Ask the Experts with Anthony Conway: What are “TCR-NKs”?

While significant progress has been made in the field of cell therapy to treat hematological malignancies, substantial hurdles remain with regard to the provision of widespread and affordable access to these treatments and achieving efficacy in patients with solid tumors.

There are currently 6 FDA-approved chimeric antigen receptor (CAR)-T therapies. These have demonstrated striking efficacy in sensitive individuals across several hematological malignancies. But 90% of cancers are solid tumors, and these continue to remain a significant challenge for cell therapy.

One reason for this is that CAR-T therapies can only target antigens expressed at the tumor cell surface, representing just 10% of the proteome. T-cell receptors (TCRs), on the other hand, are able to access antigens derived from the entire tumor cell proteome by targeting intracellularly processed and subsequently externalized peptides presented in the context of major histocompatibility antigen class 1 (MHC class 1). There are several examples of T-cell therapies engineered to express tumor antigen-specific TCRs (TCR-Ts) that have shown clinical efficacy in solid tumors. The first of these is expected to achieve regulatory approval in the next year or so.

One disadvantage of currently approved CAR-T therapies and potentially soon-to-be-approved TCR-T therapy is that they are autologous, being manufactured from an individual patient’s cells. This results in a manufacturing delay – during which time the patient’s disease may progress – as well as potential manufacturing failure, high cost of goods, a limited ability to safely and efficiently introduce cellular edits, and product heterogeneity, as each manufacturing run is derived from an individual patient.

Natural killer (NK) cell therapy is an emerging therapeutic modality that has demonstrated efficacy, and a safety profile that may be more favorable than that of T-cell therapies. One advantage of NK cells is that they can be administered allogeneically (from a donor who is not the patient) and without the need for gene editing, as they do not express an endogenous TCR and consequently have no risk of graft-versus-host disease (GvHD) – a significant potential issue for allogeneic T cell therapies. This means that they can be manufactured from healthy donor cells to produce potentially hundreds of clinical doses from a single manufacturing run. This substantially lowers the cost of goods and allows for a more homogeneous product.

Replay has partnered with The University of Texas MD Anderson Cancer Center to incorporate Syena, a pioneering TCR-NK cell therapy product company. Led by Katy Rezvani, MD, PhD, the Company is initiating first-in-human TCR-NK cell clinical studies in sarcoma and myeloma that combine the advantages of TCRs with those of NK cells. These first-in-class engineered TCR-NK cell therapies have significant potential to address patients with high unmet medical needs in a safe, effective, scalable, and cost-effective manner.