2017 Archived Content
Checkpoint inhibitors and adoptive T therapies are now in the clinic with patients showing improved survival rates and tumour shrinkage. Success depends on understanding the immune landscape which leads investigators to combine different approaches. This conference track features recent advances together with inevitable emerging challenges. It presents enhancement of T cell potency and specificity, means of overcoming off-target toxicity and adverse reactions, and includes a session on overcoming resistance to known immunotherapies.
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Recommended Short Course*
SC1: New Directions in Cancer Immunotherapy
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MONDAY 13 NOVEMBER
12:00 Registration
13:40 Welcome from PEGS Europe Team
Christina C. Lingham, Team Lead, PEGS Europe
13:45 Moderator’s Opening Remarks
Marie Kosco-Vilbois, Ph.D., CSO, NovImmune SA
13:50 Safety Considerations for Development of Immune Agonist and Immune Antagonist Biotherapeutics
Rakesh Dixit, Ph.D., DABT, Vice President, Research & Development, and Global Head, Biologics Safety Assessment, MedImmune (A member of AstraZeneca Group)
In this keynote presentation, the challenges of biotherapeutics impacting on the immune response, and the challenges investigators face managing, dose, scheduling, and satisfying the regulatory requirements will be discussed. The checkpoint pathways modulation used for cancer immunotherapy has a natural role in controlling autoimmune diseases such as Type 1 Diabetes and Lupus. Immunotherapies in general, and technologies modifying T cell function and those involving cytokines present dangers of cytokine storm, autoimmune disease, cardiovascular disorders, and additional challenges, especially when used in combination. Strategies to manage and mitigate immune related safety events will be presented.
14:30 Learning What Works from Successful Tumour Infiltrating Lymphocyte Therapy
Andrew Sewell, Ph.D., Professor, Division of Infection and Immunity, Cardiff University School of Medicine
Over 20% of melanoma patients that have been refractory to other treatments undergo complete lasting remission after adoptive cell transfer of tumor-infiltrating lymphocytes (TILs). Dissection of these extraordinary successes by examining the dominant tumor-reactive T-cell clonotypes in the TIL infusion product and patient blood after ‘cure’ has revealed some surprising, exciting new HLA-restricted and non-HLA restricted targets that are expressed by many other tumour types.
15:10 Widening the Therapeutic Index: The Next Generation of Antibody-Drug Conjugates (ADCs)
John M. Lambert, Ph.D., Executive Vice President Emeritus and Distinguished Research Fellow, ImmunoGen, Inc.
ADCs with potent tubulin-acting and DNA-acting agents can be effective anti-cancer agents with good TI. However, not all cell-surface targets have proven susceptible to the development of effective ADCs utilizing the first-generation ADC chemistries. Each element in the ADC design, the antibody, the payload, and the linker (both site of attachment on antibody and payload-release mechanism) are important considerations. Application of the growing “ADC Toolbox” to current and future ADC developments will be discussed.
15:50 Refreshment Break in the Exhibit Hall with Poster Viewing
16:50 Chairperson’s Remarks
Katherine Seidl, Ph.D., Director, Immunotherapy, bluebird bio
16:55 Targeting B Cell Maturation Antigen (BCMA) Positive Multiple Myeloma Cells with CAR-T Cell Therapy
Katherine Seidl, Ph.D., Director, Immunotherapy, bluebird bio
We developed chimeric antigen receptors (CARs) targeting B cell maturation antigen (BCMA) expressed on most multiple myeloma (MM) cells. Lentiviral vectors containing anti-BCMA single chain variable fragment (scFv), 4-1BB, and CD3zeta signaling domains were generated and a lead CAR (bb2121) was selected for clinical development (NCT02658929). Approaches for next-generation CAR-T cell products, such as ex vivo culture with a PI3K inhibitor which enhances in vivo efficacy, will be discussed.
17:25 Characterization of the Specificity of Novel Enhanced-Affinity TCRs – Not All MAGEs Are the Same!
Rachel Abbott, d.Phil., Group Leader, Preclinical Research Adaptimmune Ltd.
Enhanced-affinity optimally engineered T Cell Receptors (TCRs) are showing initial promise for adoptive T cell therapy of both solid and liquid tumors. With this promise also comes responsibility and the risk of on- and/or off-target toxicity, such as those seen in multiple differing adverse events in MAGE-A3 trials. Here I will discuss the issue of cross-reactivity and present a well-defined strategy for defining the specificity of novel TCRs and engineering for defined specificity, using a variety of MAGE family TCRs that we have progressed to open INDs as examples.
17:55 Cancer Biotherapeutics - Affimers: A Novel Scaffold for Biotherapeutics
Amrik Basran, Ph.D., CSO, Avacta Life Sciences
Affimers® are a new protein scaffold with great potential for the generation of biotherapeutics. Based on the protease inhibitor Stefin A, large diverse libraries have been created by engineering in peptide loops into the scaffold backbone. Using phage display, we have identified competitive binders to a range of targets, including the immune check point, PD-L1. We have shown that the scaffold is amenable to being engineered with a range of half-life extension technologies.
18:25 Welcome Reception in the Exhibit Hall with Poster Viewing
19:25 End of Day
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TUESDAY 14 NOVEMBER
07:45 Registration and Morning Coffee
08:30 Chairperson’s Remarks
Andrew Sewell, Ph.D., Professor, Division of Infection and Immunity, Cardiff University School of Medicine
08:35 KEYNOTE PRESENTATION: ErbB-Targeted CAR T-Cell Immunotherapy of Solid Tumours
John Maher, M.D., Ph.D., Consultant and Senior Lecturer, Immunology, Cancer Studies, King’s College London
T4 immunotherapy consists of a CD28+CD3 z-based chimeric antigen receptor (CAR), targeted against the extended ErbB network, and which is co-expressed with an IL-4 responsive chimeric cytokine receptor. Pre-clinical efficacy and safety has been demonstrated in models of head and neck, ovarian, breast cancer and mesothelioma. Phase I clinical evaluation is now ongoing in patients with locally advanced or recurrent head and neck cancer, employing intra-tumoural delivery to minimize toxicity.
09:05 Exploiting Natural Killer Specificity for CAR-T Cell Therapy of Cancer
Peggy Sotiropoulou, Ph.D., Manager, Research and Development, Celyad
Natural Killer cells possess innate capacity to target ‘abnormal’ cells through the recognition of a range of target ligands, many of which are present on tumor cells. Engineering NK receptors into a CAR format and expressing in T cells takes advantage of both NK specificity and T cell effector functionality. This approach will be discussed in the context in the pre-clinical setting and discussion of on-going clinical trials testing this approach.
09:35 Problem-Solving Breakout Discussions (View All Breakout Discussions)
Pathways to Overcome Tumor Micro-Environment Suppression of Immunotherapy Approaches (Focused on Adoptive T Cell Therapy)
Moderator: Katherine J. Seidl, Ph.D., Director, Immunotherapy, bluebird bio
- Difficulties with attacking solid tumors
- The most important immunosuppressive pathways to overcome in the tumor microenvironment
- Which are more effective: adoptive cell intrinsic (i.e. “armed”) cells or adoptive cell extrinsic approaches (i.e. combinations)?
- Will “universal” adoptive cell therapy approaches be necessary to crack the solid tumor nut?
Approaches for Patients Unresponsive to Known Immunotherapy Treatments
Moderator: Mark Cragg, Ph.D., Professor, Experimental Cancer Research, Antibody & Vaccine Group, Cancer Sciences, University of Southampton
- Experiences of non-responsiveness to immunotherapies seen in the clinic
- How tumours develop mechanisms of resistance
- Emerging approaches and targets that may be of benefit
- Integrating small molecules with immunotherapy
- Safety considerations
Challenges with Targeting Immune Checkpoint Inhibitors
Moderators: Frederick Arce Vargas, MD, Ph.D., MRCS, Research Associate, UCL Cancer Institute
And
John Wagstaff, MD, MB ChB, Director, South West Wales Cancer Institute & Professor, Medical Oncology, Swansea University College of Medicine
Preclinical challenges
- Different ways in which the immune response is “checked” in cancer
- Benefits of multiple checkpoint blockade
- In vitro assays for checkpoint inhibition
- Finding appropriate mouse models for proof of concept
Challenges in the clinic
- Safety concerns
- Side effects that can occur and how they are overcome
- How the treatment regimen can depend on the patient, and how patients can be categorized
- Other challenges to anticipate
10:35 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Modern Immunotherapy for Cancer Patients: Trials and Tribulations
John Wagstaff, M.D., MB ChB, Director, South West Wales Cancer Institute & Professor, Medical Oncology, Swansea University College of Medicine
Metastatic melanoma and renal cell carcinoma have a very poor prognosis. Immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1 antibodies produce response rates in the order of 60% with 2-year survival being 64% in patients with melanoma. In renal cancer, the anti-PD1 Antibody nonvolume gave a median survival of 25.6 months as second/third line therapy. These antibodies are active in a wide variety of human cancers. Their use is transforming the lives of cancer patients.
11:45 The Tumoral Immune Landscape and the Design of Immune Modulatory Antibodies
Frederick Arce Vargas, M.D., Ph.D., MRCS, Research Associate, University College London Cancer Institute
Modulation of the anti-tumor immune response with antibodies targeting co-inhibitory and co-stimulatory molecules is a promising strategy in cancer therapy. In some cases, the effectiveness of these antibodies is not limited to receptor activation or blockade and relies on depletion of regulatory T cells (Treg). Characterizing the expression density of these targets in different T cell compartments and the myeloid cells involved in Treg depletion is therefore paramount for the design of the next generation of immune-modulatory antibodies.
12:15 Novel Target Identification and Specificity Screening of Biotherapeutics
Elizabeth Kingsley, Ph.D., Consultant, Retrogenix Limited
Human cell microarray screening enables rapid discovery of primary cell surface receptors and off-targets for a variety of ligands. Case studies will demonstrate successes in identifying novel immunotherapy targets as well as in specificity screening for biotherapeutics, including CAR T cells, to aid safety assessment and support IND submissions.
12:45 Luncheon Presentation: The Use of in vitro Assays to Accelerate Cancer Immunotherapy Development & Reduce the Risk of Unwanted Immunogenicity
Sofie Pattijn, Chief Technology Officer, ImmunXperts
During the last years, significant advancement has been made in the clinical application of cancer immunotherapies. Early evaluation of the effectiveness of candidate therapeutics and combination therapies can be done using mouse models and in vitro bioassays with mouse or human immune cells. The use of customized in vitro assays supports the candidate selection, unwanted immunogenicity screening and functionality testing of new oncology leads.
13:15 Session Break
13:30 Dessert Break in the Exhibit Hall with Poster Viewing
14:00 Chairperson’s Remarks
Peggy Sotiropoulou, Ph.D., Manager, Research and Development, Celyad
14:05 Identification and Development of Antagonist Anti-TIGIT Monoclonal Antibody: In vitro and in vivo Mode of Action
Gregory Driessens, Ph.D., Head, In Vivo Pharmacology, iTeos Therapeutics
TIGIT is a co-inhibitory immune receptor expressed by T and NK cells. iTeos Therapeutics has developed a high affinity anti-TIGIT antagonist antibody cross-reactive to mouse and cynomolgous TIGIT. This antibody increases the effector function of CD8 T cells and inhibits tumor growth as monotherapy and in combination with checkpoint inhibitor. We will present data characterizing the development and mechanism of action of anti-TIGIT antibody in vitro and in vivo.
14:35 MEDI1873: A Potent, Stabilized Hexameric Agonist of Human GITR with Regulatory T-Cell Targeting Potential
Lisa Bamber, Ph.D., Scientist I, ADPE, MedImmune
MEDI1873, a novel hexameric human GITR agonist was optimized through systematic testing. This optimized format exhibits oligomeric heterogeneity and superiority to an anti-GITR antibody, with respect to evoking robust GITR agonism. In vitro testing recapitulates several aspects of GITR targeting described in mice. We have demonstrated that MEDI1873 is a potent T-cell agonist in vivo, reinforcing the potential of targeting the GITR pathway as a therapeutic approach to cancer.
15:05 Use of IL-2 Immunotherapy in Cancer: Efficacy, Resistance, and Combinations
Onur Boyman, M.D., Professor and Chair Immunology University Hospital Zurich, University of Zurich
The recent impact of immune checkpoint inhibitors on advanced cancer has firmly established the importance of tumor immunotherapy. However, current approaches are limited to immunogenic tumors that can acquire adaptive resistance. Interleukin-2 (IL-2) immunotherapy can result in remarkable long-term responses in some cancer patients, however, this approach is limited by its adverse effects. IL-2 complexes overcome these adverse effects and potentiate IL-2 immunotherapy. Data will be presented on efficacy, adaptive resistance, and use in combinations of IL-2 complexes.
15:35 Sponsored Presentation (Opportunity Available)
15:50 AptaAnalyzer™- A New NGS Analysis Tool for Improved Identification of Peptide and Antibody Ligands
Michael Blank, Ph.D., CSO, AptaIT GmbH
AptaAnalyzer™ is an intuitive software tool enabling the improved identification of ligands from biopanning experiments or of B-cell receptors derived from defined stages of the immune system. AptaAnalyzer™ enables archiving of experiments as well as improved identification and optimization of rare but relevant peptide or antibody ligands.
16:05 Refreshment Break in the Exhibit Hall with Poster Viewing
16:45 Development of Anti-APRIL Antibody for Multiple Myeloma Leading up to First-in-Man Studies
John Dulos, Ph.D., Director, Aduro Biotech Europe
Studies with APRIL, a proliferation-induced ligand / TNFSF 13, demonstrate strong selectivity as a marker for multiple myeloma. I will describe the mode of action of the anti-APRIL antibody, a regular humanized antibody, in regulating resistance to chemotherapy and immuno-suppressive activity, and present in vitro and in vivo data, and demonstration of in vivo activity.
17:15 Overcoming Tumour Resistance to Antibody-Mediated Immunotherapy
Mark Cragg, Ph.D., Professor, Experimental Cancer Research, Antibody & Vaccine Group, Cancer Sciences, University of Southampton
Monoclonal antibodies are transforming the way we treat cancer. However, despite their undoubted impact, responses remain variable and require improvement. The focus of our current research is therefore to unravel the principal modes of action of these reagents, identify the ways in which tumours subvert their activities and design strategies to overcome them to improve efficacy. Using lymphoma as a paradigm, I will outline how FcgR modulation is central to the success of these endeavours.
17:45 Cancer Vaccines Inducing High Avidity T Cells and Modified Vaccines Inducing Proinflammatory CD4 T Cells
Lindy Durrant, Ph.D., Professor, Cancer Immunotherapy, University of Nottingham; Joint CEO and CSO, Scancell
High avidity of T cells to epitopes is achieved by focusing the immune response on a small selection of tumour rejection epitopes, encoding them within the antibody CDR region and using the Fc region to target high affinity receptors on DCs in vivo. Clinical studies have shown good tumour clearance in resected patients. This approach combines well with checkpoint inhibition. Vaccines targeted citrullinated epitopes, stimulate killer CD4 T cells without the need for checkpoint inhibition.
18:15 End of Novel Immunotherapy Strategies
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