WP6 Validation of next-generation EURE-CART cells
Objectives of WP6
- identify new therapeutic targets and generate appropriate CARs
- investigate the combinatorial targeting of two tumour antigens at once
- broadly test and validate our CAR T cell approaches
- validation of new tumour targets and CAR T cells
CS1 is a molecule which is broadly expressed on the surface of multiple myeloma cells. The potency of using CS1 as a therapeutic target has already been shown by antibody-based approaches. In our study, we will validate a new CAR binding to the CS1 surface molecule and will compare its efficiency to that of the CD44v6-specific CAR. Different designs of the CAR molecule structure will be studied to find the most potent CS1-specific receptor. We will create CS1 CAR T cells and test their ability to react to and kill tumour cell lines as well as tumour cells directly derived from multiple myeloma patients. A continuous effort of EURE-CART will also be to identify novel candidate CAR targets and examine their expression on primary tumour cells and normal tissues.Investigation of combinatorial antigen targeting by CARsTo enhance the potency of CAR T cell therapy and put cancer cells under more pressure, tumours could be attacked by two different CARs at the same time. This strategy might confer more rapid and complete tumour eradication and prevent recurrence of disease. Unfortunately, every cancer type shows a different profile of typically expressed surface molecules. Therefore, distinct targeting strategies are required for an optimal attack of AML and MM cells. For AML a combinatorial targeting of the CD44v6 antigen and the Flt-3 molecule by CAR T cells seems to be very promising. For MM the combination of CD44v6 CAR T cells and CS1 CAR T cells could be the favourable strategy. Both CAR combinations will be extensively tested in our lab and the benefit of this strategy in comparison to single antigen targeting will be evaluated. Furthermore, combinatorial antigen targeting could be used to make CAR T cell therapy safer and prevent side effects on healthy tissues. Therefore, the CAR design has to be altered, so that T cells are only activated when they encounter both tumour antigens in combination. This strategy will also be studied at our lab.Evaluation of EURE-CART cells in a “personalised” model We want to find a more precise way to predict the outcome of CAR T cell therapies in patients. Therefore, we are striving to develop a personalised model system, where we test CAR T cells from recruited patients against autologous tumour cells. We will study the rapidity and durability of tumour regression, emergence of tumour relapse/location, and occurrence of antigen loss variants and verify whether the model reflects anti-tumour activity observed in patients. With this strategy we hope to find a tool that will guide further developments in the field of CAR T cell immunotherapy.