The selection of appropriate preclinical models based on similarity to human biology and disease genotype and phenotype carries considerable potential to ensure higher predictability of preclinical trials. The design and interpretation of first-in-man
trials remains a major challenge in the development of novel anticancer agents. Key study design elements such as schedule, escalation strategy, targeted patient population, etc. rely heavily on preclinical (usually in vivo) data. This situation
brings into question the predictability of preclinical tumor models, as well as the method of analysis and translation of the results of preclinical studies. It is especially difficult to model for preclinical assessment of cancer immunotherapy, the
most actively developing area in oncology. The need for simulating the response of the immune system adds to the complexity of preclinical models and their applications. Cambridge Healthtech Institute’s Third Annual Preclinical Models for Cancer Immunotherapy and Combinations conference aims to bring together cancer researchers and clinicians in order to initiate knowledge and opinion exchange around predictability of preclinical tumor models, including immunocompetent models, and the strategies for preclinical design
and assessment of cancer immunotherapy and combination therapy.
Final Agenda
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27 November: Single-Cell Analysis
27 November Dinner Course: SC3: The Origins, Optimization and Application of Organ-on-a-Chip Systems
28-29 November: Preclinical Models for Cancer Immunotherapy and Combinations
29-30 November: Translational Biomarkers in Immuno-Oncology
29 November Dinner Course: SC5: Humanized Mouse Models: Technology and Applications in Preclinical Assessment of Cancer Immunotherapy
Wednesday 28 November
7:00 Registration and Morning Coffee
8:20 Welcome Remarks
Marina Filshtinsky, Executive Director, Cambridge Healthtech Institute
8:25 Chairperson’s Remarks
Sara Colombetti, PhD, Head of Oncology Discovery Pharmacology, Roche Innovation Center Zürich
8:30 Immunotherapy Combination: How Can Preclinical Models Guide the Selection of the Best Combo Partner
Sara Colombetti, PhD, Head of Oncology Discovery Pharmacology, Roche Innovation Center Zürich
Preclinical mouse models are key tools to evaluate the activity of cancer immunotherapies. They are instrumental to understanding the mechanism of action of tested compounds, and help with identifying rationale combination partners for best anti-tumor
efficacy. We show here how the Pharmacology Group at the Roche Innovation Center Zurich has been developing over the past years a cutting edge mouse models platform for in vivo profiling of immunotherapies and their
combinations.
9:00 Maximizing Therapeutic Index of the PI3K Inhibitor Alpelisib Using Selective Circadian Timing
Michael Rugaard Jensen, PhD, Director, Head of ONC Discovery Pharmacology
Basel, Novartis Institutes for BioMedical Research
Clinically, the PI3K inhibitor alpelisib (NVP-BYL719) is facing on-target tolerability challenges (hyperglycemia) that limit the dose administered in the morning. As glucose metabolism is highly regulated by circadian rhythms, an integrative circadian-timing
approach was adopted in preclinical models. Using radio-telemetry technology, real time blood glucose levels were recorded in freely moving rats at different dosing regimens. Based on results from these preclinical studies, a clinical treatment schedule
predicted to increase therapeutic index is being explored.
9:30 Check-Point Inhibitors Efficacy Assessment in Immunocompetent Preclinical Models Featuring Human Immune Checkpoints
Kader Thiam, Vice President, Transgenic Technologies, genOway
genOway developed a pipeline of immuno-competent mouse expressing humanized immune check-point for pre-clinical immunotherapies studies (PD-1, VISTA, GITR, SIRPa, OX40, CTLA-4, Tim3...). Validation studies confirmed that humanized targets behave as its
mouse counterpart and models allow in vivo assessment of human ICP targeting compounds.
9:45 The Hollow Fiber Model – Testing Drug Efficacy Against Three Cancer Cell Lines in One Mouse? Yes, We Can!
Bettina Stahnke, PhD, Business Development, ProQinase
Identifying the best tumor model and best drug to proceed with is a challenge for every cancer drug discovery process. The Hollow Fiber Model allows to test a given drug on three cell lines simultaneously in each mouse, providing an economic way to explore
multiple treatment options in short time.
10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Preclinical Modelling of Immune-Oncology Therapies: Challenges and Solutions
Kelli Ryan, PhD, Senior Scientist, Oncology Department, MedImmune
Medimmune is a leading global biologics R&D company with a strong track record of discovering novel immunotherapies for cancer treatment. Over the last several years, we have generated extensive preclinical pharmacology packages to support transition
of multiple drug candidates into clinical phase. Our pipeline includes therapies with diverse mechanisms of action and novel platforms each of which have posed a unique set of in vivo challenges to deliver essential
in vivo pharmacology data for project progression. Presented here will be an overview of some of these challenges and the ways in which we responded to overcome those challenges, including characterization of syngeneic
models, and adaptations of our models and study designs to answer specific pharmacology and mechanistic questions. By doing so, we demonstrate the utility of our approaches to preclinical pharmacology to support project progression despite the increasing
complexity of our drug modalities.
11:15 Combining STING Agonists with an Anti-PD-1 Antibody Results in Marked Anti-Tumor Activity in Poorly Immune-Infiltrated Tumor Models
Samanthi A. Perera, PhD, Associate Principal Scientist, Merck
& Co. Inc.
We synthesized a novel STING agonist that activates both mouse and human STING with higher in vitro potency than cGAMP. The STING agonist was administered to immune-competent mice bearing MC38 syngeneic tumors to monitor
pharmacodynamics, pharmacokinetics and in vivo efficacy. Intratumoral doses provided complete responses in 100% tumors. Tumor models such as CT26 and B16-F10 that are intrinsically resistant to single-agent therapy
with anti-PD-1 antibody also demonstrated long-term tumor regressions.
11:45 Meet the Nanoimager, the Next Generation
Platform for Preclinical Studies
Mariya Georgieva, PhD, Business Development, ONI
Quantitative imaging techniques are powerful tools enhancing the predictability and reliability of pre-clinical models for drug discovery and target validation. ONI crafts desktop-compatible instruments with single-molecule sensitivity allowing for
direct observation and measurement of molecular interactions, cellular dynamics and complex tissue phenotypes.
12:15 Enjoy Lunch on Your Own
13:45 Chairperson’s Remarks
Marc Davies, PhD, CAR Mechanics Laboratory, Research Oncology, Division of Cancer Studies, King’s College London
13:50 Selected Poster Presentation: A Highly Tumor-Specific T Cell Engaging Bispecific Antibody Targeting TA-MUC1 Induces Strong T Cell Infiltration in 3D MCF-7 Tumor Spheroids
Timo Lischke, PhD, Scientist, Preclinical Pharmacology & Cancer Immunology, GLYCOTOPE GmbH
14:00 Selected Poster Presentation: Anti-Tumor Efficacy of Anti-GITR in Preclinical hGITR Model
Kader Thiam, Vice President, Transgenic Technologies, Director Business Development, genOway
14:10 Selected Poster Presentation: New Spontaneous and Carcinogen Induced Mouse Derived Isograft (MDI) Tumor Models for Drug Development of Novel Immune Therapeutic Approaches
Bettina Stahnke, PhD, Business Development, ProQinase
14:20 Generation of Chimeric Antigen Receptor (CAR) T-Cells for Solid Malignancies
Marc Davies, PhD, CAR Mechanics Laboratory, Research Oncology, Division
of Cancer Studies, King’s College London
Despite demonstrating unparalleled responses in the treatment of B-cell and plasma cell malignancies, Chimeric Antigen Receptor (CAR) T-cells have had a more modest response against solid malignancies. This talk will focus on the successful generation
of CAR T-cells against a variety of target antigens expressed in solid malignancies and the translation of one of these CAR into a first-in-man Phase I clinical trial.
14:50 Interactive Breakout Discussion Groups - View Details
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and
active networking.
Preclinical Modeling and Combination Therapy Development: Models and Strategies
Moderators: Sara Colombetti, PhD, Head of Oncology Discovery Pharmacology, Roche Innovation Center Zürich
Michael Rugaard Jensen, PhD, Director, Head of ONC Discovery Pharmacology Basel, Novartis Institutes for BioMedical Research
Next Generation 3D Models and Co-Clinical Trials
Moderator: Christian Schmees, PhD, Head of Tumor Biology, Molecular Biology Department, NMI Natural
and Medical Sciences Institute at the University of Tübingen
- Which approaches can be applied to better mimic in vivo physiology in 3D disease models?
- iPSCs as a reproducible source for macrophages in 3D co-cultures.
- Definition and control of comprehensive, international quality standards for patient-derived 3D models.
- Medical informatics approaches to establish internal and external access points to clinical data and for data integration.
- Application of 3D disease models in precision medicine approaches.
16:00 Refreshment Break in the Exhibit Hall with Poster Viewing
16:45 Patient-Derived 3D Microtumors (PDMs) – A Versatile Platform for Compound Profiling and Efficacy Testing in Precision Oncology
Christian Schmees, PhD, Head of Tumor Biology, Molecular Biology Department,
NMI Natural and Medical Sciences Institute at the University of Tübingen
A significant aspect of personalized cancer treatment is the integration of clinical with molecular data including multi-omics and functional analyses to assess individual signaling perturbations as vulnerabilities to tailored therapy. Patient-derived
ex vivo models enable the implementation of this concept within a clinically relevant time frame. I will introduce our PDM platform co-cultured with autologous tumor-infiltrating lymphocytes (established
for 11 human cancer types), and present data from transcriptomic and proteomic profiling as well as compound testing using chemo- and immunotherapeutics, and small molecules.
17:15 Patient-Derived Organoids: Promises, Hurdles and Potential Clinical Applications
Somaieh Hedayat, Higher Scientific Officer, Centre for Molecular Pathology, The Institute of Cancer Research
Patient-derived organoids (PDOs) have recently emerged as robust preclinical models. We have recently shown that PDOs from metastatic, heavily pretreated, colorectal and gastroesophageal cancer patients mirror the phenotype and the genotype
of their parental biopses and recapitulate clinical responses observed in patients. The combined use of PDOs, PDO-xenotransplants and ex vivo PDO co-cultures has the potential to accelerate drug discovery
and improve patients’ selection in early phase clinical trials.
17:45 CO-PRESENTATION: 3D-3-Culture: A Tool to Unveil Macrophage Plasticity in Tumor Microenvironment
Catarina Brito, PhD, Lab Head, Advanced Cell Models Lab,
Animal Cell Technology Unit, iBET - Instituto de Biologia Experimental e Tecnológica; ITQB-NOVA
Catarina Pinto, Postdoctoral Fellow, Advanced Cell Models
Lab, Animal Cell Technology Unit, iBET - Instituto de Biologia Experimental e Tecnológica; ITQB-NOVA
We have been exploring culture platforms based on alginate microencapsulation and stirred culture systems to develop tools to study macrophage plasticity in response to therapy. In 3D-3-cultures (co-culture of tumor cell spheroids, fibroblasts
and monocytes), features of immunosuppressive cancer microenvironments are recapitulated. We have observed accumulation of cytokines, ECM and metalloproteinases, with infiltration of macrophages in the tumor mass and trans-polarization
into M2-like phenotypes. Challenging of the system with therapeutic compounds induced modulation of the M2-like phenotype.
18:15 Welcome Reception in the Exhibit Hall with Poster Viewing
19:15 Close of Day
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Thursday 29 November
8:00 Registration and Morning Coffee
8:25 Chairperson’s Remarks
Anita Seshire, PhD, Lab Head, Cellular Pharmacology, Translational Innovation Platform Oncology, Merck KGaA
8:30 CRISPR-Based Models in Drug Discovery: Developments, Caveats and Future Perspectives
Danilo Maddalo, PhD, Lab Head, ONC Pharmacology, Novartis
Institutes for BioMedical Research, Novartis Pharma AG
The development and the application of genome editing techniques in vivo has expanded the toolkit of preclinical models to assess drug efficacy and toxicology as well as the effect of compounds on tumour-microenvironment
interaction. Cost- and time-efficient, the talk will give an overview of CRISPR models, how they impacted significantly the workflow of preclinical drug discovery and their limitations and caveats.
9:00 Modelling Pancreatic Cancer Subtypes and Immunosuppressive Tumor Microenvironments by Genome Engineering in Mice
Dieter Saur, Professor of Molecular Biology, Technical University
of Munich
We generated novel PDAC models that permit spatial and temporal control of gene expression and modelling of PDAC subtypes and their respective microenvironments. These tools provide unparalleled access to the native biology of cancer cells
and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets in autochthonous tumours and subtype specific drivers in the immune system.
9:30 Utilization of New Humanized Mouse Models to
Better Understand Emerging Immunomodulation Therapies
James G. Keck, PhD, Senior Director, Innovation
& Product Development, In Vivo Services, The Jackson Laboratory
The JAX® Onco-Hu® platform utilizes humanized mice engrafted with tumors to enable in vivo investigation of the interactions between the human immune system and human cancer. Next generation humanized NSG strains with potential for
immune-oncology research will be presented and will include the NSG-SGM3, which produces human T and myeloid cells, NSG-HLA A2, a transgenic mouse that allows HLA class I autologous studies and the NSG-IL15 transgenic which produces T
and natural killer cells.
10:00 Coffee Break in the Exhibit Hall. Last chance for poster viewing.
10:45 Utilizing 3D Models for Cancer Stem Cell Target Validation and Drug Discovery
Anita Seshire, PhD, Lab Head, Cellular Pharmacology,
Translational Innovation Platform Oncology, Merck KGaA
Tumor spheres are three-dimensional structures that spontaneously form under non-adherent and serum free conditions. Sphere formation is an exclusive function of tumor initiating cells (cancer stem cells). We show how to utilize 3D-spheres
for
in vitro and in vivo models for therapeutic antibody validation.
11:15 Targeting CD47 in Cancer with Bispecifc Antibodies
Krzysztof Masternak, PhD, Head of Biology, Novimmune SA
To evade the immune system, cancer cells hijack CD47, a ubiquitously expressed marker of “self” that healthy cells display to macrophages and DCs to transmit a “don’t eat me” signal. Dual-targeting bispecific
antibodies allow for selective, tumor-directed CD47 blockade, enhancement of antibody directed tumor cell phagocytosis and antigen cross-presentation, and strong anti-tumor responses in vivo.
11:45 Preclinical Characterization of BiTE® Antibody Constructs for the Treatment of Hematological Malignancies
Petra Deegen, Senior Scientist, Nonclinical Safety Sciences
within Comparative Biology & Safety Sciences (CBSS), AMGEN Research (Munich) GmbH
Understanding approaches to validate new BiTE constructs nonclinically are important to lay a robust path to the clinic. This presentation will cover in vitro and in vivo studies supporting clinical development of a BiTE antibody construct for the treatment of multiple myeloma.
12:15 Close of Conference
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