Despite tremendous progress in our understanding of cancer biology, the majority of novel anticancer therapies fail in clinical trials, which indicates failure of conventional translational approaches. A major challenge in the development of novel anticancer agents is the design and interpretation of first-in-man trials. The 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 to analyze and translate the results of preclinical studies. In that regard, better in vivo models, coupled with careful translational PK/PD modeling hold the potential to significantly increase the value of preclinical results. Better predictive modeling would hopefully permit more effective evaluation of novel cancer therapeutics, (for example, cancer immunotherapeutics), as well as the more rational design of potent anticancer drug combinations. Cambridge Healthtech Institute’s Fourth Annual Predictive Pre-Clinical Models in Oncology is designed to highlight cutting edge advances in in vivo, in vitro and in silico modeling and to facilitate a discussion about effective translational approaches in cancer research.
Final Agenda
Monday, March 7
10:30 am Conference Program Registration Open
11:50 Chairperson’s Opening Remarks
Arijit Chakravarty, Ph.D., Director, Modeling and Simulation (DMPK), Takeda Pharmaceuticals International Co.
12:00 pm Utilizing Large Scale in vivo Screening with PTX Models Predicts Drug Response in Cancer Patients
Juliet Williams, Ph.D., Head, Oncology Pharmacology Drug Discovery, Novartis Institutes for BioMedical Research
Profiling candidate therapeutics using a limited set of cancer models during preclinical development hinders accurate predictions of clinical efficacy. We established ~1000 patient-derived tumor xenograft models, with comprehensive genomic landscape analyses. Subsequently, we performed population-based in vivo compound screens using a 1x1x1 experimental design to assess the response and resistance of 70 treatments across six indications. We demonstrate both the reproducibility and clinical translatability of this approach and additionally demonstrate examples of PTX superiority over cell-based xenografts in predicting clinical response.
12:30 Visualizing and Interacting with Clinical/Molecular Cancer Big Datasets
Eric C. Holland, M.D., Ph.D., Senior Vice President & Director, Human Biology, Solid Tumor Translational Research, Nancy and Buster Alvord Brain Tumor Center, Fred Hutchinson Cancer Research Center, University of Washington
We are developing computational tools that allow interactive visualization of large datasets of clinical and molecular cancer patients. These tools are able to analyze any tumor type, but are initially created around the TCGA Glioma data as a demonstration dataset. Using this data, groups of structurally similar tumors can be identified, and the clinical outcomes of these groups can be determined. This tool can be used to identify more homogenous populations of patients for clinical trials.
1:00 Session Break
1:15 Luncheon Presentation I: Patient-Derived Tumor Xenografts in Humanized NSG-SGM3 Mice: A New Immuno-Oncology Platform
James G. Keck, Ph.D., Senior Director, Clinical Lab & in vivo Pharmacology Services, The Jackson Laboratory
Humanized mice engrafted with tumors enable in vivo investigation of the interactions between the human immune system and human cancer. We have recently found that humanized NOD-scid IL2Rγnull (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of check-point inhibitors. Next-generation NSG strains include triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSG-SGM3). Here we provide a direct comparison of check-point inhibitors evaluation in NSG and NSG-SGM3 mice engrafted with CD34+ human hematopoietic progenitor cells (HPCs) from the same donor and implanted with PDX tumors.
1:45 Luncheon Presentation II (Sponsorship Opportunity Available)
2:15 Session Break
2:30 Chairperson’s Remarks
Arijit Chakravarty, Ph.D., Director, Modeling and Simulation (DMPK), Takeda Pharmaceuticals International Co.
» 2:40 KEYNOTE PRESENTATION: The Mechanistic Basis of Cancer Immunotherapy
Priti Hegde, Ph.D., Anti-angiogenesis Cancer Immunotherapy Franchises Biomarker Lead, Oncology Biomarkers, Genentech
3:10 Epigenetic Priming for Immunotherapy in Breast Cancer
Pamela N. Munster, M.D., Professor of Medicine; Program Leader, Development Therapeutics; Director, Early Phase Clinical Trials’ Program, Helen Diller Cancer Center, University of California, San Francisco
A break down in immune tumor surveillance plays a crucial role in the development of metastatic cancer. Targeting the programmed death receptor (PD-1) and its ligand (PD-L1) have been major breakthroughs. In breast cancers however, particularly in hormone-driven breast cancer, immune responses are often absent. In reverse-translating clinical findings from the patient to preclinical models we show that epigenetic modulation leads to epigenetic immune priming and enhancement of immune response.
3:40 The Human as the Animal Model: Preclinical and Intra-Clinical Translation in Oncology
Arijit Chakravarty, Ph.D., Director, Modeling and Simulation (DMPK), Takeda Pharmaceuticals International Co.
The challenges of Oncology drug development are legion, and differ subtly from those of other therapeutic areas. On the one hand, disease tissue from patients is readily available for study. On the other hand, the real translational unknown is the toxicity profile. In this presentation, I will make a (contrarian) case for improving the modeling of clinical toxicity data and increasing the reliance on preclinical xenograft efficacy data.
4:10 Advanced PDX Tumor Biology Platforms for Drug Advancement
Neal Goodwin, Vice President, Corporate Research & Development,
Champions Oncology
Collections of PDX models have tested investigational compounds for efficacy predictions, and PDX-based platforms can be used with spontaneous mouse models and GEMMs to discover new therapeutic targets, resistance mechanisms, and biomarker signatures of response. There are, however, limits to their use in clinical trial simulation. Coupled-PDX trials are being advanced - clinical trials are combined with companion PDX studies to help guide follow-on trial design. Matched patient-PDX-directed trials will see PDX models used to screen for experimental drug efficacy, with patients enrolled onto trials based on their PDX drug response.
4:40 Refreshment Break and Transition to Plenary Session
5:00 Plenary Keynote Session
6:00 Grand Opening Reception in the Exhibit Hall with Poster Viewing
7:30 Close of Day
Tuesday, March 8
7:00 am Registration Open and Morning Coffee
8:00 Plenary Keynote Session
9:00 Refreshment Break in the Exhibit Hall with Poster Viewing
10:05 Chairperson’s Remarks
Chad May, Ph.D., Director, Oncology Research Unit, Pfizer
10:15 Preclinical Tumor Models for Evaluating Bispecific Redirected T-Cell Therapeutics
Chad May, Ph.D., Director, Oncology Research Unit, Pfizer
Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T-cell populations via the CD3 complex in the presence of tumors expressing target antigens.
10:45 Assessing ENPP3 as a Renal Cancer Target for Bi-Specific T-Cell Engager (BiTE®) Therapy
Olivier Nolan-Stevaux, Ph.D., Senior Scientist, Oncology Research, Amgen, Inc.
BiTE® therapeutics are single chain antibody constructs harboring two binding moieties: one directed at a tumor antigen and one directed at the CD3e protein, which triggers T-cell mediated cytotoxicity against targeted cancer cells. Here, we will present the development of BiTE® Antibody Constructs recognizing the ENPP3 protein, a target prominently expressed in clear cell Renal Cell Carcinoma, and the assessment of these molecules in vitro and in preclinical models.
11:15 Improved Systemic Responses through the Rational Combination of Immunotherapy with Radiation
James W. Welsh, M.D., Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center
The immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.
11:45 Selected Poster Presentation: Preclinical Development of CXCR4 Antagonist Antibody for Cancer Immunotherapy
Dmitry Poteryaev, Ph.D., Acting CSO, Head of Molecular and Cell Biology Department, IBC Generium, LLC
12:15 pm Session Break
12:25 Luncheon Presentation I: Precision Research Models of Human Immune System and Metabolic Function: Applications in Oncology Drug Discovery
Michael Seiler, Ph.D., Associate Director, Product Management, Taconic Biosciences
The development of animal models to mimic human immune responses is crucial to study the pathophysiology of cancer. We will focus on the current state of immune system engraftment models, the next generation huNOG-EXL which extends the functionality of current systems, and recent advances in immuno-oncology.
12:55 Luncheon Presentation II (Sponsorship Opportunity Available)
1:25 Refreshment Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
Bruce R. Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical School
2:10 Markers, Mechanisms and Treatment of Resistant Cancer
Bruce R. Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical School
Focusing on resistance to taxanes, we have uncovered novel mechanisms of chemoresistance that depend on upregulation of cell surface Prohibitin 1 (PHB1). XIAP levels are upregulated in several human cancers and correlate with decreased survival in patients with non-small cell lung cancer (NSCLC). Our recent results demonstrate that PHB1 promotes resistance to apoptosis by stabilizing the X-linked inhibitor of apoptosis, XIAP. We further find that systemic delivery of nanoparticles carrying siRNA to PHB1 results in restoration of taxane sensitivity in preclinical models of NSCLC.
2:40 Mouse Models for Oncology Drug Development: Translational Tales
Mallika Singh, Ph.D., Director, Oncology Pharmacology, ORIC Pharmaceuticals
3:10 A Complete Workflow for Isolating Pure Tumor Cell Populations from Primary Tissue for Improved Downstream Analyses
Olaf Hardt, Ph.D., Senior Project Manager, Research & Development, Miltenyi Biotec
Both tumor and non-tumor cells exist within the tumor environment. Reliable analyses of tumor cells therefore requires pure cell populations, as contaminating non-tumor cells can affect the results of downstream assays. Depletion of mouse cells from xenograft tumors or stromal cells from human or mouse tumors is simple with our tumor cell isolation workflow.
3:25 A Tissue-Engineered Vascularized Tumor Microenvironment for Preclinical Testing of Anticancer Therapeutics.
Henning Mann, Ph.D., Senior Research Scientist, Research & Development, Nortis, Inc.
Nortis provides microfluidic chips for tissue engineering 3D vascularized tissue microenvironments. Endothelial vessels induced to sprout in response to growth factors create a vascular network that invades tumor tissue. The model will be used to test anticancer therapeutics.
3:40 PANEL DISCUSSION: Modeling and Researching Cancer Drug Resistance
Moderator: Bruce R. Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Department of Surgery, Harvard Medical School
Panelists:
David L. Rimm, M.D., Ph.D., Yale University School of Medicine
Klaus Pantel, M.D., Professor and Founding Director, Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf
Chad May, Ph.D., Director, Oncology Research Unit, Pfizer
What is the best way to study resistance? What are the challenges in translating promising therapeutic interventions to a clinical setting? These seemingly distinct questions are deeply intertwined. This panel discussion will cover these and other practical topics at the interface of basic science and practical applications in cancer.
4:10 St. Patrick’s Day Celebration in the Exhibit Hall with Poster Viewing
5:00 Breakout Discussions in the Exhibit Hall
These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.
Modeling for Preclinical Assessment of Combination Therapy
Olivier Nolan-Stevaux, Ph.D., Senior Scientist, Oncology Research, Amgen, Inc.
• Are in vitro assays useful in predicting clinically efficacious immune therapy combinations?
• Are current syngeneic mouse models adequate to test immune therapy combinations? What are the alternatives?
• Can we predict the toxicity of individual or combined immune therapies using preclinical models?
• Are Cynomolgus studies providing clinically relevant toxicity information?
Reverse Translation and Epigenetic Priming in Immuno-Oncology
Pamela N. Munster, M.D., Professor of Medicine; Program Leader, Development Therapeutics; Director, Early Phase Clinical Trials’ Program, Helen Diller Cancer Center, University of California, San Francisco
• How predictive are so call immunocompetent mouse models?
• Is human the best model for cancer immunotherapy?
• Is it possible to skip preclinical assessment all together?
• Logistics of information exchange between clinical and preclinical scientists
6:00 Close of Day
Wednesday, March 9
7:00 am Registration Open
7:00 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:00 Plenary Keynote Session Panel
10:00 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall
10:50 Chairperson’s Remarks
Anderson Clark, Ph.D., Director, in vivo Pharmacology, Oncology, EMD Serono Research & Development
11:00 Integration of PDX Modeling into Clinical Trials: Biological, Clinical and Statistical Perspectives
Joint Presentation: David Gandara, M.D., Professor of Medicine, Division of Hematology/Oncology, University of California, Davis School of Medicine; Director, Thoracic Oncology Program, Senior Advisor to the Director, UC Davis Comprehensive Cancer Center; Chair, Lung Committee, Southwest Oncology Group (SWOG)
Philip C. Mack, Ph.D., Associate Adjunct Professor, Internal Medicine, Hematology and Oncology, University of California Davis Medical Center
Mary Redman, Ph.D., Lead Statistician, Lung Cancer Committee Southwest Oncology Group, Lead Statistician, Lung Map Trial, Fred Hutchinson Cancer Research Center
12:00 pm The Use of Patient-Derived Xenograft (PDX) Models at EMD Serono: Employing Clinically Relevant Study Design and Analysis
Anderson Clark, Ph.D., Director, in vivo Pharmacology, Oncology, EMD Serono Research & Development
At EMD Serono, data from PDX (patient-derived xenograft) models of cancer are used to make clinical decisions for Phase II. In increasing the predictive value of these animal models, we have addressed questions about what constitutes a preclinical response in relationship to clinical RECIST criteria and what the proper statistical analyses of these models would be, and these outcomes will be presented.
12:30 Session Break
12:40 Luncheon Presentation: Precise Genetically Engineered Swine Models of Cancer
David Largaespada, Ph.D., CSO, Surrogen, Inc.
Over the past decade the technology for engineering swine genome has advanced tremendously. Swine models of cancer have great potential for preclinical safety studies, including efficacy & toxicity testing of pharmaceuticals in genetically prone individuals. We are applying precision genetics to provide swine models that mimic human genetic conditions associated with cancer. We will describe our use of TALENs & CRISPR targeted nucleases to develop novel porcine models of cancer with broad preclinical applications.
1:10 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing
1:50 Chairperson’s Remarks
Byron C. Hann, M.D., Ph.D., Research Scientist and Laboratory Director, Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center
2:00 Modelling Breast Cancer Requires Identification and Correction of a Critical Cell Lineage-Dependent Transduction Bias
Mina J. Bissell, Ph.D., Distinguished Scientist, Life Sciences Division, Lawrence Berkeley National Laboratory
We have developed a number of versatile assays for human cells to study tissue specificity, breast cancer, dormancy and metastases. These assays have been published and I will briefly describe them to you. I will also discuss some very recent work where we have explored the reason behind the lack of normal and malignant epithelial cell lines for drug discovery and signaling.
2:30 Cell Line Genomics in Drug Discovery
Christiaan Klijn, Ph.D., Computational Biology, Genentech
Tumor-derived cell lines have served as vital models to advance our understanding of oncogene function and therapeutic responses. Understanding cell line genomics is critical to the effective and accurate use of cell lines in preclinical studies. I will describe our effort to map the transcriptome of more than 600 cell lines and various preclinical applications of this data.
3:00 Genetic Modeling and Screening of Cancer in Mice Using CRISPR
Sidi Chen, Ph.D., Assistant Professor, Department of Genetics and Systems Biology Institute, Yale Cancer Center and Stem Cell Center, Yale University School of Medicine
3:30 Modeling Checkpoint Blockade Using Heterogeneous Chemically-Induced Carcinomas
Rosemary J. Akhurst, Ph.D., Professor and Director, Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center
The large majority of patients do not benefit from checkpoint blockade agents when used as monotherapies. It is important to identify agents that accentuate response rates and improve overall survival. We present a novel chemically-induced syngeneic carcinoma model that represents the single nucleotide mutation (SNV) spectra found in environmentally induced human cancers, e.g. melanoma and lung cancer. We tested α-PD-1 and α-pan TGFβ mono- and combination therapies and found responses only in tumors with a high SNV load. This model should be useful to study primary and acquired resistance to α-PD-1.
4:00 Session Break
4:10 Chairperson’s Remarks
Byron C. Hann, M.D., Ph.D., Research Scientist and Laboratory Director, Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center
4:15 Co-Clinical Trials of Targeted Therapies in Colorectal Cancer Patients and Patient Derived Xenografts
Joint Presentation: Chloe E. Atreya M.D., Ph.D., Assistant Clinical Professor, Gastrointestinal Oncology Program, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center
Byron C. Hann, M.D., Ph.D., Associate Researcher, Manager of Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center
Patient-derived xenograft (PDX) models share molecular and phenotypic similarity to patient cancer tissue and are presumed to have superior predictive value as a preclinical model. High rates of engraftment, success using needle biopsy starting material, and rapid growth make colorectal cancer (CRC) an ideal model to test this hypothesis. We compare PDX and clinical response to targeted therapeutics, and demonstrate concordance. We conduct co-clinical trials in CRC patients and PDX and aim to use response in PDX to direct selection of experimental agents for CRC patients.
5:15 A Humanized Ossicle-Niche Xenotransplantation Model with Improved Hematopoietic Engraftment
Andreas Reinisch, M.D., Ph.D., Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University
Current xenotransplantation models do not recapitulate human bone marrow (BM) microenvironment components and exhibit limited engraftment of many human hematopoietic malignancies. We developed a xenotransplantation model bearing subcutaneous humanized accessible BM microenvironments formed by in situ differentiation of BM-derived mesenchymal stromal cells. In these humanized microenvironments, we detected extensive engraftment of diverse primary acute myeloid leukemia samples at levels much greater than in unmanipulated mice allowing for the identification of leukemia-initiating cells
5:45 Close of Conference Program