oNKo-innate: Connecting memory-like NK cells with CD16-based engagers to improve immune cell therapy for cancer immunotherapy
Researchers have started pairing engagers with NK cells to get the most from both therapies. Last year, Rezvani and her colleagues reported their findings on a CD16-based engager made by Affimed, a pharmaceutical firm in Mannheim, Germany, in combination with cord-blood-derived memory-like NK cells. The trial tested different levels of cells in people with blood cancer, most of which had undergone at least seven lines of therapy. Of the 36 people who were given the highest dose of NK cells plus the engager, 72% experienced complete remission13.
Nicholas Huntington, a cancer Immunology researcher at Monash University inMelbourne, Australia, says that the tumour microenvironment is challenging to operate in. “We’re looking at ways of improving their metabolism, fitness and function so we can restore some of that innate natural killing ability.” oNKo-innate is focused on finding targets for small molecule drugs that could enhance NK-cell function. One of its drug candidates, for example, enhances NK-cell and T-cell sensitivity to IL-15.
Innate Pharma has also designed a suite of molecules called engagers, which simultaneously activate immune cells and bring them into close proximity to their targets by binding known tumour antigens. Engagers that bind T-cell receptors are already in clinical use, but they carry a high risk of cytokine release syndrome. NK-cell engagers pose a safer alternative that could still ignite anti-cancer immunity. There is a new region in the tri-specific engager that stimulates CD16 on NK cells, but not on Treg cells. It was difficult for immunotherapy to work with mouse studies showing the impact of the engager.
The work and wait is well worth it for Bachanova, because she has seen a few of the side effects associated with T-cell therapies disappear over the years. She says that the patients feel good. You can see that. It is powerful.
The researchers are studying whether memory-like NK cells, like stem-cell transplants, can be combined with a therapy for patients with acute myeloid leukemia. In experiments in which the NK cells came from the same donor, the cells multiplied 1,000-fold and lasted for at least 2 months9. His team is detailing how the characteristics of memory-like NK cells are distinguished using tools such as mass cytometry which can measure dozens of important factors in millions of cells at a time. Fehniger is the co-founding member of the St Louis based company, which obtained a licence for the memory-like NK-cell protocol. Wugen is now testing its own cryopreserved off-the-shelf NK-cell product in people with AML and some solid tumours.
The study also revealed important variables about the cell source that affected NK-cell activity. People who had the best outcomes were recipients of cells from umbilical- cord blood that were frozen within 24 hours of collection, and lacked nucleated red blood cells, an indicator of physical stress. The one-year survival rate was 70% for those who received cells from the optimal cord blood units. 5% was the amount of cord blood that did not meet the standards. “The minute we came up with this, we went and changed all of our protocols,” Rezvani says — now she uses only optimal cord blood.
CAR-T therapy requires the extraction of an individual’s own T cells and a two-to-four week wait for the cells to be engineered. After the cells are injected back into individuals, at least one-third of recipients develop cytokine release syndrome, in which a rush of inflammatory molecules causes fever, low blood pressure and other symptoms requiring hospitalization. It’s life threatening for about one-quarter to develop neurotoxicity. All of this makes the price of therapy high — around US$400,000 — and limits it to people who are able to withstand the side effects.
In January, 37 people who had been through failed treatments for blood cancer received infusions of genetically enhanced immune cells that they hoped would clear their disease. The concept was not new — therapies based on T cells have been approved since 2017. The source of the cells was obvious.
Ten million people a year are killed by cancer. According to one study, this disease, in all its many forms, will cost the world a whopping 25 trillion international dollars — an artificial currency used to compare economies — over the next 30 years (S. Chen et al. The results of the JAMA Oncol. 9, 465–472 are available. More than 50 years after the US declaration of a war on cancer, many hoped that the disease would be closer to defeat than these statistics suggest. The side effects and uncertain outcomes of radiation, surgery and chemotherapy can be hard to ignore when you are diagnosed with cancer. New treatments for cancer are needed to turn the tide decisively — and they are rapidly arriving.
The results are impressive because of the combination of therapy and diagnostics. It is proposed to send radioactive particles into the body to identify and locate cancer, then follow that with different types of radiation that can kill cancer cells. Artificial intelligence can be used to work out which therapy is best for an individual. It might be time to rethink the clinical trial system so people don’t lose out on the most effective treatments.
We are very grateful for the grant funding from MSD as well as the financial support from Pfizer. Nature has sole responsibility for all editorial content.
