6:36 PM
Jun 07, 2018
 |  BC Innovations  |  Tools & Techniques

NK cell check-in

How new NK cell targets could lead to more powerful checkpoint inhibitors

Until recently, there’s been scarce overlap between the NK cell field and the world of checkpoint inhibitors, with the former focused on cell therapies to kill tumor cells directly and the latter on relieving immune suppression of T cells. But a new class of checkpoint inhibitors is growing that sits at the intersection of those fields, with the potential to harness both mechanisms to produce more potent immunotherapies.

Two companies are leading the way, Innate Pharma S.A. and Oxford BioTherapeutics Ltd., building pipelines on the strategy that the intersection of NK cells and checkpoint inhibition can mix the benefits of both.

Companies developing checkpoint inhibitors for cancer have chiefly focused on activation of T cells, because they kill tumor cells in a selective fashion through recognition of tumor antigens. T cells are also long-lived, and remain ready to strike if the tumor antigen shows up again.

NK cells also kill tumors, though they recognize them via a different mechanism. Most commercial activity has centered on using the cells directly as autologous or allogeneic therapies.

However, like T cells, NK cells express checkpoint receptors that tumors use to prevent them from mounting an immune attack.

Most checkpoint proteins on NK cells are enriched on the cell type rather than specific to them, and are also found on T cells.

According to Christian Rohlff, CEO of Oxford BioTherapeutics, finding the targets with the highest expression on NK cells and cytotoxic T cell subsets, and the lowest expression on other types of immune and non-immune cells, could solve two of the biggest problems with current T cell-directed checkpoint therapies: low response rates and toxicity.

“One of the problems with existing checkpoint inhibitors is toxicity,” said Rohlff. “The targets we have like PD-1 are expressed on normal tissues too. The goal now is to activate only CD4+ and CD8+ T cells and NK cells,” he said.

“The goal now is to activate only CD4+ and CD8+ T cells and NK cells.”

Christian Rohlff, Oxford BioTherapeutics

A growing list of NK cell checkpoint receptors is now offering opportunities to find targets with the right balance.

The most advanced inhibitor is Innate Pharma’s monalizumab, a mAb against the NK cell checkpoint protein NKG2A, acquired from Novo Nordisk A/S and now partnered with AstraZeneca plc. NKG2A was one of the first NK cell checkpoints identified, and is an inhibitory receptor that is enriched on NK cells and present on a few other immune cell types including T cells. Monalizumab is in Phase II development for various cancers.

At the American Association for Cancer Research (AACR) meeting in April, Innate presented preclinical data revealing SIGLEC9 as a new NK cell-expressed checkpoint. At the same meeting Oxford BioTherapeutics presented preclinical data on a novel undisclosed NK cell checkpoint receptor-ligand pair it thinks is among the most selective for NK and T cells to date.

The new targets bring the total number of NK cell checkpoints in company pipelines to 13, according to BioCentury’s BCIQ database (see “Targeting Natural Killers”).

Table: Targeting Natural Killers

At least 13 products targeting NK cell receptors and ligands are...

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