Combining two immunotherapy strategies into a single therapy is more effective than either alone in treating certain blood cancers, such as leukemia, according to a new study.
The study was conducted by the researchers at Washington University School of Medicine in St. Louis. It was published online in the journal Blood.
Evidence also suggests that the new approach could be safer than one of the most recent cellular immunotherapies to be approved by the FDA, called CAR-T cell therapy, in which the immune system’s T cells are engineered to target tumor cells.
In the new research, scientists have harnessed the technology used to engineer CAR-T cells and, instead of modifying specialized immune cells called T cells, they have used similar technology to alter different immune cells called natural killer (NK) cells.
The resulting immunotherapy combines the benefits of both strategies and may reduce the side effects that are sometimes seen in CAR-T cell therapy. In some patients, for example, CAR-T cell therapy causes a cytokine storm, a life-threatening overreaction of the immune system.
“Immunotherapies show great promise for cancer therapy, but we need to make them more effective and more safe for more patients. This combined approach builds on the treatment strategy that we developed for leukemia patients using natural killer cells”, said co-senior author Todd A. Fehniger, MD, PhD, a professor of medicine.
“We can supercharge natural killer cells to enhance their ability to attack cancer cells. And at the same time, we can use the genetic engineering approaches of CAR cell therapy to direct the natural killer cells to a tumor target that would normally be overlooked by NK cells. It fundamentally changes the types of cancer that NK cells could be used to treat, both additional blood cancers and potentially solid tumors as well,” Fehniger added.
In past work, Fehniger and his colleagues showed that they could collect a patient’s own NK cells, expose the cells to a specific recipe of chemical signals that prime the cells to attack tumors, and then return the primed cells to patients for therapy.
This chemical exposure is a sort of basic training for the cells, according to the investigators, preparing the NK cells to fight the cancer. When the cells are then returned to the body, they remember their training, so to speak, and are more effective at targeting the tumor cells. Because their training has given the NK cells a memory of what to do when they encounter tumor cells, the researchers dubbed them memory-like NK cells.
In small clinical trials conducted at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, such cells were effective in putting some patients with leukemia into a lasting remission, but they didn’t work for everyone.
Some tumor cells still evaded the memory-like NK cells, despite the cells’ basic training. To help the cells find the tumor cells, so their basic training can kick in and kill the correct target, the researchers modified the memory-like NK cells with the same CAR (chimeric antigen receptor) molecule that is typically used to target T cells to tumor cells. The CAR molecule is flexible and can be modified to direct the cells to different tumor types, depending on the proteins on the surfaces of the cancer cells.
The resulting hybrid cells were more effective in treating mice with leukemia than memory-like NK cells alone, leading to longer survival for mice treated with CAR memory-like NK cells. The researchers also found the therapy to be effective despite the fact that the mice were given relatively low doses of the cells.
“One aspect of this study I find most exciting is how nicely these hybrid NK cells expand in the mice to respond to their tumors. We can provide a tiny dose and see an incredible amount of tumor control. To me, this highlights the potency of these cells, as well as their potential to expand once in the body, which is critical for translating these findings to the clinic,” said co-senior author Melissa Berrien-Elliott, PhD, an instructor in medicine.
Fehniger also pointed out that an advantage of NK cells in general — and for biological reasons that the scientists are still working to understand — NK cells don’t trigger a dangerous immune response or the long-term side effects that T-cell therapy can cause in attacking the patient’s healthy tissues, a condition called graft-versus-host disease.
“In all of the clinical trials exploring any type of NK cells, we don’t see the troublesome side effects of cytokine release syndrome or neurotoxicity that we see with CAR-T cells that can profoundly affect patients,” Fehniger said.
“These side effects can be life-threatening and require intensive care. We’re still working to understand how NK cells are different. But if you can get the benefits of CAR-T cells with few if any of the side effects, that’s a reasonable line of research to pursue. Another benefit of this safer therapy is the potential to give these cells to patients at an earlier stage in their disease, rather than using them as a last resort,” Fehniger added.