While much attention in immunotherapy to-date has been given to checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4, there’s a rising interest in agonist targets such as OX40, 4-1BB, CD27, GITR, ICOS, TNFR receptors, STING, etc., as it’s been
found that antagonists alone are not enough to elicit response in the majority of patients.
PEGS Europe’s Inaugural Agonist Immunotherapy Targets and Combination Therapies presents updates and exciting development of these co-stimulatory agonists in monotherapy or in combination with co-inhibitory antagonists.
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THURSDAY 15 NOVEMBER
13:00 Registration (Foyer C)
13:15 Dessert Break in the Exhibit Hall with Poster Viewing (Pavilion 1)
14:00 Chairperson’s Opening Remarks
Patrick Mayes, PhD, Executive Director, Head of I-O Biotherapeutics, Incyte
14:05 Interleukin-2: Releasing an Immune System Brake to Attack Tumors
Rodrigo Vazquez-Lombardi, PhD, PostDoc,
Laboratory for Systems and Synthetic Immunology, Department of Biosystems Science and Engineering, ETH Zurich
Interleukin-2 is an established therapeutic agent used for cancer immunotherapy. It is generally believed that treatment efficacy is mediated by CD8+ and NK cell activity, and considerable efforts have focused on generating IL-2 variants that expand these
subsets systemically. Here we describe a second and unexpected mechanism, namely the selective depletion of CD25+ CD4+ regulatory T-cells (Tregs), as a major determinant of antitumour activity. Our results outline mechanisms of action and provide
important guidance for the development of next-generation cytokine therapeutics.
14:35 Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells
Jeonghyun Ahn, PhD, Research Asst Prof, Cell Biology, University
Tumor cells are notoriously non-immunogenic and acquire properties that enable them to evade the immunosurveillance system. Here we demonstrate that defects in cytosolic DNA activated innate immune signaling pathways, controlled by STING, enable pre-cancerous
cells to escape DNA-damage mediated cytokine production. We further demonstrate that tumor cells additionally avoid aggravating antigen presenting cells (APCs) by efficiently simulating regular dying cells which following phagocytosis are prevented
from initiating autoinflammatory responses. However, dying tumor cells containing exogenous cytosolic DNA, viral DNA or cyclic di-nucleotides potently activate APCs in trans through extrinsic STING-signaling to generate cytotoxic T lymphocytes (CTLs)
activity. Our data provides an explanation as to how tumor cells avoid triggering immune responses and provides a therapeutic strategy to stimulate anti-tumor immunity.
15:05 POSTER HIGHLIGHT I: Novel Multimers of Bicyclic Peptides Cluster and Activate CD137 (4-1BB): A Costimulatory T -Cell Checkpoint Receptor
Liuhong Chen, PhD, Group Leader, Discovery, Bicycle Therapeutics Ltd
Bicycles represent a new therapeutic class - fully synthetic, constrained bicyclic peptides that combine the drug-like attributes of antibodies, small molecules, and peptides. Panning against CD137 with a hugely diverse library of Bicycles yielded hits
that were affinity matured to ~80nM Kd. These monomeric Bicycles were antagonists of CD137 signaling as they bound at the ligand binding site and competed with the natural homotrimeric ligand CD137L (4-1BBL). Monomeric Bicycles were then coupled chemically
to PEG spacers at different positions and assembled into multimers with different central hub molecules. Multimerization of the Bicycles resulted in a significant increase in affinity and in addition, the multimeric Bicycles elicited a range of activities
in a reporter gene assay. The mono and di-valent Bicycles were inactive whilst trimeric and tetrameric Bicycles gave activations equivalent or superior to soluble CD137L. In vivo profiling of these multimers is in progress. In summary the novel Bicycle
platform enabled the identification and optimisation of the first small molecule, fully synthetic agonists of CD137.
15:35 Networking Refreshment Break (Foyer D)
16:00 HERA: Engineering Next-Generation TNFR-SF Agonists for Cancer Immunotherapy
Oliver Hill, PhD, Vice President, Molecular
Biology/Protein Engineering, Apogenix AG
The HERA technology platform developed by Apogenix is based on trivalent but single-chain molecular mimics of the TNF-SF Receptor binding domains (scTNFSF-RBDs) fused to a dimerization scaffold. Being hexavalent by design, the HERA fusion proteins are
potent TNFR-SF agonists on their own and do not need secondary crosslinking events for their activity. The underlying engineering concept as well as selected in vitro and in vivo data obtained with HERA-CD40L, HERA-CD27L and HERA-GITRL will be presented.
16:30 Agonistic Activation of TNFR-SF Receptors by HexaBody IgG-induced Oligomerization
Rob de Jong, PhD, Assistant Director,
Protein Chemistry & CMC, Genmab BV
17:00 End of Day
17:00 Dinner Short Course Registration* (Foyer C)
17:30 – 20:30 Dinner Short Courses
Recommended Short Course*
SC10: Engineering of Bispecific Antibodies - View Detailed Agenda
Nicolas Fischer, PhD, Head, Research, Novimmune SA
Michela Silacci, PhD, Director, Discovery Research, Covagen AG, part of J&J
By attending this interactive workshop, you will learn about the various approaches used for the engineering of bispecific antibodies and bispecific scaffold-based binding proteins. Different technologies will be compared, and examples for applications
of bispecific antibodies in drug development will be presented with a focus on candidates that are currently being evaluated in clinical trials. Opportunities and challenges as well as current trends in the field of bispecific antibodies will be discussed.
*Separate registration required.
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FRIDAY 16 NOVEMBER
08:00 Registration (Foyer C) and Morning Coffee (Foyer D)
08:30 Chairperson’s Remarks
Rodrigo Vazquez-Lombardi, PhD, PostDoc, Laboratory for Systems and Synthetic Immunology, Department of Biosystems Science and Engineering, ETH Zurich
08:35 KEYNOTE PRESENTATION:
NKTR-214: Cytokine Engineering to Access the IL-2 Pathway
PhD, Senior Vice President, Research, CSO, Nektar Therapeutics
NKTR-214 is a CD-122-biased agonist that targets the IL-2 pathway to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ). NKTR-214 preferentially activates and expands NK and effector CD8+ T cells over T-regulatory
cells in the tumor microenvironment. In addition, NKTR-214 promotes an invigorated immune phenotype and drives cell surface expression of costimulatory molecules, such as ICOS, and coinhibitory receptors, such as PD-1 on the surface of newly proliferating
lymphocytes. The immune replenishing mechanism of action of NKTR-214 makes it an ideal combination partner with multiple immune oncology mechanisms.
09:05 ATOR-1017 – An Agonistic Tumor Directed Fcγ-Receptor Cross Linking Dependent CD137 Antibody
Anna Säll, PhD, Scientist, Alligator
ATOR-1017 is an agonistic CD137 IgG4 antibody with a unique functional profile compared to the 4-1BB antibodies currently in clinical development. The functional activity depends on cross-linking mediated by Fcγ receptors, which directs the
immune activation to the tumor area and reduces the risk of inducing systemic immune activation and liver toxicity. ATOR-1017 is currently in preclinical development and clinical trials will start in the second half of 2019.
09:35 Tumor-Targeted DARPin® Drug Candidates for Tumor-Restricted Immune Cell Co-Activation
PhD, Senior Scientist Lead Generation, Protein Engineering, Molecular Partners AG
Dose-limiting toxicity can hamper effective dosing and combination with checkpoint inhibitors and other immune stimulating drugs. By using the DARPin® toolbox, we have developed a set of multi-specific molecules that enable tumor-restricted immune
cell activation, thereby largely reducing the risk of systemic side effects. Data from the preclinical development of tumor-restricted agonists will be presented on MP0310, a 4-1BB/FAP bispecific DARPin drug candidate promoting T cell expansion
in a strictly FAP-dependent manner. FAP is highly expressed in human tumor stroma cells.
10:05 Networking Coffee Break (Foyer D)
10:35 Multispecific and Multivalent Antibodies as OX40 Agonists
Bryan Glaser, PhD, Vice President, Research, Invenra, Inc.
OX40 agonists have demonstrated significant therapeutic potential in preclinical models; however, their efficacy in clinical trials is minimum. We hypothesize the efficacy in humans is limited by insufficient crosslinking in the tumor microenvironment.
Thus, we aimed for biparatopic antibody to directly crosslink OX40 and successfully developed soluble agonists, which are potent in the absence additional crosslinker. This strategy together with high-throughput bispecific antibody screening is
applicable to agonist discovery for a wide range of receptors.
11:05 What’s Next for GITR and OX40 Agonists?
Patrick Mayes, PhD, Executive
Director, Head of I-O Biotherapeutics, Incyte
A discussion of combination approaches for GITR and OX40 agonist antibodies in cancer. Integration of tumor biomarker analyses in response to agonist antibody treatment to inform upon GITR and OX40 combinations.
11:35 POSTER HIGHLIGHT I: Anti-Tumor Efficacy of Anti-GITR in Preclinical hGITR Model
Kader Thiam, PhD, Vice President, Transgenic Technologies, genOway
We have developed immune-competent mouse model that express ICP humanized protein: Glucocorticoid-induced TNFR family related gene (GITR). Here, using our newly generated humanized GITR (hGITR) mouse model, we show that hGITR expression follows a
pattern similar to mGITR. hGITR is functional ex vivo and in vivo. In particular, in vivo: agonist GITR mAb treatment drastically reduces tumor growth in MB49 bladder tumor model. hGITR model thus provides new opportunities for immune intervention
based on GITR modulation. By enabling the assessment of GITR modulating drug and their mechanisms of action, this model would be of value not only in immuno-oncology, but also as a tool for testing new antagonizing GITR drugs for the treatment
of autoimmune/inflammatory diseases.
11:50 POSTER HIGHLIGHT II: HERA-CD40L: A Unique Hexavalent CD40 Agonist for Cancer Immunotherapy
Katharina Billian-Frey, PhD, Senior Scientist, Drug Discovery, Apogenix AG
The hexavalent HERA-CD40L is a member of a novel class of TNFR superfamily agonists having the natural ligand conformation in common. The biological in vitro and in vivo activities of HERA-CD40L - determined by immune cell activation,
repolarization of M2 macrophages and anti-tumor efficacy in mouse models - demonstrated superiority over other agonistic formats and bivalent antibodies without requiring crosslinking events. Therefore, HERA-CD40L is an excellent candidate for
further development into a next generation CD40 agonistic immuno-oncology drug.
12:05 Problem-Solving Breakout Discussions with a Light Snack (Foyer
Enhancing Tumor Response to Antibodies Moderator: Alison Betof Warner, MD, PhD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center What do recent successes and failures from combination trials teach us about sensitization to checkpoint inhibitors? How can we therapeutically modulate tumor microenvironment to improve success with antibodies? What role do patient selection, stratification, and biomarkers play? Are there strategies to enhance tumor response to antibodies without significantly increasing immune-mediated adverse events?
Agonist Discovery and Human Efficacy
Bryan Glaser, PhD, Vice President, Research, Invenra, Inc.
- How does the desired agonist mechanism of action and target biology impact discovery strategy?
- What is the optimal format (ligand-fusion, Fc-modified, bispecific, etc.) of the final candidate and how is it determined?
- How do we best judge activity using in vitro and in vivo models?
- What is the best way to evaluate agonists that lack mouse cross-reactivity?
13:00 Chairperson’s Remarks
Dafne Muller, PhD, Group Leader, Institute of Cell Biology and Immunology, University of Stuttgart
13:05 CB307, a Novel T-Cell Agonist Humabody Therapeutic for PSMA-Positive Tumours
James Legg, PhD, Vice President, R&D, Crescendo Biologics
13:35 AcTakines: A Novel Class of Cancer Immunotherapeutics
Erik Depla, PhD, Director, Biology,
Type I IFN-derived AcTakines targeting dendritic cells displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without detectable toxic side effects. Combined with
immune checkpoint blockade or chemotherapy, complete tumor regression and long-lasting tumor immunity were observed. Our findings indicate that AcTakines targeted to dendritic cells provide a novel class of highly efficient, safe, and broad-spectrum
14:05 Presentation Cancelled. Revised Schedule below Chemotherapy Combinations to Enhance Tumor Response to Agonist Antibodies Allison
Betof Warner, MD, PhD, Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center Stimulation of glucocorticoid-induced tumor necrosis factor receptor (GITR) has been shown to enhance antitumor immunity by stimulating effector CD4+ and CD8+ T cells and attenuating suppression and depleting by CD4+Foxp3+ regulatory T cells (Treg).
However, GITR monotherapy does not effectively control tumor growth. I will discuss our data showing that cyclophosphamide (CTX), a cytotoxic chemotherapeutic agent with key immunomodulatory properties, can enhance the potency of GITR engagement
anti-tumor effects. 14:35 14:05 Tumor-Targeted Combination of TNFSF Agonists and IL-15 for Cancer Immunotherapy
Dafne Muller, PhD, Group
Leader, Institute of Cell Biology and Immunology, University of Stuttgart
Costimulatory members of the TNF-superfamily and IL-15 have shown great potential to support the generation and development of an antitumor immune response. In order to improve the efficacy of such molecules at the tumor site, we designed different
formats of bi- and trifunctional antibody-fusion proteins, focusing on tumor-targeted presentation and combined mode of action of diverse immunomodulatory molecules, demonstrating enhanced immune responsiveness in vitro and antitumor activity in a mouse model in vivo.
15:05 14:35 Oncorus Oncolytic HSV, a Platform for Combination Immunotherapy
PhD, CSO, Oncorus
Oncorus is developing the next generation HSV-based oncolytic virus with enhanced potency for tumor cell killing and recruitment of the immune system. Our innovative miR-attenuation strategy enables robust viral replication in tumor cells, while
preventing replication in healthy tissue. Oncorus’ oHSV are armed with multiple immunomodulatory payloads to synergistically increase recruitment and effector function of immune cells, thus harnessing the full potential of OVs to evoke
an abscopal immune response.
15:35 15:05 End of Summit
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