Investigators are building on recent advances in genetic engineering to enhance the immune response to cancer. This conference track presents advances with T cell receptor (TCR) engineering for infinity enhancement to tumour antigens, T cells engineered to express chimeric antigen receptors specific for tumour targets (CAR-Ts), bispecifics targeting CD3 on T cells and advances with tumour-infiltrating lymphocytes. Most studies to date are for B cell leukaemias and multiple myeloma but efforts are underway for targeting the less accessible solid tumours.

Case studies include identification and validation of suitable targets, measures to overcome cross reactivity; engineering for enhancement of efficacy; preclinical models, design of clinical studies and clinical data, manufacturing and supply of T cell products, and targeting of solid tumours.

Final Agenda

Monday, 20 March

07:30 Conference Registration and Morning Coffee

08:30 Chairperson’s Opening Remarks

David Gilham, Ph.D., Vice President, Research and Development, Celyad S.A.

KEYNOTE PRESENTATION

08:40 Progress in the Clinic with Tumour Infiltrating Lymphocytes

Robert Hawkins, Ph.D., Professor, Cancer Sciences, Cellular Therapeutics, University of Manchester

This presentation will describe the stimulation of cells with cytokines and means of minimising toxicity, and examine means of enhancing automation and simplifying the process. Results from the clinic will be presented together with a description of how potentially responsive patients were selected. The potential for combining this approach with others such as checkpoint inhibitors will be discussed.

CHIMERIC ANTIGEN RECEPTOR TECHNOLOGY: FOCUS ON SPECIFICITY AND SAFETY

09:10 ErbB-Targeted CAR-T Cell Immunotherapy of Cancer: A Strategy to Maximise the Window of Therapeutic Opportunity

John Maher, M.D., Ph.D., Consultant and Senior Lecturer, Immunology, Cancer Studies, King’s College London

We have developed the T1E28z CAR that targets the extended ErbB network and demonstrates anti-tumour activity in several xenograft tumour models. Although it also engages mouse ErbB receptors, intravenous or intratumoural delivery is non-toxic in SCID Beige mice. By contrast, intraperitoneal administration elicits macrophage-dependent cytokine release syndrome. To de-risk this approach, a Phase I trial employing intra-tumoural delivery has commenced in patients with locally advanced/ recurrent head and neck cancer.

09:40 Increased Specificity Using Boolean Logic Gated CARs for Adoptive T-Cell Therapy

Shaun Cordoba, Ph.D., Research Scientist, Autolus

One large limitation when targeting non-haematological cancers is intolerable “on-target off-tumour” toxicity. With this risk of serious adverse effects, CAR therapy has largely been limited to target antigens exclusively expressed on the cancerous tissue or co-expressed on the cancer and non-essential normal tissues. We will discuss novel approaches used to increase CAR T-cell specificity in the absence of expression restricted antigens. This approach promises to open CAR therapy to numerous cancerous tissues where no appropriate antigen has yet been identified.

10:10 Overcoming CAR-T Toxicity and Manufacturing Challenges Using Non-Viral, mRNA-Mediated Engineering of Fresh Cells
Madhusudan Peshwa, Ph.D., CSO, MaxCyte
CD19-targeted CAR-engineered therapies can result in durable clinical responses, however, can be challenging against solid cancers due to specificity for shared tumor antigens that lead to 'on-target/off-tumor' toxicity. MaxCyte developed a non-viral approach using mRNA CAR-transfected T cells to control toxicity. Early trials demonstrated the safety and anti-tumor activity of this strategy. We explored the feasibility of using mRNA CAR transfection of freshly isolated PBMCs for clinical scale manufacturing to reduce ex vivo cell handling.

10:40 Coffee Break in the Exhibit Hall with Poster Viewing

CAR Ts: ENHANCED EFFICACY AND MULTIPLE TARGETING

11:20 B Cell Maturation Antigen (BCMA) CAR-T Cells for Patients with Multiple Myeloma

Katherine J. Seidl, Ph.D., Director, Immunotherapy, bluebird bio

B cell maturation antigen (BCMA) is expressed on most multiple myeloma (MM) cells. We developed lentiviral vectors expressing chimeric antigen receptors (CARs) with anti-BCMA single chain variable fragment (scFv) using 4-1BB and CD3zeta T cell signaling domains. We selected anti-BCMA CAR (bb2121) for clinical development. Ex vivo culture of bb2121 T cells with a PI3K inhibitor leads to enhanced efficacy in vivo and thus represents an attractive option for next-generation CAR-T cell products.

11:50 Exploiting NK Receptors for Adoptive T (CAR T) Cell Therapy

David Gilham, Ph.D., Vice President, Research & Development, Celyad S.A.

The early phase clinical success reported with CD19 Chimeric Antigen Receptor (CAR) T cell therapy has driven a surge of interest in the exploitation of CARs for therapy beyond B cell malignancies. CARs typically exploit antibody based targeting technology ensuring a high degree of specificity for a single tumour antigen. This specificity is attractive but also limits the range of tumours that may be targeted by a single receptor. CARs exploiting natural receptors such as the natural killer group 2D (NKG2D) which target 8 different ligands provides an extension of the CAR approach that enables a broader spectrum of tumour targeting by a single receptor. The NKR-2 receptor is a fusion of the NKG2D receptor with CD3z and in pre-clinical models effectively challenges established haematological and solid tumours. These concepts will be discussed along with an outline of the early clinical development of NKR-2 cell therapy.

12:20 Session Break

NEXT GENERATION CAR-T CELLS / PRODUCTION STRATEGIES

14:15 Chairperson’s Remarks

John Maher, M.D., Ph.D., Consultant and Senior Lecturer, Immunology, Cancer Studies, King’s College London

14:20 Of CARs and TRUCKs: The Next Generation of CAR-T Cell Therapy

Hinrich Abken, Ph.D., Professor & Head, Research, Molecular Medicine, University of Cologne

Cancer cells which lack the cognate antigen are invisible to CAR-T cells and thus may contribute to deadly tumour relapses. We discuss the fourth generation of CAR-T cells, so called TRUCKs, which release inducible IL-12 upon CAR engagement in the targeted tumour lesion. Locally accumulating IL-12 in turn attracts an innate immune cell response towards those cancer cells that are invisible to CAR T cells. The strategy combines antigen-redirected immunotherapy with an antigen-independent anti-tumour response.

14:50 Managing Risk in a Multiproduct Manufacturing Facility

Ryan Guest, Ph.D., MRSB, Cellular Therapeutics Ltd.

Cell and Gene therapy is an extremely exciting field with decades of academic proof of principle now demonstrating high impact patient benefit, especially in the Oncology T cell space. This has now lead a drive to transfer these treatments & technologies from largely non-profit institutions to commercially viable marketed medicines. Ultimately, the route to success is through clearly understanding and managing the risks while maintaining the key quality critical attributes that make these products efficacious.

15:20 Refreshment Break in the Exhibit Hall with Poster Viewing

GENETIC ENGINEERING OF T CELLS

16:00 Cancer Therapy with Engineered T Cells

Hans Stauss, M.D., Ph.D., Professor and Director, Immunity & Transplantation, University College London

Immunotherapy has transformed cancer treatment in the past years by achieving clinical responses in patients who have failed all available conventional therapies. T cells can specifically recognise target antigens that are either present on the surface of cancer cells or expressed intracellularly. The purpose of this presentation is to review the genetic engineering technologies that have been developed to produce therapeutic T cells for antigen-specific immunotherapy of cancer.

16:30 Genetically-Engineered T Cells for Cancer Treatment

Chiara Bonini, Ph.D., Università Vita-Salute San Raffaele and Ospedale San Raffaele, Milan

This presentation will outline the unique gene transfer and gene editing technology that we use together with the identification of cell surface and intracellular target antigens. This approach removes the original TCRs from the T cell and thereby enhances efficacy and reduces the risk of toxicity of adoptive cellular immunotherapy. Results and future perspectives will be presented and discussed.

17:00 Problem Solving Roundtable Discussions

Table 1: Immune Cell Engagers: Targeted Treatment in Synergy with Additional Immunotherapies

Moderator: Martin Treder, Ph.D., CSO, Affimed

Table 2: Enhancement of Specificity and Efficacy of CAR-T Cells

Moderator: Katherine Seidl, Ph.D., Director, Immunotherapy, bluebird bio

Table 3: How the Industry Can Benefit from Tumour-Infiltrating Lymphocyte Technology

Moderator: Andrew Sewell, Ph.D., Distinguished Research Professor and Wellcome Trust Senior Investigator, Infection & Immunity, Cardiff University School of Medicine 

Table 4: Preclinical Models for Safety Assessment of Immunotherapies

Moderator: David Gilham, Ph.D., Vice President, Research & Development, Celyad S.A.

Table 5: T-Cell Product Manufacturing Challenges to Anticipate

Moderator: Ryan Guest, Ph.D., MRSB, Cellular Therapeutics Ltd.

18:00 Welcome Reception with Exhibit and Poster Viewing

19:00 End of Day One of Novel Approaches for Cancer

Tuesday, 21 March

08:30 Chairperson’s Remarks

Kerry Chester, Ph.D., Professor, UCL Cancer Institute

TCRs, TILs AND MORE CAR Ts

08:35 Utilising in vitro Preclinical Packages for Assessment of TCR-Based Bispecific Biologics: Experience, Application and Predictability

Dan Blat, Ph.D., Senior Scientist & Manager, Pre-Clinical Biology Immunocore Ltd.

TCRs can recognise peptides derived from intracellular proteins, presented by Class I MHC on the surface of target cells, thus offering a unique advantage over current antibody therapies. Such peptides are short, 2D in nature and typically human specific. Therefore traditional in vivo models are unsuitable for safety assessments. Immunocore’s in vitro preclinical approach to this challenge will be discussed including the predictability of this method, along with potential challenges.

FEATURED RESENTATION

09:05 Crystal Ball Gazing: What Successful Tumour Infiltrating Lymphocyte Therapy Teaches Us About the Future of T-Cell Therapy? 

Andrew Sewell, Ph.D., Distinguished Research Professor and Wellcome Trust Senior Investigator, Infection and Immunity, Cardiff University School of Medicine

Treatment of end stage end-stage metastatic melanoma with tumour infiltrating lymphocyte (TIL) therapy currently results in a complete, lasting remission in >20% of patients with a partial remission and disease steadying in a further third of patients. We have dissected the T-cell responses to tumour from patient cures and made some unexpected findings that might indicate how and why this therapy is sometimes successful.

09:35Engineering 2nd Generation SPEAR™-T cells to Overcome TGF-β-Mediated Immunosuppression for Adoptive Cell Therapy

Jo Brewer, Ph.D., Head, Platform Science, Adaptimmune

Adoptive Cell therapy with NY-ESO SPEAR-T cells, is showing promising initial clinical responses in clinical trials for solid and liquid tumors. However, the depth and durability of responses may be affected by inhibitory cytokines such as Transforming Growth Factor-β (TGF-β). We investigated whether SPEAR-T cells engineered to express a dominant negative TGF-β receptor (dnTGFβRII) were resistant to the inhibitory effects of TGF-β in vitro.

10:05 Panel Discussion: Pros and Cons of the Different Approaches: CAR Ts, Modified TCRs and TILs

Panelists:
Kerry Chester, Ph.D., Professor, UCL Cancer Institute

Ryan Guest, Ph.D., MRSB, Cellular Therapeutics Ltd.

John Maher, M.D., Ph.D., Consultant and Senior Lecturer, Immunology, Cancer Studies, King’s College London

Andrew Sewell, Ph.D., Distinguished Research Professor and Wellcome Trust Senior Investigator, Infection and Immunity, Cardiff University School of Medicine

Jo Brewer, Ph.D., Head, Platform Science, Adaptimmune

• Relative limitations and strengths of these approaches
• Challenges with specificity and off-site toxicity
• Potential for attacking solid tumours
• Can these approaches be automated and simplified
• Possibilities for non-personalised therapies
• Preclinical and clinical challenges to anticipate

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:10 Preclinical Evaluation of an Optimal-Affinity MAGE-A4 T Cell Receptor for Adoptive T Cell therapy

Andrew ‘Jez’ Gerry, Ph.D., Director, Preclinical Research, Adaptimmune

MAGE-A4 is an attractive target antigen for adoptive T cell therapy using enhanced affinity TCRs. To ensure the safety of novel T cell receptor therapies, it is important both that expression of the target antigen is tightly restricted to tumour, and that the TCR does not display off-target activity. We have generated and characterised an optimal enhanced-affinity TCR, with enhanced potency against MAGE-A4-positive tumour targets whilst maintaining specificity. An IND is open for trials in multiple tumour indications.

BISPECIFICS FOR NK- AND T-CELL ENGAGEMENT

11:40 Engaging Innate and Adaptive Immunity to Fight Cancer

Martin Treder, Ph.D., CSO, Affimed

Bispecific immune cell engagers developed through Affimed’s proprietary antibody platform are well differentiated not only through their bivalent, high avidity binding and specificity, but also due to their lack of competition with circulating IgGs, resulting in significantly stronger activation and modulation of NK or T cells. Preclinical experiments for Affimed’s lead candidate, AFM13, a prototypic NK-cell engager currently in Phase II clinical development, have demonstrated synergistic efficacy of AFM13 in combination with checkpoint modulators such as anti-PD-1 antibodies, resulting in activation of both innate and adaptive immunity.

12:10 Mechanistic Mathematical Model for Bispecific Antibody Interaction with Cellular Targets: The Role and Importance of Lateral Diffusion on the Cell Membrane

Armin Sepp, Ph.D., Senior Scientific Investigator, Systems Modeling and Translational Biology, GlaxoSmithKline

Bispecific antibodies can specifically bind to the cells expressing two different membrane-bound target antigens even when the average distance between them exceeds the reach of the Fab arms of the mAb. This can be understood from first principles as the cross-linking of targets afforded through their lateral diffusion in cell membrane bilayer. The model can be used to devise the optimal affinities for a bispecific mAb.

12:40 End of Novel Approaches for Cancer