Molecular bridges can make potent NK cell therapies for lymphoma

In the race for new cancer immunotherapy strategies, natural killer (NK) cells have distinguished themselves among their immune cell peers. They contain an arsenal of toxic molecules that can destroy even metastatic cancer cells, and engineered anti-cancer NK cells can be transplanted into a patient without triggering an immune response against the foreign cells.

Engineering and manufacturing a cellular product is challenging, however. “We see what the results of cell therapies are — now let's try to find other assets to do the same thing,” said Eric Vivier, the Chief Scientific Officer of Innate Pharma, a cancer immunotherapy company based in France.

Vivier’s team at Innate Pharma is focusing on an increasingly popular strategy: NK cell engagers. These molecules act on immune cells that are already in the patient to form what Vivier calls “molecular bridges” between the immune cells and their target cells. In doing so, NK engagers preclude the need for an infusion of immune cells. Instead, they harness the immune cells that already exist in the patient.

In a new study published in Science Immunology, Vivier’s team showed that carefully designed, four-pronged engagers can spur NK cells to fight B cell non-Hodgkin lymphoma in animal models (1). Although this cancer type is a popular target for immunotherapy development, Innate Pharma’s results suggest that NK cell engagers could help restore the anti-cancer response in patients who fail to respond to other immunotherapies.

A schematic of an NK cell on the left, a tumor cell on the right, and an NK cell engager between them. — NK cell engagers are molecules that harness the immune cells that already exist in a patient to form “molecular bridges” between the immune cells and their target cells.
CREDIT: Innate Pharma

This work builds on prior work published by the Innate Pharma team. In 2019, they designed an NK cell engager that targeted three molecules: one that identifies the cancer cells and two activating molecules on NK cells called CD16 and NKp46 (2). They built this engager by identifying pieces of monoclonal antibodies that already targeted these molecules and assembling the building blocks into a single molecule. “In a sense, we are gluing NK cells to target cells,” Vivier said. “But at the same time, we are providing activating signals to the NK cells.”

This combination can lead to a more powerful attack targeted at specific cells, said Todd Fehniger, an oncologist at Washington University in St. Louis who was not involved in this work. “It has a greater ability to potentially repair or enhance NK cells in cancer patients that are often dysfunctional,” he said.

Vivier’s team then went one step further, expanding their trispecific engager into a tetraspecific engager that also targeted part of the interleukin-2 (IL-2) cytokine receptor to further activate NK cells without having off-target effects on T cells (3). In the current study, they used this four-pronged engager to rally NK cells to kill malignant B cells in B cell non-Hodgkin lymphoma.

They chose to target the cancer antigen CD20 — a protein found on the surface of B cells. In mouse and non-human primate models, the engager successfully activated NK cells, killed B cells, and didn’t cause serious side effects. Vivier was intrigued to see that the NK cells weren’t limited to killing cancer cells expressing the antigen; they also killed cancer cells lacking CD20.

“I think this is extremely important,” he said. “T cells cannot do that, but NK cells can.”

Fehniger was excited to see these preliminary results in a wide range of cancer models. “What I like about this engager is that it hits some of the big challenges that need to be overcome in NK cell-directed therapies,” he said, referring to both its ability to achieve high affinity and high specificity activation of NK cells through NKp46 and CD16, as well as the proliferation signals triggered by the IL-2 receptor to sustain a robust anti-cancer response.

What I like about this engager is that it hits some of the big challenges that need to be overcome in NK cell directed therapies.
- Todd Fehniger, Washington University in St. Louis

This NK cell engager is already in Phase 1 clinical trials, which Fehniger hopes will provide essential data on its safety and efficacy in humans. For example, he is curious about how the heterogeneity of lymphoma across patients might influence the engagers’ performance. Vivier already has some interesting insights into how these engagers might fare against human lymphomas: When his team tested the engagers in blood from lymphoma patients who had previously received T cell immunotherapies but relapsed, they found that even in these samples, the engagers triggered a strong anti-cancer response. He thinks NK cell engagers could be a useful second-line treatment for patients who fail to achieve remission through T cell immunotherapies.

To Vivier, these engagers are part of a larger platform that Innate Pharma is building: a system for building engagers from monoclonal antibodies that can target any cancer molecules of interest, alongside immune receptors and key NK cell activation receptors. By making the engager platform flexible, he hopes it can even marshal effective NK cell responses against solid tumors, which have long evaded traditional immunotherapies, and autoimmunity. Innate Pharma has many engagers already in the clinical trial pipeline, including some in collaboration with Sanofi.

“Having the flexibility to aim the NK cell activation at different tumor-associated antigens will be a powerful tool to use in different types of malignancies,” Fehniger said. “All of these engagers that use modular designs will have that advantage.”

References