- 新癌症治療法 -
The field of biologic drug development for cancer therapies has been greatly energized by the broad spectrum of innovative approaches and their stunning success. The Novel Therapies for Cancer and Emerging Targets track at PEGS Europe will provide a comprehensive picture of the preclinical and clinical development of novel biotherapeutics against cancer, including bispecific, ADC and immunotherapy approaches. Recent results will be reviewed and analyzed to reveal insights into why some strategies fail while others prove to be successful. New approaches to making immunotherapies safer and more effective will be considered and latest clinical progress will be shared. A session dedicated to emerging targets will be featured.
Day 1 | Day 2
THURSDAY 15 NOVEMBER
13:15 Dessert Break in the Exhibit Hall with Poster Viewing
NEW APPROACHES TO SOLID TUMORS
14:00 Chairperson’s Opening Remarks
Kerry Chester, PhD, Professor, Molecular Medicine, University College London Cancer Institute
14:05 TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis
Daniele Tauriello, PhD, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
We crossed mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. From the resulting tumours, we derived organoids to transplant in syngeneic, immunocompetent mice. Cancers display key hallmarks of human microsatellite-stable colorectal cancers. Inhibition of TGFβ unleashed a potent cytotoxic T-cell response against tumour cells, preventing metastatic initiation in mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1/PD-L1 therapy.
14:35 Developing an ROR1 Bispecific T-Cell Engager for Treatment of Solid Tumors
Amit C. Nathwani, PhD, Professor, Haematology, University College London
We have developed a humanized Bi-Specific T-Cell Engager (BiTE) targeting Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), a cell surface antigen present on a broad range of malignancies, many with significant unmet therapeutic needs. In preclinical studies, the ROR1 BiTE-mediated T cell and tumour antigen-specific cytotoxicity against of a range of histologically distinct, ROR1 expressing solid tumour cell lines at exceedingly low concentrations (0.1ng/mL) and low effector to target ratios. In vivo studies showed that the ROR1-BiTE prevented engraftment of tumour in xenograft murine models and significantly reduced the size of established subcutaneous tumours. To validate its wider therapeutic potential, we next demonstrated significant cytotoxicity against ovarian cancer in an in vitro and in vivo setting and T cell mediated killing. Final preclinical data to support a clinical trial will be presented together the obstacles encountered in the generation of clinical grade ROR1-BiTE, a promising immunotherapy approach.
15:05 Developing an Integrated Summary of Immunogenicity (ISI) to Effectively Manage Regulatory Risks in Product Development
Josefin- Beate Holz, PhD, NDA Associate Clinical Consultant, NDA Group AB
Therapeutic proteins have the potential to induce immunogenicity in humans. Such findings in clinical development would be regarded as an unfavourable effect if they are associated with a negative impact on the benefit-to-risk conclusion. The determination of the immunogenicity potential and its impact is an essential element of the development of a protein therapeutic. The Integrated Summary of Immunogenicity is a highly effective approach that provides regulatory reviewers with all data on immunogenicity for assessment.
15:35 Networking Refreshment Break
NEW APPROACHES TO COMBINATION THERAPY
Horacio G. Nastri, PhD, Senior Director, Antibody Biotherapeutics, Incyte Corpora
16:00 Empirical Determination of Optimal Combination Therapies Targeting Immunological Pathways
Michael Schmidt, PhD, Vice President of Antibody Discovery & Engineering, Compass Therapeutics
At Compass, we combine high-throughput antibody discovery with proprietary platforms for multi-specific generation and screening to empirically determine optimal combinations for drugging immunological pathways. Here, we apply this approach to generate novel combination therapies targeting members of the TNFR superfamily, Nectin/Necl checkpoint pathways, and NK cell activation.
16:30 Novel Therapies for Cancer
Andres A. Gutierrez, MD, PhD, CMO and Executive Vice President, Advaxis Inc.
The approval of checkpoint inhibitor antibodies and CAR-T cells have transformed the way we evaluate and treat cancer patients. Thus, novel biologics are at the center of ongoing clinical research with the aim to further increase the immune responses and anti-tumoral responses, including, vaccines (e.g., peptide-, mRNA-, DNA-based), oncolytic viruses, bacterial vectors (e.g., Lm), TCRs, etc. A high level overview of relevant results with these agents will be presented at this session.
17:00 End of Day
Day 1 | Day 2
17:00 Dinner Short Course Registration*
17:30 – 20:30 Dinner Short Courses
Recommended Short Course*
SC8: Selection, Screening and Engineering for Affinity Reagents
Julia Neugebauer, PhD, Director, MorphoSys AG
Birgit Dreier, PhD, Senior Scientist and Group Leader HT-BSF, Plückthun Lab, University of Zurich
Biologics such as recombinant antibodies and alternative binding scaffolds are routinely used in a wide variety of applications from basic research to clinical indications. This success has led to the development of a vast number of different selection, screening and engineering technologies for these molecules. This short course will give a comprehensive overview on different display technologies as well as screening approaches for the selection of specific binders. In addition, it will discuss engineering strategies including affinity maturation and how to implement these strategies. Classical antibodies and antibody fragments as well as alternative binding scaffolds such as DARPins will be covered.
*Separate registration required.
FRIDAY 16 NOVEMBER
08:00 Registration and Morning Coffee
IMMUNOCYTOKINES: Clinical Applications, Successes to Date and Hurdles to Be Overcome
08:30 Chairperson’s Remarks
Soldano Ferrone, MD, PhD, Division of Surgical Oncology, Surgery, Massachusetts General Hospital, Harvard Medical School
08:35 Clinical Approaches for Immunocytokine Therapy Based on Antibody and Cytokine Modifications
Stephen D. Gillies, PhD, Founder & President & CEO, Provenance Biopharmaceuticals Corp.
Immunocytokines target cytokines with anti-tumor activity to the tumor microenvironment. The earliest immunocytokines to be studied in the clinic were based on human IgG1 with full effector functions that, in some cases, led to dose-dependent toxicities. Later generation immuncytokines had various modifications in structure that eliminated effector functions, modified the bioactivity of the cytokine, or were dosed subcutaneously or intra-tumorally. The pros and cons of these approaches will be discussed.
09:05 Cancer-Targeted IL-12 Controls Human Rhabdomyosarcoma by Senescence Induction and Myogenic Differentiation
Karin Schilbach, PhD, Hematology/Oncology, University Children’s Hospital, Tübingen
Interleukin 12 is the major Th1-polarizing cytokine for innate and adaptive immunity. The antibody-IL-12 fusion protein NHS-IL12 binds histones of necrotic cells. NHS-IL12 therapy of human sarcoma in humanized mice combined with either IL-7 (FcIL-7) or IL-2 (IL-2MAB602) induced massive tumor infiltration and innate and adaptive antitumor immunity, permanently arrested cancer cell proliferation and initiated myogenic differentiation in rhabdomyosarcoma cells. NHS-IL12 significantly improved survival and induced long-term remissions when combined with IL-2.
09:35 Unexpected Effects of Directed Therapy on Immune Recognition of Cancer Cells
Mar Valés-Gómez, PhD, Spanish National Research Council, CSIC; Spanish National Center for Biotechnology
Directed therapies can affect the recognition of tumour cells by Natural Killer cells due to the modulation of NKG2D ligands. These proteins are present in cancer patient sera both as soluble molecules and recruited to extracellular vesicles. NKG2D ligands can be used as markers of tumour progression and we propose that it is important to consider them as a factor contributing to tumour immune response and evasion.
10:05 Networking Coffee Break
NEW STRATEGIES FOR LEAD GENERATION
Soldano Ferrone, MD, PhD, Division of Surgical Oncology, Surgery, Massachusetts General Hospital, Harvard Medical School
10:35 Affinity Modulation of Various Antibodies Using Universal Allosteric Switch Modules
Stefan Duebel, PhD, Professor & Head, iTUBS Innovationsgesellschaft Technical University Braunschweig
Insertion of mutated variants of calmodulin to substitute the linker of scFv fragments allowed to modulate antigen binding affinity of five different antibodies. Regulation was achieved without the need of ion concentration or pH changes, and worked both for VH-VL and VL-VH architecture. We expect that this switch linker design provides a universal allosteric regulation principle which can easily be applied to many different scFv antibodies.
11:05 Recombinant Human B Cell Repertoires Enable Screening for Rare, Specific, and Natively Paired Antibodies
Saravanan Rajan, PhD, Scientist II, Antibody Discovery & Protein Engineering, MedImmune
The human antibody repertoire is increasingly being recognized as a valuable source of therapeutic grade antibodies. However, methods for mining primary antibody-expressing B cells are limited in their ability to rapidly isolate rare and antigen-specific binders. Here we show the encapsulation of two million primary B cells into picoliter-sized droplets, where their cognate V genes are fused in frame to form a library of scFv cassettes. We used this approach to construct natively-paired phage-display libraries from healthy donors and drove selection towards cross-reactive antibodies targeting influenza hemagglutinin. Within four weeks we progressed from B cell isolation to a panel of unique monoclonal antibodies, including seven that displayed broad reactivity to different clinically-relevant influenza hemagglutinin subtypes. Most isolated antibody sequences were not detected by next-generation sequencing of the paired repertoire, illustrating how this method can isolate extremely rare leads not likely found by existing technologies.
11:35 Sponsored Presentation (Opportunity Available)
12:05 Problem-Solving Breakout Discussions with a Light Snack
NEW TARGETS AND STRATEGIES IN IMMUNOTHERAPY
13:00 Chairperson’s Remarks
Mitchell Ho, PhD, Chief, Antibody Therapy Section, Laboratory of Molecular Biology, National Cancer Institute, NIH
13:05 Identification of Functional Antitumor Antibodies from Immunoglobulin Sequence Repertoires of Cancer Patients
Daniel Emerling, PhD, Senior Vice President, Research, Atreca, Inc.
We sequenced over a quarter million natively-paired, immunoglobulin (IgG) heavy and light chains from the activated B cells of patients having effective anti-cancer responses and used both sequence and repertoire feature analyses to select specific IgG’s for recombinant expression and characterization. Remarkably, antibodies from patients across several cancer types bound to non-autologous human-derived tumor tissues at a high rate, consistent with recognition of public tumor antigens. Some antibodies caused regression of, and durable immunity toward, established tumors in mouse cancer models, with activity greater than that of an anti-PD-1 inhibitor, and these have provided leads for early development. This reverse translation approach, starting from effective anti-tumor responses in patients, establishes a discovery strategy for novel cancer therapies and targets.
13:35 Targeting the Intracellular Proteome: Antibodies with T-Cell Receptor-Like Specificity towards the MHC-Peptide Complex
Yoram Reiter, PhD, Professor and Head of the Laboratory of Molecular Immunology, Faculty of Biology, Technion-Israel Institute of Technology
We have generated unique recombinant antibodies that mimic the fine specificity of the T-cell receptor and recognize tumor and viral specific class I peptide-MHC complexes, as well as class II complexes associated with autoimmunity and inflammation. The molecular feature of these molecules/approaches and their in vitro and in vivo activities will be described. The future development of these approaches as new modalities to immunotherapy, bridging antibody and T lymphocyte attack on cancer cells, will be discussed in the context of their development path to clinical trials humans. The use of these novel molecules to study basic questions of tolerance will be described as well, demonstrating the bridge between basic and translational immunological research.
14:05 Targeting p53 in Cancer Using T-Cell Receptor Mimic Antibodies
Demin Li, MBBS, MSc, PhD, University Research Lecturer, Senior Research Fellow, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford
Dysregulated tumour suppressor p53 presents in over half of all malignancies and is an attractive target for immunotherapy. We developed an antibody that recognises a p53-derived peptide presented by human major histocompatibility complex HLA-A*0201. The antibody recognises a wide range of cancers, induces cancer cell death in vitro and delays tumour growth in vivo without any detectable toxicity. Antibodies of such may represent promising new agents for future cancer immunotherapy.
14:35 CAR-Expressing NK-Cell-Based Immunotherapy for Cancer Retargeting
Prof. Dr. Ulrike Köhl, Head of Fraunhofer Institute of Cellular Therapeutics and Immunology (IZI); Director, Institute of Clinical Immunology, University and University Hospital of Leipzig; and Director, Institute of Cellular Therapeutics, GMP Development Unit and Cellular Therapy Centre, Hannover Medical School (MHH)
Based on both our previous clinical phase I/II trials with allogeneic NK cells and our experience in manufacturing of CAR expressing T cells, we are working on CAR expressing NK cells for cancer retargeting as an “off the shelf product”. Results on next generation CAR NK cells to improve cytotoxicity against leukemia and tumors with the possibility to lower side effects will be presented.
15:05 A Novel Multi-Specific Antibody Targeting PD-L1-Overexpressing Cancers that Stimulates Antigen-Committed CD8+ T Cells through Concomitant Engagement of a T Cell Costimulatory Receptor
Stefan Warmuth, PhD, Director CMC, Numab Innovation AG
To maximize potency and improve the safety of ICM combination approaches, we designed a multi-specific molecule bearing two ICM domains that depletes PD-L1-overexpressing cancer cells via selective recruitment and stimulation of tumor-reactive effector T cells in the tumor microenvironment. The multi-specific antibody format potently blocks PD-L1/PD-1 signaling and elicits further T cell activation through its costimulatory domain solely in the presence of cells that overexpress PD-L1.
15:35 End of Summit