Immunotherapy in Hemato-Oncology · nivolumab (at a dose of 3 mg per kilogram of body weight –hu monoclonal IgtG4 Ab against PD-1) every 2 weeks until they had a complete response,

Immunotherapy in Hemato-Oncology

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

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ESMO PRECEPTORSHIP PROGRAMMEIMMUNO-ONCOLOGY

ZURICH, SWITZERLAND, NOVEMBER 2-3, 2018

Markus G. Manz – FINANCIAL CONFLICT OF INTEREST

• No pharma stocks/shares• Education / Advisory fees last 3 years (each <CHF 2000.-)

• Amgen, Bristol-Myers Squibb, Celgene, Janssen Pharmaceutica, Novartis, Roche, Sanofi-Aventis, Teva Pharma

• Research Support (material)• Novartis (CSF-1R inhibitors)

• Patents/Patent Aplications/Ownership• on gene-modified humanized mice• on definiton and use of spec hu hem progenitor cells• co-founder hu-mouse company

No financial COI regarding this pesentation

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ESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

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Hematopoiesis – A Paradigmatic Stem-Cell Supported Organ

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Hematopoietic Malignancies – Cell Of Origin (COO)(almost always) Systemic Diseases

AMLMDSMPN

B-ALL

T-ALL

Lymphoma

MyelomaLCHECD


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

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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

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• 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

Mode of immune-action Mode of application


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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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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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/Innate Checkpoint Control

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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, NHL)

• Optimized monoclonal Abs (CLL, FL, MM)

• Bispecific Abs (BiTE; ALL)

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

• Innate Immunity Checkpoint control– CD47-SIRPa axis

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CD47-SIRPa «don’t eat me» innate Immunity Checkpoint Control

Overview








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Nobel-PriceMedicine

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

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Allogeneic hematopoietic (stem) cell transplantationESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

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


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

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 November 2-3, 2018

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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ORR of >80% in r/r HD


Hodgkin’s Lymphoma Patho-Biology

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• PD-L1/PD-L2 alterations

(disomy, polysomy, copy gain,

amplification) 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 lymphomaMM: 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


aCD20 mAb in all CD20+ B-cell NPL (ALL and NHL) in clinical use

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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1.) Study-Update EHA 2018: also significant OS benefit with longer FU 2.) FL first-line R-Chemo vs. O-Chemo (GALLIUM): longer PFS (NEJM 10/2017)


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CD19CD20CD22


- -(?)- -- -

- ++ +

- -

- +



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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.”

Optimized mAb – Multiple Myeloma


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Optimized mAb – Multiple Myeloma


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 r/r MM? Better with ImID?

Optimized mAb – Relapsed/Refractory Multiple MyelomaESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

Optimized mAb – first-line MM

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CONCLUSIONSPatients with newly diagnosed multiple myeloma, ineligible for stem cell transplantation, daratumumabcombined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression ordeath than the same regimen without daratumumab. The daratumumab-containing regimen wasassociated with more grade 3 or 4 infections (pneumonia).

anti-CD38 mAb on way to first-line therapy in MM


Overview



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

• Optimized monoclonal Abs (CLL, MM)




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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 November 2-3, 2018

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TOWER-STUDY

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Now also in first-line MRD+: 78% MRD neg; Blood 2018

TOWER-STUDY

Engineering of Antibodies

Engineering Reality – Clinical Future


Overview








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New therapy for CD19+ B-ALL: CD19-CART cells

Emma Whitehead2013 20172012 NY Times 2012


Target Cell

Antigenon Cell

Binder to Antigen on

Cell CAR T cell

Target Cell

Chimeric Antigen Receptor T Cell

The principle of CAR T cell Therapy


Target Cell

Antigenon Cell

Binder to Antigen on

Cell

Target Cell

CAR T cell

Chimeric Antigen Receptor T Cell

The principle of CAR T cell Therapy


CART cells

CAR T cell

CD3

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EFS OS

CD19 CART cells – r/r ALLESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

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On the same day as the approval, the FDA expanded the indication for tocilizumab (aIL-6R mAb), a monoclonal antibody totreat CAR T-cell–induced, severe or life-threatening CRS in patients ≥2 years of age. In clinical trials of patients treated withCAR T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses oftocilizumab.Sources: U.S. Food and Drug Administration news release, August 30, 2017; Novartis news release, August 30, 2017.

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) overall remission rate in B-cell ALL patient population with limited treatment options and historically poor outcomes

www.novartis.com


CD19 CART cells – r/r NHLESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

CD19 CART cells – r/r NHL

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ZUMA-1 CTL019


CD19 CART cells – r/r NHL

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).

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

from FL)


CD19 CART cells – r/r NHLESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018


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CD19CD20CD22


- -(?)- -- -

- ++ +

- -

- +



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BCMA CART cells – Multiple MyelomaESMO-Preceptorship Immuno-Oncology, Zurich November 2-3, 2018

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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 November 2-3, 2018

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• CD19 CAR added• two genes erased (-TCR, -CD52)

CAR T cell

TCR

CD52

CD19 CAR


CAR T cell modification and combination concepts

Engineering Reality – Clinical Future


CD19 CAR T cell Therapy associated Resistance


Relapse B-ALL 7-25%

• Epitope escape

• Lineage switch

• Isoform switch/splice

variants

• CD19 mutations

• Epitope masking

Orlando EJ et al. Nat Med 2018Ruella M et al. Nat Med 2018

Overview








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• SIRPa-CD47 interaction: “don’t eat me” signal• FcR-activation by tumor-bound mAb: “eat me” signal• Additional effect on APC adaptive immunity?



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• Phase 1b r/r DLBCL und FL (n=22)• 2-10 prior therapies (Median=4)• 95% refraktär auf Ritxumab• 50% OR(CR + PR), 36% CR• Most freq AE: anemia, infusion reactions

• The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma.

• No clinically significant safety events were observed in this initial study

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Overview








An ongoing (R)Evolution

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Thank you for your attention

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Documents

Immunotherapy in Hemato-Oncology · nivolumab (at a dose of 3 mg per kilogram of body weight –hu monoclonal IgtG4 Ab against PD-1) every 2 weeks until they had a complete response,