As the expression of a
tumor associated
antigen (TAA) is commonly not restricted to
tumor cells, adoptively transferred T cells modified to express a conventional
chimeric antigen receptor (CAR) might not only destroy the
tumor cells but also attack target-positive healthy tissues. Furthermore, CAR T cells in patients with large
tumor bulks will unpredictably proliferate and put the patients at high risk of adverse side effects including
cytokine storms and
tumor lysis syndrome. To overcome these problems, we previously established a modular CAR technology termed UniCAR: UniCAR T cells can repeatedly be turned on and off via dosing of a target module (TM). TMs are bispecific molecules which cross-link UniCAR T cells with target cells. After elimination of the respective TM, UniCAR T cells automatically turn off. Here we describe novel TMs against the disialoganglioside GD2 which is overexpressed in neuroectodermal but also many other
tumors. In the presence of GD2-specific TMs, we see a highly efficient target-specific and -dependent activation of UniCAR T cells, secretion of pro-inflammatory
cytokines, and
tumor cell lysis both in vitro and experimental mice. According to PET-imaging, anti-GD2 TM enrich at the
tumor site and are rapidly eliminated thus fulfilling all prerequisites of a UniCAR TM.