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LMP1 Based Approach to Producing Multi-specific CD4+ CTLs for Cancer Immunotherapy
Dana-Farber
Cell therapy
Oncology
Pre-Clinical
Overview
Epstein-Barr virus (EBV) is a ubiquitous virus, which infects human B cells and epithelial cells and has tumorigenic potential. EBV-infected cells are eradicated by T cells, but afterwards, the virus acquires a dormant state in a small number of B cells, establishing a lifelong latent infection in ~95% of humans. EBV is under constant immune surveillance but can spread from these cells during immunosuppression, resulting in an expansion of infected B cells. The transformation of B cells by EBV is partially dependent on the expression of the latent membrane protein 1 (LMP1). LMP1, however, has a dual role: it on the one hand promotes transformation and on the other hand triggers potent immune surveillance of EBV-infected B cells in vivo. For the latter, LMP1 induces the expression and presentation of tumor-associated antigens (TAAs) along with upregulation of costimulatory ligands, which in turn induces cytotoxic CD4 T cell (CD4 CTL) and CD8 T cell responses; this represents a novel mechanism of infection-induced anti-tumour immunity.
Described is a novel method of cancer immunotherapy strategy that uses the unique immunostimulatory function of LMP1 to generate polyclonal CD4 CTLs with natural T-cell receptors (TCRs) against multiple tumor antigens, including TAAs and neoantigens, in a simple and quick manner. The generation of a wide diversity of T-cell receptors against multiple tumor antigens means that there is no need for antigen identification and can be combined with immune checkpoint blockade therapies. Moreover, the technology can be executed in the form of ACT (LMP1-expressing patient-derived tumor cells may be used to activate/expand T cells in vitro). Efficient generation of anti-tumor CD4 CTLs is a unique feature of this technology since CD4 CTLs have great potential in treating various cancers and would be important to fight cancer cells that escape CD8 killing.
Benefits
• Dana‑Farber’s approach generates CD4 CTLs targeting multiple tumor antigens in a speedy way
• This approach can be used as an ACT for multiple cancers
• CD4 CTLs are superior at in vivo persistence providing long-lasting antitumor immunity
Baochun Zhang, Il-Kyu Choi
US 11369635 B2 (2022.06.28)
Patent Family: US, EP, CN, CA, AU
"Mechanism of EBV inducing anti-tumour immunity and its therapeutic use". Choi, I et al. Nature. 2021 Feb;590(7844):157-162
