Pre-clinical Development CRISPR Update

EDIT-201: A CRISPR-Cas12a engineered Natural Killer Cell Therapy for Solid Tumours

Editas Medicine (Massachusets, US) is developing EDIT-201, an engineered allogeneic natural killer (NK) cell therapy for the treatment of solid cancers.

EDIT-201 is one of 6 ex vivo CRISPR cell medicines in Editas’ pipeline, and is being developed in collaboration with Sandhill Therapeutics (Texas, US). The collaboration combines Editas’ CRISPR-Cas technology with Sandhill’s BINATE™ production process, a novel universal donor technology to extract, isolate, and expand innate immune cells from the peripheral blood of healthy donors. These cells can then be engineered, e.g., using CRISPR-Cas, and developed as novel off-the-shelf cell therapies for the treatment of solid tumour cancers.

Natural Killer (NK) Cell Therapies

NK cells are a class of potent cytotoxic white blood cells with the ability to rapidly recognise and kill tumour cells. Recognition occurs via the expression of stress ligands or down-regulated self-antigen presentation via loss of major histocompatibility complex class I on tumour cells.

The unique ability to detect immune-evasive tumour cells has made NKs an attractive tool for novel immunotherapies against cancers, and in particular solid tumours. However, challenges exist in trafficking and infiltration of NK cells into tumour sites and their persistence and effectiveness is further hampered by low levels of the IL-15 cytokine (which is critical for NK survival) as well as immunosuppressive conditions within the tumour microenvironment, e.g, abundant transforming growth factor beta (TGF-β).

EDIT-201 Development

EDIT-201 is generated by a CRISPR-Cas12a-mediated double gene knockout in healthy donor-derived NK cells. Cas12a is delivered to donor cells as a ribonucleoprotein complex, which is programmed to disrupt the cytokine-inducible SH2-containing protein (CISH) gene - a negative regulator of IL-15 signalling - as well as the TGF-β receptor II (TGFBR2) gene. These knockouts are hypothesised to result in increased IL15 expression to support NK cell persistence as well as render the NK cells resistant to the suppressive effects of TGF-β.