‘Off-the-shelf’ NKT cell therapy can overcome ovarian cancer defenses
The experimental approach uses natural killer T-cells to subdue the cancer
A cell-based immunotherapy that’s designed to overcome the defense mechanisms that help ovarian cancer evade treatment was highly effective at killing cancer cells in preclinical experiments.
The treatment was able to kill patient-derived cancer cells grown in a lab and eliminate tumors in mouse models. It was also effective in various circumstances, including in the context of a new diagnosis and disease relapse. The findings will form the foundation of an application to the U.S. Food and Drug Administration to begin a clinical trial.
“This is the culmination of over a decade of work,” Lili Yang, PhD, a professor at the University of California, Los Angeles (UCLA), and one of the study’s senior authors, said in a university news story. “We’re on the verge of clinical development, and I’m genuinely optimistic that this therapy could fundamentally change how we treat ovarian cancer.” The study, “Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells,” was published in Med.
Initial treatment for ovarian cancer, a form of gynecological cancer, usually involves surgery and chemotherapy. This can be effective at first, but the cancer eventually returns for more than 80% of people and often takes a more aggressive and treatment-resistant course than before.
A potential treatment approach is CAR T-cell therapy, which is designed to boost the innate cancer-fighting abilities of immune T-cells. The cells are engineered to express a chimeric antigen receptor (CAR) that recognizes and binds to a protein found at high levels on cancer cell surfaces. When infused into the body, the modified T-cells can target and destroy the tumor cells.
While this class of immunotherapy has proven effective for some forms of blood cancer, it’s only shown limited success against solid tumors. Ovarian cancer in particular is difficult to target with CAR T-cell treatments because the tumors are molecularly diverse and have sophisticated defense mechanisms to avoid the immune system.
“Cancer is like a moving target because it’s constantly changing and adapting,” said Yanruide (Charlie) Li, PhD, a postdoctoral researcher at UCLA and the study’s first author. “The best strategy is to attack from multiple sites simultaneously.”
Capturing a ‘moving target’
The new approach, called CAR-NKT cell therapy, leverages a group of immune cells called invariant natural killer T-cells (NKT) to go after the cancer.
While standard CAR T-cells recognize one specific target, CAR-NKT cells can recognize multiple ovarian cancer molecular markers at once, making it harder for the tumor cells to escape detection and develop new defense mechanisms. The CAR-NKT cells are also designed to better penetrate the cellular barrier that surrounds and protects ovarian tumors from therapeutic invaders.
“These cells are special because they can directly kill cancer cells and also take down the immunosuppressive cells that protect the tumor,” Yang said.
CAR T-cell therapies usually involve collecting a person’s own T-cells, engineering them, and then returning them to their body. That can take several weeks and cost hundreds of thousands of dollars. But NKT cells don’t have to be personalized because of the way they work in the body. As such, CAR-NKT therapies can be mass-produced using donated blood stem cells to create a ready-to-use option that’s more accessible and affordable. A stem cell donation from one person is enough for thousands of treatments, making the cost of each dose around $5,000.
“Our vision is to make CAR-NKT cells available as an off-the-shelf therapy at hospitals in the U.S. and worldwide,” Yang said. “Instead of weeks-long delays for custom manufacturing, doctors could prescribe and access these cells immediately when patients need them most.”
Success in different disease contexts
The scientists profiled tumor cells from ovarian cancer patients to inform the development of a CAR-NKT therapy, then tested its ability to kill the cancer as part of lab studies.
The treatment successfully killed the tumor cells in every case, regardless of whether they came from a newly diagnosed person or someone who’d relapsed after treatment. The approach was more effective than traditional CAR T-cell therapies.
CAR-NKT therapy also showed better anti-tumor efficacy than CAR T-cells in mouse models, including models of low and high tumor burden and relapsed disease. It was also safe, leading to lower rates of certain serious side effects that are common with CAR T-cell therapy.
“When I see these results, I know we’re getting closer to offering patients like mine a more effective and permanent solution,” said Sanaz Memarzadeh, MD, PhD, a gynecologic oncologist and professor at UCLA, and one of the study’s senior authors.
Still, the researchers said clinical trials “are essential” to properly evaluate CAR-NKT cells’ therapeutic potential. They believe the CAR-NKT approach may have broader applications for several other treatment-resistant solid tumor types, including lung and brain cancers.
“Our preclinical testing across different cancer types is showing encouraging outcomes,” Yang said.
About the Author
