Chimeric antigen receptor for treatment of T-cell malignancies and HIV-1 cure

Abstract

Chimeric Antigen Receptors (CARs) T cell therapy has achieved great success in the treatment of B-cell malignancies by targeting B-cell specific antigen CD19. However, a similar approach targeting the CD4 molecule for T cell lymphoma has thus far been unrealised. CD4, a cell surface glycoprotein, is highly expressed in the majority of mature T-cell malignancies, and absent in hematopoietic stem cells. Anti-CD4 monoclonal antibodies have been widely assessed for T-cell leukaemia/lymphoma treatment, but yielded limited efficacy, suggesting more potent therapies targeting CD4 are required. Here T cells were transduced with a third-generation CAR specifically targeting CD4 molecule (CART4) via a two-step retroviral system, incorporating with truncated epidermal growth factor receptor (tEGFR) as tracking marker and inducible caspase-9 (iC9) as safety switch. CART4 transduced T cells showed remarkable cytotoxicity against CD4+ T cells in vitro. Those CART4 cells effectively eliminated CD4+ T tumour cell line and primary tumour cells from patients with adult T-cell leukaemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL). In a xenograft model bearing T cell leukaemia cell line, CART4 cells efficiently suppressed tumour progression and prolonged mouse survival, suggesting that CART4 T cells could be a promising strategy for T-cell malignancy. Besides, as CD4 as serves the primary receptor for HIV-1 entry, it was hypothesised that the anti-CD4 CAR could be applied for HIV eradication. By in vitro co-culture assays, CART4 cells effectively eliminated target cells, including CD4+ T cells, dendritic cells (DCs), and macrophages. In vivo test utilizing A humanized mouse model of HIV treatment demonstrated that CART4 cells were superior at expanding upon antigen stimulation, eliminating target cells, and controlling HIV rebound after antiretroviral therapy (ART) interruption. Together, these results support the therapeutic potential of CART4 in patients with T-cell malignancies and HIV-1 infection, respectively.