Programmed cell death protein 1-based inhibitory chimeric antigen receptor targeting Epidermal growth factor receptor and Receptor tyrosine-protein kinase erbB-4 (PD-1-based HER1/HER4 iCAR)

The PD-1-based inhibitory chimeric antigen receptor (iCAR) targeting HER1 (EGFR) and HER4 is a synthetic biology construct designed to enhance the safety and specificity of CAR-T cell therapies in solid tumors. This system utilizes an 'AND-NOT' logic gate where the engineered T-cell is programmed to attack a tumor-associated antigen via an activating CAR (aCAR) but is simultaneously inhibited if it encounters HER1 or HER4, which are antigens frequently expressed on healthy tissues such as the skin, gut, and heart. The iCAR utilizes the intracellular signaling domains of Programmed cell death protein 1 (PD-1), specifically the immunoreceptor tyrosine-based inhibitory motif (ITIM) and the immunoreceptor tyrosine-based switch motif (ITSM), to deliver a dominant negative signal that overrides the activation signal from the aCAR [1][2]. By recognizing HER1 and HER4 on non-malignant cells, the iCAR prevents 'on-target, off-tumor' toxicity, which remains a major hurdle in the clinical application of adoptive immunotherapy for solid cancers. This approach allows for the targeting of potent tumor antigens that might otherwise be shared with vital organs, effectively expanding the therapeutic window. The success of this strategy depends on the precise expression profiles of the chosen antigens and the kinetic balance between activating and inhibitory signals within the engineered T-cell [3][4]. Sources: [1] Fedorov et al., Science Translational Medicine (2013); [2] Kloss et al., Nature Biotechnology (2013); [3] He et al., Nature Reviews Cancer (2022); [4] Sandberg et al., Journal for ImmunoTherapy of Cancer (2020).

Other names

iCAR-HER1/HER4PD-1-based inhibitory CARHER1/HER4-specific inhibitory CAREGFR/ERBB4-inhibitory CARInhibitory chimeric antigen receptor (iCAR)

The iCAR functions via an AND-NOT logic gate. It consists of an extracellular domain (ECD) that recognizes HER1 (EGFR) or HER4 (ERBB4) and an intracellular signaling domain derived from PD-1 (containing ITIM and ITSM motifs). When the iCAR binds to HER1 or HER4 on healthy tissue, it triggers inhibitory signaling that recruits phosphatases (such as SHP-2) to dephosphorylate the activation signals from a co-expressed activating CAR (aCAR). This dominant-negative signal effectively 'turns off' the T-cell, preventing it from attacking healthy cells while allowing it to remain active against tumor cells that express the target antigen but lack HER1/HER4.