A new type of cancer cell therapy could avoid some of the serious side effects commonly associated with CAR-T treatments, and possibly offer an easier path to developing "off-the-shelf" treatments, suggest findings from a small study led by researchers at the MD Anderson Cancer Center in Houston, Texas.

The results, which were published Wednesday in the New England Journal of Medicine, are from just 11 patients. Other factors, such as the use of postremission therapy, limit what conclusions can be drawn about the researchers' approach, which relies on "natural killer" cells rather than the T cells used in cellular drugs like Novartis' Kymriah.

Still, the data offer a glimpse into why Japanese drugmaker Takeda agreed last November to license the CAR NK cell therapy from MD Anderson, part of the company's broader push into cell and gene treatments. Some of the data published Wednesday was previously disclosed by the pharma.

A twist on CAR-T

The success of cancer immunotherapy, of which CAR-T treatments are a major part, has put T cells at the center of a now decade-long research revival in oncology.

But T cells are only one component of the body's immune system, and scientists in academia and in biotech are exploring whether other cellular defenders could be similarly recruited.

Researchers at MD Anderson have turned to natural killer cells, which by design recognize and attack cancers or other invaders. Such cells have been tested as an anti-cancer treatment before, but using genetic engineering to improve their tumor-killing properties, which the MD Anderson team has done, is a newer innovation.

"To my knowledge, this is the largest body of evidence on the use of CAR NK cells in patients with cancer," said Katayoun Rezvani, the study's corresponding author and a professor of stem cell transplantation and cellular therapy at MD Anderson, in an interview.

Using NK cells derived from cord blood, Rezvani and her colleagues engineered the cells to express a receptor for a protein called CD19, commonly found on the surface of B-cell malignancies like leukemia and lymphoma. They also added a gene for interleukin-15 to boost the expansion and persistence of the infused NK cells, which without engineering would typically disappear after about two weeks.

While the CAR-T treatments Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) also target CD19, they are made from a patient's own T cells, which are extracted and then engineered outside the body. The personalized process is time-consuming and laborious, hampering the commercial uptake of both Kymriah and Yescarta.

By using cord blood, Rezvani and her team are pursuing an allogeneic, or "off-the-shelf," approach to cell treatment — something many consider to be the next step for the field.

Initial data look promising. Seven of the 11 treated patients, who had either chronic lymphocytic leukemia or non-Hodgkin lymphoma, responded to treatment, with the cancers of three going into remission. Most notably, none experienced cytokine release syndrome or neurotoxicity, two severe side effects that commonly occur in patients treated with CAR-T therapy.

"The lack of toxicity is very exciting here," wrote Stephan Grupp, an oncologist at Children's Hospital of Philadelphia and a leader in the CAR-T field, in comments emailed to BioPharma Dive. He was not involved with the MD Anderson study.

"We really think that this is something inherent to the biology of the natural killer cells, which means their profile of toxicity is different than that of T cells," Rezvani said.

Study participants did have blood toxicities that researchers associated with the chemotherapy given prior to infusion of the CAR NK cells.

Limiting factors

While positive, the results are limited by several factors which make drawing broader conclusions about the ultimate potential of the treatment difficult.

Five of the seven responding patients received postremission treatment, including stem cell transplants, Rituxan (rituximab) and Revlimid (lenalidomide), so researchers did not assess the duration of response to CAR NK therapy.

Additionally, a fresh CAR NK cell product was manufactured for each patient in this study, rather than using the cord blood to produce multiple therapies as would be envisioned for a true off-the-shelf product.

"I think the potential for this approach to be 'off-the-shelf' is also a little speculative at this time," wrote Grupp.

"We would need to see multiple patients treated from the same expanded product with no HLA matching to know if 'off-the-shelf' is going to be part of the story here," he added, referring to the process by which patients are matched to donor cells.

If cord blood-derived CAR NK cells were able to be given without matching to a patient's HLA genotype, any resulting treatment could be used more widely. Nine patients were partially matched in the MD Anderson study, while the last two were treated without consideration of HLA type.

The MD Anderson researchers plan to continue enrolling patients in the study and are working with Takeda to design a larger, multi-center trial.

The drugmaker is planning to advance the treatment, which it licensed and now calls TAK-007, into pivotal studies in two types of lymphoma and CLL by 2021, with a potential filing for approval in 2023.

"Targeting CD19 was a proof of concept and now that we've demonstrated that this CAR NK approach can work and is safe we want to use this platform to target other types of cancers," said Rezvani, indicating interest in multiple myeloma and acute myeloid leukemia.