Development of Novel Chimeric Antigen Receptors (CAR) to treat B-cell malignancies

The application referred to three main objectives.: 1) isolate a pre-clinically validated CAR against novel targets of B-cell lymphomas Here the candidate isolated three different targets that are all in pre-clinical validation, namely two anti-B-cell receptor isoforms (BCR, isoform kappa and lambda) and an anti-glyco-protein (Cd75w). All three targets are relevant to treat B-cell lymphoma. Although an anti-BCR-kappa chain is already tested in the clinic, the two other targets are novel and never previously reported. HH2CAR (Cd75w) and BCR-kappa-CAR have both been tested in animal model and in toxicity studies, meaning that their pre-clinical validation is almost completed. 2) establish a CAR platform that will link the Radium antibody database to the design of CAR The candidate has shown that we were able to identify antibody coding sequences from at least three hybridoma, to design a CAR molecule and test it. He has been deeply involved in the establishment of the development pipeline and even participated to the publication of a CAR manufacturing protocol (https://doi.org/10.1093/abt/tbz007). In addition, he has taken over the completion of the CD37 CAR which is a B-cell lymphoma CAR that was already cloned when he arrived in the lab. He has performed most of the in vitro and the in vivo experiments, which has led to the release of the first Norwegian CAR (PMID: 30979721). He has therefore become one of the most knowledgeable national CAR experts. 3) use this platform and the pre- and clinical practice to expand to other types of cancers We have to date (Feb. 2020) cloned >15 CAR constructs, and are now focusing on solid tumour-specific CAR. The candidate has been collaborating with colleagues on the development of constructs directed against osteosarcoma and colorectal cancer. He has not only been training them on the methods, but also participated in the establishment of validation protocols such as the one introducing 3D-like tumour structures, known as spheroids, which mimics the tumour in vitro (PMID: 30596389). Thus he has extended the knowledge acquired during the first phase of CAR production to solid tumour CAR and will co-author at least 3 papers after the completion of his thesis. Since 2017 FDA has approved 2 CAR products (Tisagenlecleucel for pediatric B-ALL and Axicabtagene ciloleucel for adult refractory/relapsed large B-cell lymphoma) and we have been informed that anti-solid tumour CAR products are on their way to be submitted for approval. CAR therapy is a game changer and has cured patients refractory to several lines of treatment. It is therefore a particularly important period for governments to support immunotherapy and in particular CAR-based research. This project has put Norway ahead of other Scandinavian countries in the development of novel CAR constructs, although our neighbours have tested CARs in the clinic in different trials, very few new CARs if any have been reported. To our knowledge our development pipeline is unique. But not for long, other major immunotherapy centres have started or will soon begin to look for CARs. We have taken advantage of the Radium hospital's long history in cancer antibody development through the work established by S. Funderud in the early '80's. The present project has led to the pre-clinical validation of the first Norwegian CAR, anti-CD37 CAR for the treatment of B-cell lymphoma. Refractory lymphoma patients in Norway have the option to be treated with CD19 CAR and CD37 CAR could become an option for CD19 CAR-refractory patients. We have been approached by other clinics to use this CAR for patients non-eligible for CD19 CAR treatment (because of the CD19 negative phenotype of their malignant cells). Solid tumour CARs are at their infancy and the research community will now increase their effort to develop more CAR-based solutions. We start this race with the advantage of a developed CAR production platform which was partly financed by this application and greatly improved by the supported candidate. Our effort is mainly focused on CAR representing alternative solutions to non-efficient treatments, which is a clear unmet need. For example we are developing an anti-osteosarcoma CAR to which the PhD candidate has contributed substantially. Here, no novel therapies have shown efficiency since the introduction of radiotherapy in the 70s. We therefore hope that the development of such a therapy in a public structure will lead to an affordable drug for these patients.