L2

MHC I/II

TCRCD3

5.- BiTEEngineeredT Cell

1.- Cytokines2.- Tumor vaccines

3.- Immune checkpointinhibitors

TCR

4.- CAR

Batlevi C, Matsuki E, et al: Nature Rev Clin Oncol 2015 (Accepted)

Therapeutic strategies to overcome immune tolerance to cancer

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Interferon prolongs survival in FL

META-ANALYSIS10 randomised trials, 1922 patients

Survival benefit of 2 years (p=0.0008) if IFN given With (NOT after) intensive chemotherapy

At a dose of ≥ 5 million UI

At a cumulative dose of ≥ 36 million UI / month

Rohatiner AZS, et al. J Clin Oncol 2005;23:2215–235th

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Vaccines are directed against idiotypes

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Vaccinated patients developing anti-idiotype Ab have a longer response after chemotherapy

Analysis of 136 patients with FL receiving idiotype (Id) vaccinationHumoral represents patients with specific anti-Id Abs

Weng WK, et al. J Clin Oncol 2004;22:4717–24

Humoral

Other

HumoralOther

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Mitumprotimut-T vs placebo

Freedman A, et al. J Clin Oncol 2009;27:3036–43

Negative vaccine trial

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Analysis of patients with advanced stage previously untreated FL

Schuster SJ, et al. J Clin Oncol 2009;27:2

“Positive” vaccine trial

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Blockade of CTLA-4, PD-1, PD-L1 in tumour immunotherapy

Ribas A, N Engl J Med. 2012;366:2517–195th

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Armand P, et al. ASH 2014; Abstract 289

Nivolumab: RR 87%, CR 17%

Responses of HL to anti-PD1 in R/R HL

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

ange

fro

m b

ase

line

, %

Moskowitz CH, et al. ASH 2014; Abstract 290

Pembrolizumab: RR 66%, CR 21%

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9p24.1Gene amplification

EBVInfection

JAK2

PDL1

Hodgkin and Reed Sternberg (HRS) Cells

CD30

HRS Cells Express High Levels of PDL-1

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Nivolumab

Abstr. 010

CHL (n = 23) ORR 87% CR 17%

B-NHL (n = 31) ORR 26% CR 10%

T – NHL (n = 23) ORR 17%

13-ICML 20155th

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PD-1 blockade by pidilizumab plus rituximab in relapsed FL

Westin JR, Lancet Oncol 2014;15:69–77

Efficacy Safety

n= 29 pts No gr 3–4 AEs

ORR 66% (CR 52%)

Median PFS 19 months

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Two strategies to engage T-cells against B-cell lymphoma

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Kochenderfer JN, Rosenberg SA. Nat Rev Clin Oncol 2013;10:267–76

CAR-T cells(Chimeric Antigen Receptor)

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*Any grade or no details of grade; **Total n=30

Summary of available data for CAR T cells in R/R ALL

19-28z(MSKCC/Juno;

n=39)1

CTL019(CHOP/UPenn/

Novartis; n=39)2,3

CD19-CAR(NCI/Kite; n=20)4

Population Adults >18 years Children (age not specified)2

Children/youngadults (1–30 yr)

Status after conditioning chemotherapy, prior to CAR T-cell treatment

MRD+ CR (<5% BMB)MRD- (<0.01% BMB)

46%0%

23%2

15%225%0%

Status after conditioning chemotherapy and CAR T-cell treatment

CR/CRi 87% 92% 70%

MRD- (in evaluable patients) 81% 82% 60%

Clinically significant/severe CRS

23% 27**3 29

Neurotoxicity (%)* 28 (Grade 3/4) 43**3 29

1. Park JH, et al. Oral presentation at ASCO 2015. Abstract 7010; 2. Grupp S, et al. Oral presentation at ASH 2014. Abstract 380

3. Maude SL, et al. N Engl J Med 2014;371:1507–17; 4. Lee DW, et al. Lancet 2015;385:517–285th

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Car T-cell therapy in refractory large B-cell lymphoma

S.S Neelapu et al. NEJM 2017; 377:2531

N = 111 pts 77 DLBCL(101 administered) 24 PMBCL or tranformed FL

Most resistant to at least second-line therapy

OR = 82%CR = 54%FU (15 months) = 48% still in responseCytokine release Sy (≥ grade 3): 13%Neurologic events: 28%

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Car T-cell therapyin refractory B-cell lymphoma

S. J Schuster et al. NEJM. 2017; 377:2545

N = 28 enrolled, 28 treated (insufficient T-cell, PD)

14 FL 89% response, CR 71%14 DLBCL 86% response, CR 43%

Severe cytokine release Sy (18%)Serious encephalopathy (13 %)

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Conclusions on CAR T cell therapy

• Unprecedented activity in R/R DLBCL• Toxic so far manageable only in specialised centres• Possibly practice changing treatment

Pending issues:• Longer follow-up needed• Ideal timing for CAR T treatment yet to be determined• Logistics are complex and restrictive• Financial limitations (USD 300’000 to 500’000 per

treatment)

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Bi-specific antibodies

Frankel SR, Baeuerle PA. Curr Opin Chem Biol 2013;17:385–92

Design and mode of action of bispecific T-cell engager (BiTE®) antibody constructs

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CR after Blinatumomab in ALL patientsrefractory or relapsed after allotransplant

Topp MS, et al. Lancet Oncol 2015;16:57–66;Topp MS, et al. EHA 2014, Abstract S722 and oral presentation

All responders

Sex FemaleMale

Age 18 to <3535 to <5555 to <65≥65

Prior Salvage 012≥3

Primary refractory Yes

Prior SCT Yes

Bone marrow blasts <50%≥50%

0 20 40 60 80 100

189 43

4641

43

443646

50

343647

3843

4542

2973

70119

16173

64125

90462825

38774232

59130

No

No

CR/CRh rate, %

36–50

34–5832–51

33–54

24–6519–5631–61

33–67

19–5322–5235–58

15–6536–51

33–5833–51

22–3860–84

N

CR/CRh

% 95% CI

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PD-L1 blockade: rejuvenating T cells in CLL

CLL prime example of tumourinteracting with microenvironment.

T-cell defects in murine CLL point to a possible huge therapeutic role of

immune checkpoint blockade.

Mc Clanahel et. al. Blood 2015; 126:203-211Blood 2015; 126:212-221 5t

h ESO-E

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Amer

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Mas

terc

lass i

n Clin

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ncolo

gy

Immunotherapy in Multiple Myeloma

• Allogenic: limited results• Car-T cells: in China ↑↑↑• Checkpoint inhibitors:

alone −+ IMID + but too toxic

• Anti CD38 (Daratumumab): Breakthrough!!!

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Conclusions (for lymphomas)

• Chemotherapy is not likely to obtain more in B-cell malignancies

• Future progress most likely to be obtained by targeted drugs and immunotherapy

• Possibly enhancement activity of IT through radiotherapy (NK/T cell!)

• One avenue of success may be the engagement of T cells against malignant B cells

• Long-term toxicity still unclear

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THANKS FOR YOUR ATTENTION!

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