The Transferrin Receptor-Directed CAR for the Therapy of Hematologic Malignancies

Abstract

As many patients ultimately relapse after chimeric antigen receptor (CAR) T-cell therapy, identification of alternative targets is currently being evaluated. Substantial research efforts are underway to develop new targets. The transferrin receptor (TfR) is prevalently expressed on rapidly proliferating tumor cells and holds the potential to be the alternative target. In order to investigate the efficacy and challenges of TfR-targeting on the CAR-based therapy strategy, we generated a TfR-specific CAR and established the TfR-CAR–modified T cells. To take the advantage of TfR being widely shared by multiple tumors, TfR-CAR T cells were assessed against several TfR+ hematological malignant cell lines. Data showed that TfR-CAR T cells were powerfully potent in killing all these types of cells in vitro and in killing T-ALL cells in vivo. These findings suggest that TfR could be a universal target to broaden and improve the therapeutic efficacy of CAR T cells and warrant further efforts to use these cells as an alternative CAR T cell product for the therapy of hematological malignancies.

Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins

“…Notably, TfR is overexpressed in proliferating cells in order to satisfy increased demand for iron (Candelaria et al, 2021 ). Overexpression of TfR is seen in human cancers (Sutherland et al, 1981 ), including most breast cancers (Singh et al, 2011 ) and various haematological malignancies (Guo et al, 2021 ). Thus, TfR overexpression has been exploited with a range of therapeutic approaches.…”

“…Thus, TfR overexpression has been exploited with a range of therapeutic approaches. For instance, an anti-TfR antibody has been used for tumour-directed delivery of immunotoxins (Wang et al, 2022 ), and TfR-directed chimeric antigen receptor (CAR) T-cells are effective in mouse models of T-cell acute lymphoblastic leukemia (Guo et al, 2021 ). To determine if PCTD could drive degradation of the reporter TfR construct, we purified from HEK-293F cells a chimeric protein composed of an anti-GFP nanobody (Rothbauer et al, 2008 ) (αGFP) fused to PCTD, termed PCTD-αGFP, and, as a control, we purified αGFP from E. coli .…”

Targeting Myeloma Essential Genes using NOT Gated CAR- T Cells, a computational approach

“…ATP1A1 was not considered further due to the mulApass nature of the protein and having a very small surface area for ScFv binding. The laTer has previously been idenAfied as a potenAal therapeuAc target in haematological malignancies 19 . However, it was clear that both these potenAal targets had extensive expression outside the haematological system (Fig.…”

Application Perspectives of Nanomedicine in Cancer Treatment

“…Intelligent NPs can be based on endogenous signals (including pH, redox and ATP) and exogenous signals (including radiation, magnetic ultrasound), to control or regulate the delivery of CRISPR/Cas9 to specific cells. For example, Wang et al designed a multifunctional NPs modified with pH-sensitive epidermal growth factor receptor targeting and nuclear guide peptides to efficiently deliver CRISPR/Cas9 and epirubicin to the human tongue squamous cell carcinoma SAS cells and SAS tumor mice, providing a pH-responsive co-delivery platform for chemotherapy and CRISPR/Cas (Wang Z. et al, 2021). Another study reported near-infrared light-responsive nanocarriers of CRISPR-Cas9 to inhibit tumor cell proliferation in vitro and in vivo through near-infrared light-activated gene editing (Pan et al, 2019).…”

“…Cancer cells grow rapidly and their demand for iron is greatly increased during DNA synthesis, differentiation and regeneration. Therefore, TfR expression is increased in cancer cells in order to adapt to the increased iron requirement and maintain rapid cell division ( Candelaria et al, 2021 ; Guo et al, 2021 ).…”