CAR-T cells are remarkably effective against blood cancers, but their effect can be transient as the cells become exhausted. Stanford researchers found a way to keep the cells effective. A new approach to programming cancer-fighting immune cells called CAR-T cells can prolong their activity and increase their effectiveness against human cancer cells grown in the laboratory and in mice, according to a study by researchers at the Stanford University School of Medicine. The ability to circumvent the exhaustion that the genetically engineered cells often experience after their initial burst of activity could lead to the development of a new generation of CAR-T cells that may be effective even against solid cancers — a goal that has until now eluded researchers.

The studies were conducted in mice harboring human leukemia and bone cancer cells. The researchers hope to begin clinical trials in people with leukemia within the next 18 months and to eventually extend the trials to include solid cancers.

“We know that T cells are powerful enough to eradicate cancer,” said Crystal Mackall, MD, professor of pediatrics and of medicine at Stanford and the Ernest and Amelia Gallo Family Professor. “But these same T cells have evolved to have natural brakes that tamp down the potency of their response after a period of prolonged activity. We’ve developed a way to mitigate this exhaustion response and improve the activity of CAR-T cells against blood and solid cancers.”

Mackall, who is also the director of the Stanford Center for Cancer Cell Therapy and of the Stanford research center of the Parker Institute for Cancer Immunotherapy, treats children with blood cancers at the Bass Center for Childhood Cancer and Blood Diseases at Stanford Children’s Health. Mackall is the senior author of the study, which was published in Nature. Former postdoctoral scholar Rachel Lynn, PhD, is the lead author.

Source: https://med.stanford.edu/

In 2010, three patients received an experimental form of immunotherapy for leukemia through a clinical trial at the University of Pennsylvania. Two of the patients went into complete remission—and stayed that way.  The treatment, known as CAR T-cell therapy, is now FDA-approved to treat certain blood cancers. It involves engineering a patient’s own white blood cells to attack cancerous cells and then returning them to the body. Since clinical trials and FDA approval, CAR T-cell therapy has already been used to successfully treat and clear certain cancers. However, CAR T-cell therapy doesn’t lead to lasting remissions for every patient, and it can cause serious side effects. A new report offers clues about why the treatment is sometimes remarkably effective.

The two patients who responded well to CAR T-cell therapy in 2010 remained disease free for over a decade. One of the men, a Californian named Doug Olson, is now 75. The other, William Ludwig, died early last year of COVID-19. Researchers were able to detect CAR T-cells lingering in Olson and Ludwig’s bloodstreams long after their cancers disappeared, although the types of immune cells that persisted were slightly different than anticipated, the team reported in Nature.

Two T-cells (red) attack an oral squamous cancer cell (white)—a fight that’s part of the natural immune response. Clinical researchers are developing a new type of therapy that modifies a patient’s T-cells to better attack cancer

“Now we can finally say the word ‘cure’ with CAR T-cells,” Carl June, the principal investigator for the University of Pennsylvania trial, told The New York Times.

Olson and Ludwig were among the earliest recipients of CAR T-cell therapy, allowing clinicians a chance to track the patients’ cells and condition over the past decade. “To use the word ‘cure,’ you really need a long time to follow up to make sure people don’t relapse,” says David Maloney, the medical director of cellular immunotherapy at the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center in Seattle. “When we get these people out to 10 and 11 years post-treatment, that encourages us to be a little more forceful in saying that perhaps patients are cured in some cases.”

Source: https://www.popsci.com/