Chimeric antigen receptor (CAR) T-cells show remarkable therapeutic effects especially in B-cell derived leukemias and lymphomas. However, clinical translation of such an innovative immunotherapeutic approach in highly heterogeneous hematological malignancies like acute myeloid leukemia (AML) or solid tumors is still challenging due to life-threatening side effects, immune escape and disease relapse. To overcome such major hurdles and to address the unmet need for further improvements in CAR therapy, we have established flexible, switchable and programmable adaptor CAR platform technologies named UniCAR and RevCAR. These modular strategies consist of T-cells engineered with adaptor CARs which are primarily inactive as they are incapable to recognize surface antigens. Universal adaptor CAR T-cells can be flexibly redirected to any tumor antigen and controlled by targeting modules (TMs) cross-linking adaptor CAR T- and tumor cells resulting in tumor cell lysis. As an advancement of UniCARs, RevCARs lack the extracellular antigen-binding moiety reducing the receptor size and facilitating the genetical modification of T-cells with several RevCARs possessing different specificity and functionality. Thus, the RevCAR platform enables combinatorial tumor targeting following Boolean logic gates. So far, we have successfully shown preclinical applicability of the UniCAR and RevCAR approaches to target hematological malignancies as well as solid tumors in a flexible and specific manner using tumor cell lines and patient-derived materials. Remarkably, efficiency and switchability of UniCAR T-cells were even proven for the first time in patients in a clinical phase I study. Furthermore, by targeting of two different tumor antigens, combinatorial OR and AND gate logic targeting according to the rules of Boolean algebra was accomplished using the RevCAR platform. These achievements have a high potential for an improved and personalized tumor immunotherapy.

The cell therapy field is experiencing rapid growth with several treatments receiving recent regulatory approval and a number of therapies currently in clinical testing. Manual processing during manufacturing can result in inconsistencies, contamination, and long throughput times. In addition, during manufacturing scale-up the maintenance of critical quality attributes of the product can be challenging. A modular end-to-end automated workflow provides both flexibility and opportunities to optimize the manufacturing process. Our Gibco™ CTS™ cell therapy devices are being developed to function as either a stand-alone system or integrated into a workflow. As a part of this workflow, the Gibco™ CTS™ DynaCellect™ Magnetic Separation System and single-use kits have been designed for scalable and robust cell processing with the CTS Dynabeads™ platform. The instrument utilizes an integrated magnet-rocker and a fluidics panel for target cell separation and subsequent bead removal in a closed system. Using the Gibco™ CTS™ DynaCellect™ Cell Isolation Kit with CTS Dynabeads, we consistently achieve >90% isolation efficiency of target cells with >95% purity with no effect on cell viability.  Furthermore, automated bead removal using the Gibco™ CTS™ DynaCellect Bead Removal Kit resulted in >85% target cell recovery. DynaCellect is highly scalable allowing up to 1 liter of reaction volume for cell isolation with throughput time of ~100 minutes. Similarly, bead removal is achieved through a continuous flow over the rocker-magnet to ensure rapid processing of volumes suitable for autologous and allogenic workflows. CTS DynaCellect Magnetic Separation System is the newest addition to our growing CTS workflow providing, automation, modularity, flexibility, and scalability of cell therapy manufacturing.

With the increasing complexity of constructing novel methodologies to further improve clinical outcome of immunotherapies, screening methods to quickly identify the best lead candidates is becoming even more essential. It has become evident that merely measuring the affinity between T cell receptors (TCRs) and peptide-MHC complexes will not accurately predict in vitro and in vivo outcome. The same holds true for the affinity of chimeric antigen receptors (CARs) or cell engagers (e.g., bispecific antibodies) to their targets. On the contrary, cell avidity (or overall cellular binding strength) provides a more complete and physiologically relevant picture that reflects the bona fide interaction between T cells and tumor cells. Therefore, this interaction can better predict cellular responses in vitro, and drive better, more informed decisions at earlier stages for drug selection and potentially improve clinical outcome. One of the main obstacles in the process of measuring avidity as being a critical parameter is the lack of fast, specific, and accurate tools to assess cellular avidity. The z-Movi® Cell Avidity Analyzer is a novel and unique instrument for direct measurement of cell–cell interaction strength using acoustic forces. This new technology provides predictive, reproducible, and fast high-throughput results at a single-cell level. Using transgenic TCRs, clinically used CARs, and T cell engagers, we will show that data obtained with the z-Movi Cell Avidity Analyzer correlates strongly with standard in vitro assays and pre-clinical mouse experiments. We will review the simple principles behind the z-Movi and demonstrate the great potential for accelerating the development of cellular immunotherapy against cancer.

BNT211 comprises a chimeric antigen receptor (CAR)-T cell product candidate targeting the tumor specific antigen claudin 6 (CLDN6) and a CAR T Cell-Amplifying RNA Vaccine (CARVac). CARVac mediates expansion of adoptively transferred CAR-T cells, resulting in improved persistence and functionality.

T cell isolation and activation is a cornerstone in manufacturing of T cell-based therapies, and precise control over both these operations is important in the development of the next generation T-cell based therapeutics. This need cannot be fully fulfilled by currently available methods. We would like to present an automated T cell selection system (ATC) as well as a modular activation reagent (Expamers), which addresses current limitations. ATC and Expamers are versatile technologies that are intended for research and clinical use. ATC system allows custom and more refined cell selection of starting material and Expamers enable precise regulation of T cell stimulation duration and provide promise of control over T cell profiles in future products. When combined, both technologies offer the opportunity of higher level of integration and automation that can be easily adopted to different T cell production formats (including short manufacturing and that novel gene editing approaches) and have the potential to increase efficacy of T cell immunotherapeutics.

“Sangamo is genetically re-programming Tregs ex vivo to add a Chimeric Antigen Receptor (CAR), in order to give Tregs the ability to target a specific protein. Our preclinical research shows that CAR-Tregs can inhibit overactive immune cells within the body and have the potential to induce long-term immune tolerance.

We are investigating the use of CAR-Tregs in diseases where an excessive inflammatory or immune reaction is at the root of the disease, such as Crohn’s disease or multiple sclerosis. We aim to develop therapies that can induce and restore immune tolerance to address a wide range of inflammatory and autoimmune diseases, with the potential for long-term remission.

We are also working on additional ex vivo genetic engineering approaches using our proprietary zinc finger nuclease (ZFN) technology to enhance the function of Tregs and bring Treg cell therapy to as many patients as possible.

In this conference, we will be presenting our latest research. The topic with be narrowed down to one or two key development programs closed to the event.”

Metabolism has emerged as a key driver of cell fate and function. There is strong evidence suggesting that metabolic properties of T cells – that is, how T cells sustain bioenergetic demands  – play an essential role in regulating their antitumor function and in dictating the effectiveness of T cell-based  immunotherapies. In this presentation metabolic strategies to improve immunotherapies will be discussed, and the newest Agilent Seahorse tools to bring live cell metabolism analysis to the next level presented. This includes how to expand your cell metabolism analysis to fewer cells and better outcomes; bioenergetic measurements optimized for Biopharma; as well as new applications to characterize and predict T cell activation, fitness, and persistence.

Accelerate the clinic Novel, New Generation Cell Therapies that are safer, more effective and have meaningful impact in diseases beyond oncology

Hear insights into:

• Novel In-Vivo Delivery
• Innovations in Gene, Base, and Prime Editing
• Novel Discovery Platforms
• Overcoming the Hostile Tumor Microenvironment
• Improving Persistence and Durability for greater Clinical Outcomes