The “T-body” approach is based on engineered T cells expressing a chimeric antibody receptor (CAR), which endows them with antibody-type specificity to any pre-defined target antigen. We designed a modular CAR construct enabling the modified, redirected T cells to undergo activation and perform their effector or regulatory function upon encountering their target. Accordingly, the composition of the CAR includes an extracellular recognition domain derived from an antibody single chain variable region fragment (scFv) linked to intracellular domains of various stimulatory and co-stimulatory molecules that dictate the function of the transduced cells. To attain antitumor reactivity, we constructed CARs made of scFv specific to human Her2/neu, CEA and CD24 (a stem cell marker of certain adenocarcinomas, such as pancreatic and colorectal cancers).
To optimize the antitumor effect in therapeutic settings, we tested the efficacy of T bodies on immunodeficient mice bearing human cancer xenografts, and on transgenic mice that spontaneously develop TAA-expressing tumors. T-bodies effectively rejected primary as well as disseminated tumors. Multiple systemic administrations of T-bodies were required for complete elimination of xenografts and of autologous murine tumors. A single intratumoral injection was sufficient to eliminate breast cancer, prostate cancer bone metastases, as well as colorectal and pancreatic cancers. Moreover, we established conditions and a time-window which allow allogeneic T-bodies to serve as universal donors.
Recently, our pioneering studies in murine models were reproduced and applied to pilot trials on end-stage cancer patients. Dramatic complete responses were reported in neuroglioma, chronic lymphocyte leukemia, and acute child and adult B cell lymphoma patients. These trials also identified several severe yet manageable treatment-related side effects, mostly associated with acute ‘cytokine-storm’ and ‘tumor lysis’ syndromes, outcomes of the vigorous antitumor response of the T-bodies, which could rapidly eliminate a large tumor mass. The dynamics of the T-body antitumor effect reflect their innate ability to specifically recognize and reject the tumor, propagate, and further differentiate into memory cells that maintain tumor surveillance.
