Cambridge Healthtech Institute’s 4^th Annual

Immunomodulatory Approaches

Harnessing the Immune Response and Overcoming Inhibitory Factors

18-19 March 2019

The Immunomodulatory Approaches conference track examines the multiple factors that interact in the tumour microenvironment including the cells involved and immunocytokines. Investigators are coming up with clever and often complex ideas for stimulating the immune response and targeting the immuno-stimulatory shield. There is a focus on T-cell effectors, myeloid-derived suppressor cells, Treg suppression, clever targeting, and innovations with antibody format regarding Fc engagement. Attendees will learn about the advances being made by the pioneers in this exciting field.

Final Agenda

MONDAY 18 MARCH

9:30 – 12:30 Recommended Short Courses*

SC1: The Tumour Microenvironment and Response to Cancer Immunotherapy - Detailed Agenda

SC2: Next Generation Immunotherapies - Detailed Agenda

*Separate registration required

12:30 Conference Registration

OVERCOMING LIMITATIONS OF CHECKPOINT INHIBITORS AND ANTAGONISTS

13:30 Organizer’s Welcome Remarks

Nicole Lyscom, PhD, Senior Conference Director, Cambridge Healthtech Institute

13:35 Chairperson’s Welcome Remarks

Dario Neri, PhD, Professor, Biomacromolecules, Chemistry and Applied Biosciences, ETH Zürich

13:45 KEYNOTE: Targeting Regulatory T Cells in Cancer: Means and Mechanisms

Sergio A Quezada, PhD, Professor, University College London Cancer Institute

Regulatory T cells have a recognised and critical role in the maintenance of immune homeostasis in mice and man. In this talk I will discuss the role of regulatory T cells in the context of cancer, as well as old and new strategies aiming to target this compartment for therapeutic gain.

14:15 Targeting Tregs to Manipulate the Tumour Vasculature and Enhance T-Cell Tumour Targeting

Awen Gallimore, DPhil, Professor, Immunology, Infection and Immunity, Cardiff University

Foxp3+ regulatory T cells (Treg) often accumulate in solid tumours where they help create an immunosuppressive niche. We have found that while depleting Treg results in significant immune activation, tumour regression after Treg-depletion is highly variable. It is becoming increasingly clear that features defining the tumour microenvironment impact on the ability of the immune system to attack tumours and represent additional targets through which the success of immunotherapy can be maximized.

14:45 Targeting Myeloid-Derived Suppressor Cells to Overcome Resistance to Checkpoint Inhibitors

R.J. Tesi, MD, CEO and CMO, INmuneBio

A predictor of resistance to checkpoint inhibitors is the number of MDSC in the patient’s blood. Combination immunotherapy with INB03 in patients with increased MDSC should reverse CPI resistance. INB03, a second-generation TNF inhibitor targets soluble TNF to decrease MDSC while improving NK/DC crosstalk and T cell recruitment. By protecting transmembrane TNF function, INB03 does not cause immunosuppression, a known off-target effect of currently approved non-selective TNF inhibitors.

15:15 Networking Refreshment Break

FOCUS ON Fc ENGAGEMENT FOR EFFECTIVE TARGETING

15:45 The Sting in the Tail of Antibody Therapy

Stephen A. Beers, PhD, Professor of Immunology and Immunotherapy, Centre for Cancer Immunology, University of Southampton

Monoclonal antibodies (mAb) are transforming cancer patient outcomes. The number of mAb reaching the clinic continues to rise rapidly, and yet despite this, successful targets are scarce and new ones frequently fail. A key issue facing novel antibody drug development is understanding why promising pre-clinical candidates do not translate to humans. Here, we will show how mAb format can be critical to efficacy and how this could be particularly important when seeking to develop new mAb to target the tumor microenvironment.

16:15 Fc-Optimized Immuno-Modulatory Antibodies

Rony Dahan, PhD, Assistant Professor, Immunology, Weizmann Institute of Science

I will present an overview of FcγR-dependent mechanisms of immunomodulatory Abs, while focusing on case study of Fc-engineered anti-CD40 agonistic Abs and approaches for increasing their therapeutic window. I will describe the use of FcγR humanized mouse models to assess the efficacy and toxicity of human immunomodulatory Abs, while explain the challenges overcome while translating findings in mice into human IgG-based therapeutics.

16:45 ATOR-1017 - A Tumor Directed Fcγ-Receptor Cross Linking Dependent 4-1BB Agonistic Antibody

Karin Enell Smith, PhD, Senior Scientist, Preclinical Development, Alligator Bioscience

ATOR-1017 is a FcγR cross-linking dependent 4-1BB agonistic antibody. ATOR-1017 was designed for an optimal efficacy and improved safety, by combining the IgG4-format that mediates a potent FcγR cross-linking with a unique binding epitope on 4-1BB. The immune activation will be directed to tumors co-expressing both specific FcγRs and 4-1BB, potential biomarkers for patient and tumor indication selection. Clinical studies with ATOR-1017 are planned for 2019.

17:15 F.I.R.S.T™ - Phenotypic Discovery of New Oncology Targets and mAb

Ingrid Teige, PhD, Principal Scientist, Oncology Director, BioInvent International AB

BioInvent have developed a holistic and patient-centric antibody and target discovery tool called F.I.R.S.T. Utilizing patient-derived tumor material, as well as a battery of well characterized immunocompetent in vivo mouse models, we perform phenotypic screenings which combine target and antibody discovery resulting in the optimal antibody for a given and desired function. This will be illustrated using an example from BioInvent’s T reg program focusing on identifying T reg depleting antibodies for cancer therapy.

17:45 Welcome Reception in the Exhibit Hall with Poster Viewing

18:45 Close of Day

TUESDAY 19 MARCH

TUMOR-TARGETED T CELL AGONISTS AND

TCR-BASED BISPECIFICS

8:00 Registration and Morning Coffee

8:30 Chairperson’s Opening Remarks

Sophia N. Karagiannis, BA, MS, PhD, Reader, Translational Cancer Immunology, St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London

8:35 FEATURED PRESENTATION

Tumor-Targeted 4-1BBL Fusion Proteins for Combination with T-Cell Bispecific Antibodies in Cancer Immunotherapy

Christian Klein, PhD, Distinguished Scientist, Head, Oncology Programs, Cancer Immunotherapy Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich

The presentation will cover rationale and efficacy data supporting the combination of T-cell bispecific antibodies with tumor-targeted 4-1BBL fusion proteins.

9:05 Key Clinical Learnings and Advancing the Pipeline of the ImmTAC TCR-Based Bi-specific Biologic Platform

Joseph Dukes, PhD, Director & Head, Biology, Immunocore, Ltd.

This presentation will introduce the TCR-based ImmTAC platform, giving insight into the key features that distinguishes the platform technology from other immunotherapies. The latest clinical data available for advanced trials in metastatic uveal melanoma will be summarised and the observation of signs of clinical benefit in immunologically cold tumours will be explored. Finally, subsequent candidates emerging from the pipeline will be discussed and presented, to illustrate the potential of the ImmTAC platform.

9:35 Problem Solving Roundtable Discussions

Importance of Fc Receptor Functions and Isotype Selection for the Development of Therapeutic Antibodies for Cancer

Moderator: Stephen A. Beers, PhD, Professor of Immunology and Immunotherapy, Centre for Cancer Immunology, University of Southampton

Challenges and Immunosuppressive Mechanisms that Restrict Anti-Tumour Functions of Monoclonal Antibodies in the Tumour Microenvironment

Moderators: Sophia N. Karagiannis, BA, MS, PhD, Reader, Translational Cancer Immunology, King’s College London

Christian Klein, Ph.D., Distinguished Scientist, Head, Oncology Programs, Roche Innovation Center Zurich

Checkpoint Refractory Patients – Solving the Problem

R.J. Tesi, MD, CEO and CMO, INmuneBio

Challenges with Targeting Immune Checkpoint Inhibitors

Moderator: Matthew McCourt, PhD, VP, Immuno-Oncology, Kymab

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

BISPECIFIC AGONISTS WITH CHECKPOINT BLOCKADE

11:15 Development of an ICOS/PD-L1 Bispecific

Matthew McCourt, PhD, Vice President, Immuno-Oncology, Kymab

We have developed a mAb² bispecific antibody called KY1055 as a human IgG1 targeting ICOS and a modified Fc (Fcab) containing binding sites to PD-L1, and demonstrated potent binding to ICOS and PD-L1. We will present in vitro characterization demonstrating potential novel biology of the mAb2 and in vivo efficacy data supporting further development. Clonal cell lines suitable for manufacture have achieved initial titres of ~ 2g/L.

11:45 Engaging Multiple T Cell Targets with Bispecific Antibodies for Selective Immune Stimulation in the Tumor Microenvironment

Michael Hedvat, PhD, Group Leader, Cell Biology, Xencor, Inc.

Xencor is developing several bispecific antibodies that engage two targets on tumor-infiltrating lymphocytes (TILs). Examples include XmAb20717 (PD1 plus CTLA4 blockade), XmAb22841 (CTLA4 plus LAG3 blockade) and XmAb23104 (PD1 blockade plus ICOS agonism). I will also discuss preclinical development of these and of XmAb24306, a potency-tuned IL15/IL15R -Fc fusion that is itself immunostimulatory, and also a platform for engineering novel immune activators such as a TIL-targeted PD1 x IL-15 bispecific.

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

13:15 Session Break

T CELL ENGAGING CONSTRUCTS

14:00 Chairperson’s Remarks

Christian Klein, PhD, Distinguished Scientist, Head, Oncology Programs, Cancer Immunotherapy Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich

14:05 Simultaneous Multiple Interaction T Cell Engaging (SMITE) Bispecifics: Silence and Synergy through T-Cell Costimulation

Colin Correnti, PhD, Senior Scientist, Fred Hutchinson Cancer Research Center

We are developing pairs of synergistic T cell engagers that simultaneously bind two cancer antigens and two T cell co-receptors. Importantly, each singleton is selected to be inactive until paired, providing T cell co-stimulation and improved cancer specificity. In this presentation I’ll describe our approach for generating silent and synergistic T cell engagers, highlighting our use of the Trianni™ mouse and automated methods for protein expression and T cell cytotoxicity assays.

14:35 New Developments with a BiTE® Antibody Construct Targeting CD33 in AML

Roman Kischel, PhD, Director, Research, Amgen Research Munich

BiTE® antibody constructs are recombinant bispecific antibodies that efficiently recruit host T-cells for redirected killing of cancer cells expressing a selected target antigen. AMG 330, a CD33/CD3 specific BiTE® antibody construct, has been extensively characterized preclinically. Data from ex-vivo studies suggests the potential for substantial antileukemic activity. Preclinical data and initial data from a phase 1 dose escalation study evaluating AMG 330 in patients with R/R AML will be discussed.

15:05 CB307: A Novel CD137/4-1BB Agonist Humabody Therapeutic for PSMA Positive Tumours

James Legg, PhD, Vice President, R&D, Crescendo Biologics

Crescendo Biologics has initiated pre-clinical development of CB307, a novel bispecific Humabody VH targeting CD137 (4-1BB) and prostate specific membrane antigen (PSMA). The talk will describe the identification, mechanism of action and preclinical characterisation of CB307. The benefits of using the modular Humabody VH platform, rather than an IgG format to develop this molecule will be discussed, including optimal (monovalent) engagement of both targets with small VH domains and the avoidance of Fc receptor interactions. The unique design of CB307 enables highly potent and tumour selective T-cell co-stimulation.

15:35 Refreshment Break in the Exhibit Hall with Poster Viewing

IMPORTANCE OF CYTOKINES/INNOVATIVE APPROACHES WITH CLINICAL BENEFITS

16:15 Next Generation Antibody-Cytokine Fusion Proteins

Dario Neri, PhD, Professor, Biomacromolecules, Chemistry and Applied Biosciences, ETH Zürich

Antibody-cytokine fusions (“Immunocytokines”) are being considered as therapeutics for the treatment of cancer and of chronic inflammatory conditions. In this lecture, I will present new concepts and experimental results for the development of products with preferential activity at the site of disease. This will include the generation of split-cytokine fusions and of potency-matched dual cytokine fusion proteins.

16:45 Exploratory Studies up to IND with NKTR255, a Memory T-Cell Stimulating Cytokine

Saul Kivimae, Team Lead, In Vivo Pharmacology, Nektar Therapeutics

This presentation will outline the mode of action in engaging the IL-15 pathway to induce long-term T cell activation and a T cell memory response and demonstrate the impact of the product on CD8 T cells and NK cells. Means of optimizing biological activity will be discussed.

17:15 A Therapeutic Antibody Targeted Approach for Triple-Negative Breast Cancer

Sophia N. Karagiannis, BA, MS, PhD, Reader, Translational Cancer Immunology, St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London

We demonstrate that aggressive high-grade triple negative breast carcinomas (TNBC), including post-neoadjuvant chemotherapy residual disease, overexpress the tumor-associated antigen Folate Receptor alpha (FRα) and feature dysregulated folate metabolism in the tumor microenvironment. We reveal FRα, the folate metabolism and associated signaling pathways as promising targets by different inhibitor and monoclonal antibody therapy approaches. These offer opportunities to treat patients with poor prognosis who may not benefit from available targeted treatments.