Challenges in the development of immunotherapiesregist2.virology-education.com/presentations/2019/ICPAD/...isk tion es Rationale framework to design and assess combination therapy

Challenges in the development of immunotherapies

Candice Jamois, Clinical Pharmacology, Pharmaceutical Sciences

International Workshop of Clinical Pharmacology of AntiCancer DrugsAmsterdam, Friday 22nd November 2019

No disclaimer

• Except that I am a Roche employee

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2018 Nobel Prize Awarded for Cancer ImmunotherapyJames P. Allison and Tasuku Honjo : for their discovery of cancer therapy by inhibition of negative immune regulation

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T cell

Cancer cell

“Their work , the foundation for an entirely novel form of cancer treatment — immune checkpoint therapy — which has been credited with saving thousands of lives within the first few years since its approval.”

• James P. Allison, from the MD Anderson Cancer Center (University of Texas) for his work on CTLA-4 (T-lymphocyte-associated protein 4) blockade,

• Tasuku Honjo, from the Graduate School of Medicine of Kyoto University for his work on PD-1 blockade (programmed cell death protein)

T-cell Checkpoint Regulation, an evolving era since 2011

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Centanni et al. Clin PK, 2019

6 Check Point Inhibitors approved by FDA, 5 of them by EMA

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

Hodi FS et al. New England Cancer of Medicine, 2010

gp=glycoprotein 100 peptide vaccine

The Cancer-Immunity Cycle – Activating T-cells against CancerPresentation, recognition, activation, and expansion are key factors for an efficacious tumor response

Chen DS and Mellman I, Immunity, 2013. APC= Antigen-Presenting-Cells; TME= Tumor micro environment; CTL= Cytotoxic T Lymphocytes

Tumour

Lymph node

Blood vessel

Release of cancer

cell antigens

(cancer cell death)

1

Cancer antigen

presentation

(dendritic cells/APCs)

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Priming and

activation (APCs

and T cells)

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Infiltration of T cells

into tumours

(CTLs, endothelial cells)

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Recognition of cancer

cells by T cells

(CTLs, cancer cells)

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Killing of cancer cells

(immune and cancer

cells)

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Trafficking of T cells

to tumours (CTLs)4

Ability to create an Antigen-specific T cell response

Ability to infiltrate the TME (Homing and extravasation)

Ability to Kill tumor cells

GeneratorsIncrease number of antigen-specific T-cells

or increase antigen presentation

Examples:

aCD40

“Endogenous” vaccines

ModulatorsAccelerate or remove brakes on T-cell response

Examples:

aPD-L1

CEA-IL2v

aCSF-1R

EngagersBring T-cells in contact with

cancer cells

Examples:

CEA-TCB

Cancer Immunotherapy => Host directed

Adressing the Cancer Challenge with innovative IO agents Generators, Modulators, Engagors

Dosing and Pre-Clinical Model Translation Classical models of Pharmacology Dose Decision Making Process most of the time do not apply for IO agents

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Cancer immunotherapies (biologics and cell based therapies) are not compatible with conventional pharmacological approaches (NOAEL) when determinig dosing because:

• Efficacy is directly mechanistically linked to immune mediated adverse outcomes

• Immune responses are stochastic and highly dynamic

Human

dose

Apply safety factor

Select appropriate animal species

Convert NOAEL to Human Equivalent Dose

Determine no observed adverse effect levels (NOAEL) in animal species

➢ An in vitro MABEL (minimum anticipated biological effect level) approach is often preferred over the in vivo NOAEL approach

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▪ Binds simultaneously with 1 arm to CD3e on T cells and with 2 arms to CEA on tumor cells

▪ Flexible 2- to -1 format enables high-avidity binding and selective killing of high CEA-expressing tumors cells

▪ Extended half-life compared to non-Fc based TCBs

▪ Silent Fc results in reduced risk of FcgR-related cytokine release/ infusion related reactions

CD3 T cell engagement

Silent Fc forhalf-life extension

High avidity binding to tumor antigen

CEA-TCB, first bispecific antibody with a 2- to 1- format leading to T cell mediated killing of tumor cells

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“2+1” format Fab range of motion in TCB

Bacac M, et al. AACR 2015 and Clin Cancer Res. 2016.; Pr Joseph Tabernero ASCO 2017 CEA=Carcino Embryonic Antigen; TCB = T cell bi specifics

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Determination of the EIH starting-dose of CEA-TCB leveraging 3 MABEL approaches

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Key Methods for Starting Dose Assessment with Associated CD3e Receptor Occupancies (RO)

In vivo efficacyIn vitro assessment

Tumor Cell LysisReceptor occupancy

403 µg/Kg

(38% RO)

0.736 µg/Kg- EC20

(0.11% RO CD3e)

6.7 µg/Kg

(1% RO CD3e)

Starting dose (52 µg)

o The tumor cell lysis assay was selected for the determination of the starting-dose as the most sensitive

of the three MABEL approaches

o The starting-dose selected was well below the level at which cytokine release was observed in the

Whole Blood Assay (safety factor applied to suggested MABEL dose).

Bacac M, et al. AACR 2015 and Clin Cancer Res. 2016.

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PK properties lead to exposure reduction following multiple dosing Extent of exposure reduction is dependent on the dose and frequency of administration

Grimm H.P., PAGE 2016IL2v cytokine

Tumor target High affinity for tumor antigen (CEA)

Inert Fc part

Modified IL2-variant

Advantages over wild type IL2

• Tumor targeting

• Improved PK properties

• Reduced toxicity

Tumor-targeted immune cytokine

CEA = Carcinoembryonic antigen, IL2=Interleukin 2, cytokine for cell signaling

Grimm et al. PAGE 2016 ; Silber-Baumann et al. PAGE 2017 ; Ribba B, ACOP 2017

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Dose

Frequency Exposure reduction

Drug concentration

Receptor concentration

AUC by treatment cycle

QW

Q2W

Q3W

Time (days) Time (days) Cycle

A quantitative model integrating PK and PET imaging data was developed to predict the impact of Dosing Regimen on Antibody Tumor Uptake and identify the best schedule

PET imaging study with radiolabeled CEA-IL2v

Drug in

interstitial

space

Bound drugDose

Drug in

plasma

Drug in tumor

Predicted tumor uptake QWPredicted tumor uptake Q2W

PET data were incorporated into a model for tumor uptake

Intensifying the dosing frequency is predicted to significantly improve tumor uptake despite peripheral target expansion and reduced exposure

Ribba B et al. CCR, 2018

• Specific tumor uptake after the 1st dose

• Reduced uptake following repeated dosing (Q2W)C

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Bell-Shape Kinetics of the tri-molecular synapse between bi-specific Ab, T cell, and Tumor cell : a new Challenge for Clinical Development

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• Too much bispecific Ab may saturateantigens, and limit cross-linking

• Too little bispecific Ab may not enhanceTarget Cells and T cells cross-linking

Structure of the Target cell-Biologics-Effector Cell complex –based cell killing model

Xiling Jiang et al. MABS, 2018

Bell Shape Kinetics - Illustration

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Immune related Adverse Events (IrAEs), inflammatory side effects caused by IO agents

13Immune-related adverse events with immune checkpoint blockade: A comprehensive review. Eur J of Cancer, 2016

C. Lee Ventola. Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations. 2017

Immune related adverse events with Check Point blockers

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Harnessing the Host Immune System while still Controlling it : Cytokine Release Syndrome, a Major Challenge with T cells engaging IO therapies

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Engineered T cells - Chimeric antigen receptor (CARs)

▪ Outstanding clinical efficacy with CD19 CARs in B-cells malignancies

▪ Activity associated with high toxicity (such as CRS)

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Managing immune mediated adverse events : a Challenge Some safety measures may compromise efficacy potential

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Maude S.L., Barrett D., Teachey D.T., Grupp S.A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20:119–122

• Corticosteroids may control some of these toxicities, however their potential to block T cell activation/proliferation and abrogate clinical benefit is a concern

• Tocilizumab , anti IL6R, an alternative to manage patients’ safety without compromising efficacy

Kaplan-Meier curves of OS according to the use of steroids

Nivolumab

Giovanni Fuca et al. ESMO 2019

Nivolumab + steroids

Early use of steroids, associated with poor disease control in patients with mNSCLC

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Obinutuzumab (Gazyva®) pre-treatment to mitigate the risk of CRS. Shared target : when CD20 molecular format and receptor occupancy (RO%) drive the response

• G pre-treatment is given as 1000 mg IV, on Cycle Day -7

• CD20-TCBa,b RO% determined in the presence of circulating G pre-treatment using standard approachesc

• Average RO% (AvgRo%) used to examine relationships with efficacy and safety and inform RP2D

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https://www.biooncology.com/pipeline-molecules/cd20-tcb.html

aBacac M et al. Blood. 2016;128:1836. bBacac M et al. Clin Cancer Res. 2018.cSaji Salahudden M et al. Saudi Pharm J. 2017. ASH 2019

-assumes binding equilibrium and serum RO% correlates with response

-does not account for absolute number of receptors

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Rationale framework to design and assess combination therapy

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• > 2300 FDA registered clinical trials are on-going based on targeting PD-1 pathway

• Most large pharma companies in IO would have up to 15,00-20,00 combination therapies

• Modeling can help identify dosing, combinations, timing, mixing cell based therapies & vaccines with biologics….

From Tang J et al., Nature Reviews Drug Discovery 17, 854-85, 2018

Despite impressive clinical outcomes, RR for all CPIs administered as single agents < 50 % regardless of tumor type

Combotherapy Landscape

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Multi-trial platform - Novel way to test Cancer Immunotherapy Combinations

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How to identify optimal clinical dose?

How to identify optimal sequencing?

For each combinationThrough understanding

of drug response variability

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Some Perspectives The success of combination immunotherapy will depend on our ability to manage development hurdles

• Design of the right preclinical experiments and the translation of those into the clinic,

• Optimization of the dose and schedule of the combination regimen,

• Safety management (risk of overlapping toxicities with immunotherapies).

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The application of Quantitative Clinical Pharmacology Approaches in the translational space and throughout clinical development may help to address these challenges; in collaboration with System Pharmacology

and Machine Learning

Doing now what patients need next