BiCisCAR Targeting Multiple TAAs Challenges Heterogeneous Expression in NB

Tian M, Cheuk AT, Wei JS, et al. An Optimized Bicistronic Chimeric Antigen Receptor Against GPC2 or CD276 Overcomes Heterogeneous Expression in Neuroblastoma. Journal of Clinical Investigation. 2022; (doi: 10.1172/JCI155621).

Researchers have developed a bicistronic chimeric antigen receptor (BiCisCAR) may overcome immunotherapy treatment barriers in neuroblastoma (NB), which is challenged by the heterogeneous expression of targeted tumor-associated antigens (TAAs). CAR T cell interventions directed at single antigens generally have not been effective in solid tumors with heterogeneous TAA expression, which mediates tumor immune escape. Investigators therefore explored an approach that simultaneously targets multiple antigens. In NB and a number of other pediatric cancers, glypican 2 (GPC2) and CD276 are both overexpressed on the surface of tumor cells, with little to no expression in normal tissues, making them promising targets for immunotherapy. Cytotoxicity assays pinpointed the most effective CAR for each target, and those CARs were then coupled to create the BiCisCAR. Not only did the technique eliminate tumor cells expressing GPC2 or CD276, but it overcame other treatment barriers associated with solid tumors — such as T cell exhaustion and limited T cell persistence. The study authors intend to develop the BiCisCAR as a new adoptive immunotherapeutic for the high-risk NB population and suggest their process may have use for a broad range of other solid tumors.

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