GUARD-IT: Generating Unique Single Domain Antibody-based Chimeric Antigen Receptors for Directed ImmunoTherapy

A challenge in the development of effective CAR-T therapy is the instability of current CAR binding domains, which can limit persistence of CAR-T cells. Persistence is essential for the effectiveness of treatment. In this project, the UMCG is collaborating with Cortalix, a Groningen start-up specialized in single domain antibodies (sdAbs), to identify new stable binders for CAR-T therapy. SdAbs are small, stable and excellent candidates as binders for CAR-T therapy. The project goal is to develop innovative Point-of-Care (PoC) CAR-T cell products for new indications utilizing sdAbs. Hereto, prototype sdAb-CAR constructs will be developed using a new CAR-tailored library and will be validated preclinically at the UMCG, with the aim of selection for near-future clinical production in our academic PoC CAR-T program.

GUARD-IT’s mission is to make PoC therapy of innovative CAR-T prototypes a reality for cancer patients in the Netherlands. Due to long lead times and prohibitive costing of current commercial CAR-Ts, the implementation of PoC CAR-T is expected to strongly contribute to reducing mortality, as sick patients are more rapidly treated, more terminal patients will become eligible for treatment and more indications can be reimbursed. With a clear implementation path through the UMCG PoC CAR-T program, this project is expected to, in the near-future, decrease avoidable mortality.

The GUARD-IT innovations for PoC CAR-T treatment of additional indications and possible future implementation will strongly contribute to sustainable patient care. For instance, the current CD19 PoC CAR-T product costs are estimated at ~€100k/patient, whereas costs for analogous commercial CAR-Ts cost are >€350k/patient. Thus, nationwide implementation in the current indication will save ~€60 million per year. By expanding the indication area for PoC CAR-T therapy, including into orphan indications not interesting for commercial parties, treatment opportunities for new indications can be realistically provided. This project thus has a compelling economic perspective for both UMCG and Cortalix.