Director Department of Hematology and Oncology, University ... · nivolumab (at a dose of 3 mg per kilogram of body weight –hu monoclonal IgtG4 Ab against PD-1) every 2 weeks until

Immunotherapy in Hemato-Oncology

Markus G. ManzDirector Department of Hematology and Oncology, University Hospital Zurich

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ESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

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Hematopoiesis – A Paradigmatic Stem-Cell Supported Organ

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Hematopoietic Malignancies – (Always) Systemic Diseases

AML

MDS

MPN

B-ALL

T-ALL

Lymphoma

Myeloma


Cancer Death Rates CH 2009

(Quellen für Zahlen: Zahlen Institut für Krebsepidemiologie und –Registrierung NICER)

[Prozent]

(7)(6)

(10)

(5)

Leukemia and lymphoma about 10% of all neoplasias


Inzidenz pro 100.000 Einwohner Zentraleuropa

ALL: ~1.5 / 100.000 / year

AML: ~2.5 / 100.000 / year

CLL: ~3 / 100.000 / year

CML: ~1 / 100.000 / year

„Diseases of an ageing population“

Hematopoietic Cancer Incidence


Expected scenario 2030:

Doubling of population > 65 y

Doubling of hematologic (and

other neoplasias) in case of

stable incidence and

prevalance

http://www.bfs.admin.ch/bfs/portal/de/index/themen/01/03/blank/key/ind_erw.html

Demographic Evolution in CH


Therapeutic Target essential for Tumor («Driver»)Result: Efficacy of therapy high Tumor-Elimination

Therapeutic Target exclusively on/in Tumor and not on/in healthy tissue (e.g. neoantigen)

or

Therapeutic Target on/in Tumor and on/in healthy tissue but there not functionallyrelevant (e.g. in adult individual inactive protooncogene)

or

Therapeutic Target on/in Tumor and on/in healty tissue but healthy tissue itselfnot essential for survival/health of patient (e.g. pan-B cell antigen)

Result: No or few side effects

Result: „Magic Bullet“

1.)

2.)

1.+2.)

The Ideal of «Precision Medicine»ESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

CML – the rare ideal malignancy for «Precision Medicine»

ArsenMilz-RT

BusulfanHydroxyurea

Allo-HSZT (~50% LZ-Überleben)

KombinationstherapienIFNa (~30% LZ-Überleben)

TKIs

Behandlungseffektivität

1847R. VirchowLeukämieArch Path Anat.

1960Nowell, HungerfordPh-ChromScience

1973J. Rowleyt(9;22)Nature

1983Bartram et al.ABL-transloc.Nature

1990Daley et al.Mu Mod.Science

1996Druker et al.TKI Mu Mod.Nat Med

2001 Imatinib feasibility + safety NEJM

2003 IRIS NEJM

2006 2.-line 2.-gen TKI NEJM

2010 1.-line 2.-gen TKI NEJM

2010 1.-line 1.gen TKI+IFNa NEJM2010 STIM Lancet Onc

1987 Sokal-Score1998 Hasford-Score

1998 EBMT-Score

2006 ELN-Guidelines2009 Updated ELN-Guidelines

„a priori scores“ „kont. Beh.-Guidelines“

1999 Medical Progress

CL SawyersNEJM


Potential Functional (Driver) Targets in AML

Analysis of 111 genes in 1540 patients in three prospective trials of intensive therapy

Analysis of 18 genes in 398 patients younger than 60 years of age


At least 8 functional mutational categories in AML (Cancer Genome Atlas Research Network): Gain of function – natural target

TF Fusions

Tumor Suppressors

DNA MethylationActivated Signaling

Chromatin Modifiers

Spliceosome ComplexNPM1

Cohesin Complex


• T-cell mediated

• Antibody mediated

• NK-cell mediated

• Phagocyte mediated

• Artificial, intelligent «designer-

immune» mediated

Potential Immune-Mediated Mechanisms Against Cancer

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Transfer of

immune

effectors


Activation of

endogenous

immune

effectors

MHC I

tumor cell

T cell

TCR

CD3

(Tu)Surface Ag(CD..XY..)

Dendritic cell / APC

T cell

TCR

CD3++

+

Cytokine+ +

Cytokine++

-

PD1

PD1L

CD86

CD28

MHC II

MHC I KILL TC!

Immune-mechanisms: T-cell mediated killing

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MHC I

tumor cell

T cell

TCR

CD3



T cell

TCR

CD3++

+

Cytokine+ +

Cytokine++

-

--PD1

PD1L

--

CD86

CD28

MHC II

MHC I

DON’T KILL TC!


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MHC I

tumor cell

T cell

TCR

CD3



T cell

TCR

CD3++

+

Cytokine+ +

Cytokine++

-

--PD1

PD1L

--

CD86

CD28

MHC II

MHC I

DON’T KILL TC!

«Enhance the Enhancers!»

-Adjuvant / Co-Stimulation

-Cytokines

-Vaccination (Peptides, DCs)


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MHC I

tumor cell

T cell

TCR

CD3



T cell

TCR

CD3++

+

Cytokine+ +

Cytokine++

-

--PD1

PD1L

--

CD86

CD28

MHC II

MHC I

DON’T KILL TC!

«Inhibit the Inhibitors!»

-mAb interference


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Immune-mechanisms: Antibody-mediated killing

tumor cell

NK cell

Surface Ag (e.g. CD..XY..)

Macrophage

FcR

FcR

Complement-dependentcytotoxicity

Antibody-dependentcellular cytotoxicity

Antibody-dependentcellular phagocytosis

Direct antibody-dependent toxicity


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tumor cell

T cell

TCR

CD3

Surface Ag(CD..XY..)

Immune-mechanisms: Artificial designer (immune) killing

CAR T cell

CD3

+ Conjugate or modification

Chimeric Antigen Receptor T cellSuper-armed single chain mAb

(MHC independent)

Optimized “Super”-mAb(enhanced mAb function or drug targeting)

BiTEBispecific T cell Engager

(MHC independent)

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tumor cell

“don’t eat me!”

Macrophage

FcR

SIRPa

CD47

“eat me!”(calreticulin +…?)

Immune-mechanisms: Macrophage activation and killing

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EAT and KILL TC!


Overview

Immunotherapy in Hemato-Oncology (examples)

• Allogeneic hematopoietic (stem) cell transplantation

• Checkpoint control (post-allo-HSCT, HD)

• Optimized monoclonal Abs (CLL, MM)

• Bispecific Abs (BiTE; ALL)

• CART cells (CD19 CART, ALL, MM; BCMA CART, MM)

• «eat me» control – CD47-SIRPa

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Overview








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Allogeneic hematopoietic (stem) cell transplantation

NK

HD-Chemo-/RT-Therapie

Time

Patient

HSCDonor

T

Day 0

Reconstruction of hematopoiesis

Active Tumor-Therapy

Infection-ProtectionGvL (GvHD against hematopoiesis)GvHD

aGvHD cGvHD

Causes of death-GvHD-Infection-Relapse

Day 14

GvL

Day 100+

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therapeutic activity



Nobel-PriceMedicine

Since >50y “Bench-Mark” for any future SC therapy in regenerative medicine

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Allo-HSCT:

• currently only routinely applied CELLULAR immunotherapy and only clinical SC therapy

• GvL is GvHD against Hematopoiesis (+hematologic malignancy)

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Overview








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Ipilimumab – a CTLA4-blocking mAb


Best Response Examples Ipilimumab post allo-HSCT relapse

Hodgkin’s Lymphoma

Bone Marrow

Leukemia Cutis


All seven patients (of 28) with CR or PR, as compared to patients thatdid not have a response, had someprior GvHD (p=0.08)


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Checkpoint control - Hodgkin’s Lymphoma ESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

n=20 responding pt

23 patients with relapsed or refractory Hodgkin’s lymphoma that had already been heavily treated receivednivolumab (at a dose of 3 mg per kilogram of body weight –hu monoclonal IgtG4 Ab against PD-1) every 2weeks until they had a complete response, tumor progression, or excessive toxic effects.

Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (alsocalled CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.

Checkpoint control - Hodgkin’s Lymphoma

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Hodgkin’s Lymphoma Patho-Biology

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• PD-L1/PD-L2 alterations are

a defining feature of cHL

• Amplification of 9p24.1 is

more common in patients with

advanced stage disease and

associated with shorter PFS


Checkpoint inhibition in other Lymphoma(s)+MM?

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Large B-cell lymphoma PD-L1 overexpression is not commonly seen on B NHL cells.ORR of 30-40% in heavily pretreated r/r DLBCL and also patients with r/r primary mediastinal large B-cell lymphoma

Mantle cell lymphoma: no larger pt group data available

Follicular lymphoma: Ten FL patients were included in a phase I study of nivolumab in a variety of r/r hematologic malignancies; the ORR was 40% and three responses were ongoing after a median follow-up of 91.4 weeks, which encouraged further clinical trials.

Chronic lymphocytic leukemia: Richter syndrome, showed an ORR of 21%

Other Lymphoma: T cell lymphoma and virus-related lymphomas (i.e. Epstein-Barr virus- or hepatitis C virus-related) might be susceptible, CNS Lymphoma, Testicular Lymphoma, Primary mediastinal B cell lymphoma

MM: Trials ongoing


Overview








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Antigen Expression in B Cell Maturation

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CD19CD20CD22

CD38CD138BCMACD319(SLAMF7)

Expression outside ofBlood / B-Cell Compartment

- -(?)- -- -

- +

+ +

- -

- +


mAb – aCD20 in CLL

(p=0.0001)

FC

FCR

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CLL-8


As a type II antibody, GA101 binds differently than type I mAbs, leading to distinct modes of cytotoxic activity against B-cell malignancies3-6

Glycoengineering Type I/II

Complement-dependentcytotoxicity (CDC)

Antibody-dependentcellular cytotoxicity (ADCC)

Direct cell death

++ +

+++-+++

Type I antibody

(Rituximab)

Glycoengineered Type II antibody

(GA101)

Modes of action of GA101 (obinutuzumab): The first glycoengineered, type II anti-CD20 mAbOptimized mAb

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Roche


Goede V, et al. N Engl J Med 2014; 370:1101–1110,

Monate

MabThera + Clb

GAZYVARO + Clb

MabThera + Chlorambucil vs. GAZYVARO + Chlorambucil

Optimized mAb - CLL

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CD19CD20CD22


- -(?)- -- -

- +

+ +

- -

- +



Optimized mAb – Multiple Myeloma

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“Daratumumab represents a landmark advance in the treatment of myeloma. It is likely to

be incorporated into the treatment of all stages of the disease over the next several years.”


Multiple Myeloma HSPC (CD45 dim)

CD38 Expression in MM vs normal Progenitors

Delta:Therapeutic

Windowfor CD38

Targeting?

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CASTOR:

DVd vs Vd

POLLUX:

DRd vs Rd

Daratumumab: New “Rituximab” for MM? Better with ImID?

Optimized mAb – Relapsed/Refractory Multiple MyelomaESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

Overview








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α-CD19 Blinatumomab1,2

Single-chain antibodyα-CD3

Single-chain antibody

Linker

VL

VH

• 55 kDa• Very short distance between arms –

allows T cells and tumour cells to come into close proximity

1. Nagorsen D, Baeuerle PA. Exp Cell Res 2011;317:1255–60;2. Baeuerle PA, Reihnardt C. Cancer Res 2009;69:4941–4;

Bispecific Ab (BiTE) - ALL

95–100% of B-precursor ALL cases are CD19+

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Amgen


Amgen

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Bispecific Ab (BiTE) - ALLESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

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TOWER-STUDY


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TOWER-STUDY (NEJM 2017)


Overview








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CD19 CART cells – r/r ALL

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Emma WhiteheadNY Times DEC. 9, 2012

“Last spring Emma, then 6, was near death from leukemia. She had relapsed twice after chemotherapy»


http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/chemotherapy/index.html?inline=nyt-classifier

CART cells

CAR T cell

CD3

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EFS OS



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On the same day as the approval, the FDA expanded the indication for tocilizumab, a monoclonal antibodyto treat CAR T-cell–induced, severe or life-threatening CRS in patients ≥2 years of age. In clinical trials ofpatients treated with CAR T cells, 69 percent of patients had complete resolution of CRS within two weeksfollowing one or two doses of tocilizumab.Sources: U.S. Food and Drug Administration news release, August 30, 2017; Novartis news release, August30, 2017.

The U.S. Food and Drug Administration (FDA) approved the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel for the treatment of pediatric and young adult patients with B-cell precursor acute lymphocytic leukemia (ALL) that is refractory or in second or later relapse. This is the first gene therapy available in the U.S. and is “ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases,” the FDA said.

First-in-class therapy showed an 83% (52/63) overallremission rate in B-cell ALL patient population with limitedtreatment options and historically poor outcomes

www.novartis.com


CD19 CART cells – r/r NHL

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Approval was based on data from the multicenter ZUMA-1 trial, which included 111 patients (median age = 58 years; range =23-76 years) with previously treated DLBCL, primary mediastinal large B-cell lymphoma, or transformed follicular lymphomafrom 22 institutions.

January 27, 2017, 101 patients (91%) had received axicabtagene ciloleucel 2×106 cells/kg, following conditioning with low-dose cytarabine and fludarabine.

ORR=72%, CR = 51% (95% CI 41-62).

Median duration of response was 8.1 months; Six-month OS rate was 80 percent.The most common grade ≥3 treatment-related adverse events included neutropenia (66%), leukopenia (44%), anemia (43%),febrile neutropenia (31%), thrombocytopenia, (24%), and encephalopathy (21%).The drug carries a boxed warning for cytokine release syndrome (CRS) and neurologic events, and it was approved with aRisk Evaluation and Mitigation Strategy. In the study, 13 percent and 28 percent of patients experienced severe grade ≥3 CRSand neurologic events, respectively. Fatal cases of CRS and neurologic toxicity occurred.In the subset of 70 patients who experienced CRS or neurologic events, 43 required treatment with tocilizumab and 27required treatment with tocilizumab and steroids, but the treatments did not decrease the efficacy of axicabtagene ciloleucel(ORR = 84% and 78%, respectively).

Axicabtagene ciloleucelapproved for adult patients whose disease failed torespond to at least two prior treatments, as well as forthe following indications:• diffuse large B-cell lymphoma (DLBCL)• primary mediastinal large B-cell lymphoma• high grade B-cell lymphoma• DLBCL arising from follicular lymphoma


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CD19CD20CD22


- -(?)- -- -

- +

+ +

- -

- +



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BCMA CART cells – Multiple MyelomaESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

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• Results demonstrate for the first time that CAR T-cells targeting an antigen other than CD19 can induce complete remissions of a hematologic malignancy.

• Importantly, CAR-BCMA T cells have powerful activity against MM that was resistant to standard therapies.

BCMA CART cells – Multiple MyelomaESMO-Preceptorship Immuno-Oncology, Zurich Nov 4th 2017

CART cells – off-the-shelf – the future?

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Great Ormond Street Hospital (GOSH) and University College London:

Used cells from a healthy donor• DNA added (+CD19 CAR)• two genes erased (-TCR, -CD52)

CAR T cell

TCR

CD52

CD19 CAR


Overview








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CD47-SIRPa «eat me» control

SIRPa-CD47 interaction: “don’t eat me” signalFcR-activation by tumor-bound mAb: “eat me” signal

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CD47-SIRPa «eat me» control

Overview








An ongoing (R)Evolution

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Thank you for your attention

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Documents

Director Department of Hematology and Oncology, University ... · nivolumab (at a dose of 3 mg per kilogram of body weight –hu monoclonal IgtG4 Ab against PD-1) every 2 weeks until