Development of alternative CAR constructs targeted against refractory B-cell malignancies

About this project

<p>Chimeric antigen receptor (CAR) T cell immunotherapy directed against CD19 antigen represents a major advancement in the personalized therapy of highly pretreated patients with B cell malignancies.<br> However, in spite of a very effective initial response, the durability of the treatment is suboptimal. The ALTER CAR project unites three partners with complementary expertise: Medical University of Warsaw,<br> Oslo University Hospital, and the Polish enterprise -Pure Biologics SA, committed to develop alternative CAR-based therapeutic solutions for leukemia and lymphoma patients with poor prognosis.<br> In the first stage of the project, we will employ a combined bioinformatics-transcriptomic-proteomic approach to select new targets for CAR T cells using established tumor cell lines. Chosen antigens will be<br> further validated in primary cells isolated from acute lymphoblastic leukemia and lymphoma patients refractory to standard-of-care treatment. As a result of WP1, we will select 2-4 antigens as candidates for<br> CAR therapy, which in the second stage of the project will be used for designing a panel of CAR constructs. The initially designed CARs will be affinity-optimized and in a subsequent stage of the project<br> validated in pre-clinical settings using well-established in vitro and in vivo models. In a final stage, selected CAR/s will be manufactured as GMP-grade RNA for the first-in-man study. The final product of this<br> proposal will be one or more alternative CARs to be used in the treatment of patients.<br> Overall, the ALTERCAR project provides a unique opportunity to implement CAR T cell technology in Poland and develop alternative CAR T cells with new specificities, which may constitute a significant<br> advancement in CAR therapy. The long-term outcome of the project will be the establishment of a sustainable Polish-Norwegian network for the development and production of CAR-based therapies and other<br> adoptive strategies for clinical studies in various forms of cancer.<br> &nbsp;</p>

Bilateral cooperation results

The project benefited from the CAR development platform of the Norwegian partners who are fully equipped to run a complete pre-clinical assessment of a CAR T cell product. The communication was smooth and all the results were shared. The targets were defined in Warsaw, and depending on the product, the molecular cloning of the CAR was performed in Oslo. The process was completely open. This collaboration led to the definition of two novel therapeutic targets and the isolation of potential therapeutic molecules. All the results are shared between the teams. The results were well defined in the project and we followed our application on the work distribution. When the work required more hands, scientists from Warsaw came to provide support to the Oslo team. Material was also prepared in one site and ship to the other sites. The constant dialogue and the sharing of data has definitely led to wider effects such as the beginning of new collaboration (e.g. solid tumour CAR), the implication of external collaborators located outside Poland or Norway. We have now established a strong collaboration that is beyond ALTERCAR. While we aim at pursuing the development and the eventual clinical launching of ALTERCAR molecules, we are also working on new projects focused on solutions for refractory patients as well as novel CAR molecules targeting solid tumours.

Project partners

• Oslo University Hospital Donor project partner· Norway
• Pure Biologics S.A. Project partner· Poland