1/1/2024 0 Comments Safest cue splitterThis critical downside has prompted the search for combinations of antigens (present or absent) as well as non-antigenic cues, which could define new targetable tumor-specific signatures. However, the vast majority of CAR antigens expressed on solid tumors or cellular components of the tumor microenvironment (TME) that are presently investigated are expressed by vital nontumor tissues ( 7– 11) and their targeting poses a severe safety concern. Chimeric antigen receptors redirect T, and other immune killer cells to recognize antigens in an MHC-independent manner and are thus ideally suited for this purpose. Ready-to-use, donor-derived T/NK cells genetically reprogrammed to recognize a given type of cancer will vastly accelerate treatment and assure quality and quantity of the cell product ( 4). In adoptive cell therapy (ACT) of cancer, great effort is made to develop off-the-shelf genes, designed for redirecting autologous T or NK cells to selectively eradicate tumor cells while avoiding on-target off-tumor attack ( 1– 3). This review focuses on attempts to define the targetable signatures of tumors and assesses different strategies employing advanced synthetic biology for translating such information into safer modes of immunotherapy, implementing the principles of Boolean logic gates. Additional cues, antigenic or non-antigenic ones, which characterize the tumor microenvironment, could be harnessed to further increase precision. Moreover, the expression of a shared tumor antigen along with the lack of a second antigen that is expressed by normal tissues can also be exploited for precise recognition. Recent studies suggest that this risk could be obviated by targeting instead combinations of two or more antigens, which are co-expressed by tumor but not normal cells and, as such, are tumor-specific. Almost all antigens that are currently explored as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR)-T cell therapy are also expressed by healthy cells and the risk of on-target off-tumor toxicity has remained a major concern. Although the quest for widely shared, strictly tumor-specific antigens has been the focus of tremendous effort, only few such candidates have been implicated. The identification of antigens, which are expressed by a large fraction of tumors of a given type and, preferably, across various types, but not by normal cells, holds the key to developing safe, off-the-shelf immunotherapies. Targeting solid tumors with absolute precision is a long-standing challenge in cancer immunotherapy. 2Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel.1Laboratory of Immunology, MIGAL - Galilee Research Institute, Kiryat Shmona, Israel.Mohammed Azharuddin Savanur 1,2, Hadas Weinstein-Marom 1,2 and Gideon Gross 1,2*
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