Natural killer cells: a thriving frontier in allogeneic cell therapy

kai pinkernell glycostem nk cell therapy

Kai Pinkernell, chief medical officer at Glycostem, discusses how natural killer (NK) cell therapies could usher in off-the-shelf cancer immunotherapies.

Since their first approvals in 2017, chimeric antigen receptor (CAR)-T cell immunotherapies have showcased the potential of immuno-oncology in providing long-lasting treatments for cancer. This impact was felt in not just the CAR-T cell therapy space, but also other forms of cancer cell therapy.

“In the T cell space, a big push to the industry came from CAR-T cell development,” said Kai Pinkernell, chief medical officer at the Dutch cell therapy firm Glycostem. He added that prior to this point, most of the interest was in topics like regenerative medicine, but soon “CAR-T cells kicked it off for the hematology and oncology space.”

However, CAR-T cell therapies have several big drawbacks. One is that they are limited in treating solid tumors, with their main indications being forms of blood cancer. Another is that first-generation therapies are autologous: they require the extraction of the patient’s T cells, which are sent to a central facility, genetically engineered to hunt cancer and reinfused back into the patient. This can cost the patient precious weeks, and some die before the product arrives.

“There is a need within the field to get over the restrictions of the autologous space,” said Pinkernell. 

Pinkernell started his career as a physician interested in cardiovascular cell therapy. He then switched focus to immuno-oncology, with leading roles at Miltenyi Biotech, Medigene and later Glycostem in 2021.

Glycostem is developing cancer cell therapies based on a type of immune cell called NK cells, which are our first line of defense against cells that are cancerous or infected with viruses. 

Glycostem sources its NK cells from donated umbilical cord blood. This donor-based strategy, also known as allogeneic cell therapy, means the therapy can be prepared in advance, making it much faster than autologous CAR-T cell therapies.

“It is definitely an advantage if you can have them off-the-shelf and with T cells, you can’t really do this,” said Pinkernell. To have an allogeneic T cell, for example, you need to genetically modify it to reduce the risk of the infused immune cells attacking the host in a condition called graft-versus-host disease (GVHD). In contrast, NK cells are naturally less likely to cause GVHD, making them easier to provide off-the-shelf.

Pinkernell said that NK cells were a large unknown when Glycostem was founded 15 years ago. “Now there’s an NK cell company opening up every day.”

NK cells are good at hunting cancer cells because they can detect many tumors that have evolved to hide common signals of cancer from T cells. However, some tumors are able to evolve their evasion tactics against NK cells, and the patient’s NK cells can also be caught in the crossfire when the patient receives waves of chemotherapy. 

“NK cells have a half-life of about 10 to 15 days, so you’re constantly rebuilding them,” said Pinkernell. “If you get one chemotherapy after the next, your whole immune system takes a hit. So giving allogeneic NK cells to a cancer patient has some benefit.” 

Traditional NK cell therapies are based on NK or stem cells extracted from a donor’s bloodstream or from umbilical cord blood. NK cell therapies can be given fresh, but to be truly off-the-shelf, Glycostem aims to make NK cell therapies that can be frozen and stored: a process called cryopreservation. 

According to Pinkernell, the process of freezing NK cells is a lot harder than with T cells as many NK cells don’t survive the cryopreservation process. 

“NK cells are much more susceptible to cryopreservation-induced cell death,” explained Pinkernell. “You have to be really careful how you do it and what you use as cryoprotection. It’s something that sets us apart from the field.”

Glyostem’s lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. The trial is expected to be complete early next year. The company is also planning to test the potential of the therapy in solid tumors.

In addition, Glycostem is developing an allogeneic NK cell therapy that is genetically modified with CAR proteins to hunt cancer cells. That way, the therapy blends the antitumor action of CAR-T cell therapies with the innate defenses and allogeneic potential of NK cells.

“If you have a CAR-NK, you have the benefit of the specificity of the CAR,” said Pinkernell. “Bringing our genetically modified cells into the clinic is the really big milestone.”

There’s a lot of activity in the NK cell therapy field with many investors and big pharma companies excited with the potential of NK cells. For example, the Dutch firm Kiadis Pharma was snapped up by Sanofi in 2020. In the last few months, Zelluna Immunotherapy and Neukio Biotherapeutics bagged investments to bankroll the development of NK cell therapies.

There are plenty of challenges in developing NK cell therapies. One major obstacle is adverse conditions in the global market, driven by a range of factors including rising inflation and energy prices.

“The funding landscape has dried up,” Pinkernell explained. “Investors have a huge aversion to risk at the moment so they are hunkering down and waiting for the storm to settle.”

Other headwinds to push through include the relative novelty of cell therapy for the market and regulators, in addition to finding clinical trial centers.

Nonetheless, Pinkernell explained that the NK cell therapy field has been buoyed with promising clinical performances from NK cell therapies. One was promising phase 1 results from a group at the University of Texas MD Anderson Cancer Center in the U.S., which is now working with Takeda to develop NK cell therapies.

Another source of excitement comes from developers of drugs that can activate NK cells against cancer called NK cell engagers. One veteran in the field, Affimed, landed a collaboration deal with Genentech worth up to $5 billion in 2018. Last year, Affimed unveiled interim phase 1/2 results of its engager candidate mixed with an NK cell therapy from MD Anderson. The results showed that all 11 patients with Hodgkin lymphoma receiving the highest dose responded to the treatment.

“By bringing it in closer proximity to the target with this engaging molecule, they had a great response,” said Pinkernell. “I think that opens up quite a different arena.” 

It’s worth bearing in mind that Hodgkin lymphoma is not a solid tumor, so some caution is sensible when judging the potential of NK cell therapies. However, Pinkernell added that the increasing focus on the NK cell field and other forms of immunotherapy will lead to “another logarithmic expansion of knowledge over the next 10 years.”

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