Development of novel α-CEA target modules (RevTMs) for the switchable RevCAR system


Development of novel α-CEA target modules (RevTMs) for the switchable RevCAR system

González Soto, K. E.

Cancer is one of the main causes of death and represents a worldwide health problem. Most of the cancer-related deaths are associated with the appearance and progression of a solid tumor. Even though effective conventional treatments exist, they share a common drawback, which is their incapacity to strictly distinguish between malignant and healthy cells. Since it was observed that immune cells are capable to eliminate cancer cells, extensive research has been made to retarget immune cells towards malignant cells without damaging healthy tissue. This type of approach is termed as immunotherapy and involves diverse strategies ranging from the use of Abs to engineered immune cells. One of the most attractive immunotherapeutic strategies is based on the engineering of T cells to express chimeric antigen receptors (CARs), which can recognize specific antigens localized on the surface of cancer cells, leading to an activation of the CAR T cells and a subsequently killing of the malignant cells. Even though CAR technology has shown a strong potential in targeting cancer cells during pre-clinical and clinical studies, numerous clinical trials have also revealed that once they are infused into the patient, the activity of the modified T cells becomes uncontrollable, which represents the main safety problem from the system. For this reason, a novel modular and switchable CAR platform, termed as RevCAR system, was developed in the group of Prof. Bachmann. A crucial element of mentioned system is the design of the RevCAR. In contrast to conventional CARs, RevCARs lack an extracellular binding moiety and comprise only a short peptide epitope instead. Thus, RevCAR T cells are per se inert because they cannot bind to any antigen. Only in the presence of target modules (RevTMs), which bind on the one hand to the peptide epitope of RevCARs and on the other hand simultaneously to tumor targets, RevCAR T cells can be redirected and consequently activated against tumor cells. An attractive tumor-associated antigen (TAA) for the development of immunotherapies is the carcinoembryonic antigen (CEA), because it is highly overexpressed on certain cancer types associated with solid tumor formation, such as breast and lung cancer. In order to show the proof of concept that CEA is an optimal TAA to redirect the RevCAR system, two different formats of RevTMs (scFv- or IgG-based) were produced and tested for their functionality. Here we have shown, that both RevTMs were able to efficiently redirect RevCAR T cells to eliminate CEA-expressing tumor cells in an antigenand epitope-specific as well as TM-dependent manner. Moreover, here, the IgG4-based RevTM worked more efficient than the scFv-based RevTM.

  • Master thesis
    HZDR, 2019

Permalink: https://www.hzdr.de/publications/Publ-30213
Publ.-Id: 30213