Abstract
Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from “on-target, off-tumor” recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity. Furthermore, we also discuss the main strategies for improving the safety of HER2 CAR-based cancer therapies.
Highlights
The identification of human tumor-associated antigens (TAAs) recognized by the immune system initiated the field of cancer immunotherapy
A rapidly growing number of clinical trials of Chimeric antigen receptors (CARs) therapy have focused on solid tumors, targeting TAAs including carbonic anhydrase IX (CAIX) [8], folate receptor α (FRα) [9], L1 cell adhesion molecule (L1CAM) [10], mesothelin [11], carcinoembryonic antigen (CEA) [12], diganglioside GD2 [13], interleukin 13 receptor α2 (IL13Rα2) [14], EGFRVIII [15], human epidermal growth factor receptor 2 (HER2) [16], and fibroblast activation protein (FAP) [17]
Exogenous administration of IL-2 and a 5 to 8-fold increased dose of these CAR T cells were required to mediate regression of advanced, well-established 8-day macrometastases. These results suggested that first generation Human epidermal growth factor receptor 2 (HER2) CAR T cells may be suboptimal for persistence and anti-tumor activity because T cells require two signals to become fully activated, and co-stimulation is crucial to the activation, proliferation and efficient immune response of CAR T cells
Summary
The identification of human tumor-associated antigens (TAAs) recognized by the immune system initiated the field of cancer immunotherapy. Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated.
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