NATURAL KILLERS SHOW PROMISE IN TRIAL
Scripps testing drug thought to activate multitalented cells
Already having made it nearly six years longer than his doctors predicted, Jim Toillion has turned to a small group of natural killers to attack the tumors relentlessly damaging his liver.
Toillion is among a handful of patients living on the cutting edge of cancer immunotherapy, helping researchers explore the potential of natural killer T cells, a part of the normal human immune system capable of attacking all manner of threats from invading microbes to cancerous tumors.
He was the first patient to sign on to a new clinical trial at Scripps Health that uses an experimental drug derived from sea sponges thought to activate invariant natural killer T cells known to congregate in the liver. These particular sentries, explained Dr. Darren Sigal, the trial’s principal investigator, are delightfully multitalented.
“These cells sit in the liver and process or evaluate all of the food that gets absorbed in our guts to make sure that pathogens don’t infect us,” Sigal said. “They can directly kill pathogens and cancer cells, but they can also activate other components of the immune system including macrophages, B cells and dendritic cells.”
It has now been five months since Toillion, 70, received his first dose. So far, he said, he has noticed no side effects. Certainly nothing close, he added, to the generally debilitating side effects of some of the medications he has been pre
scribed to slow the growth of his cancer over the past six years.
“That’s the delightful thing about these immunotherapy drugs: They don’t make you feel awful, and that’s a blessing,” Toillion said.
Since receiving his first dose on Feb. 25, Toillion and two others who have enrolled have experienced few side effects, suggesting the initial doses received are not harmful. Soon, a larger dose will be administered. The idea is to find the largest concentration that the body can tolerate without activating such a large immune response that liver damage occurs.
Called a dose-escalation study, the natural killer investigation is the first such cancer trial to start at Scripps and be picked up by MD Anderson, the Houstonbased cancer juggernaut with which Scripps formally partnered in 2016, renaming its local oncology operation the Scripps MD Anderson Cancer Center.
Just before he received his first dose, Toillion’s liver tumors were growing, but have since not only stopped getting larger but have shrunk a bit. Blood levels of Alpha-fetoprotien — a commonly measured marker of liver tumor activity — stood at 1,802 nanograms per milliliter just before treatment in February.
Those numbers have since stabilized at 1,554, a number that is still much, much greater than the normal concentration of about 10 nanograms per milliliter, but also no longer increasing. Another of the three patients who have signed up for the trial so far, Sigal said, saw their AFP number drop from 33,267 to 16,971.
Dropping protein levels and slight tumor shrinkage, while encouraging, are not yet enough to say that the drug has made a clear difference.
“We cannot say it is an official response, because the tumor hasn’t shrunk enough yet, but it is still tumor shrinkage, which is pretty incredible since he was progressing for the past two years,” Sigal said. “At the lowest dose, if you’re already seeing some clinical benefit, it’s very reassuring.”
Natural killer T cells are part of a transformative movement in oncology called immunotherapy. The idea is that the same complex system that protects us from viruses and bacteria has also evolved to regularly spot and destroy the body’s own cells when they mutate and replicate out of control, forming tumors that gradually kill healthy tissue.
The revolution started in 1986 with Food and Drug Administration approval of interferon-alpha, a drug that can stimulate immune system activity, aiding the response at first to hairy-cell Leukemia and eventually to other types of cancer such as melanoma.
A renaissance arrived in 2014 with the approval of two drugs for melanoma. Called pembrolizumab and nivolumab (sold under the trade names Keytruda and Opdivo), the drugs were the first checkpoint inhibitors. These drugs allow the immune system to ignore cellular signposts that allow many cancers to look like they are healthy, masking their malignancy and escaping the search-and-destroy capabilities of immune systems components such as T cells.
Checkpoint inhibitors have delivered significant results in melanoma and a growing list of other cancer types. But they have been far from a panacea, leaving researchers to explore other ways that the immune system’s other components can be harnessed in new ways. Many cancer centers across the nation, for example, have been creating cancer vaccines custom built to target the most likely markers expressed in specific tumors.
They’ve certainly seemed to help Toillion. He has been on Opdivo, he said, for several years. The drug entered the standard of care just as he was diagnosed. In many ways, as is the case for a growing number of cancer patients, new immunotherapy options have arrived just as others have played out.
Of course, it’s also important not to become discouraged and stop pushing for fresh solutions.
“You have to be involved in your own health care or you’re not going to make it,” Toillion said.
While some are working to stimulate other types of T cells, natural killer cells, including those that are part of the innate immune system, have increasingly been the subject of research in labs across the country, including those of Nantworks, a research firm owned by Dr. Patrick Soon-shiong, who also owns both The San Diego Union-tribune and the Los Angeles Times.
The quest to find better ways to use natural killer cells, said Mitchell Kronenberg, president and chief scientific officer of the La Jolla Institute for Immunology, has been under way for many years. ABX196, the compound now being investigated by Scripps and MD Anderson, was first isolated in the San Diego office of Kyowa
Kirin Pharmaceutical Research Inc., a Japanese firm with an office near the University of California San Diego campus.
The company, he noted, did initial trials aimed at treating liver cancer with the compound in the late 1990s.
“It works brilliantly in mice, but it hasn’t worked so far in people,” Kronenberg said. “This is the second version of something that was tested in clinical trials 20 years ago, if you can believe it.”
There are some significant changes for the second attempt. The lab of Dr. Luc Teyton, an immunologist at Scripps Research, made modifications to the original molecule and licensed the result to French pharmaceutical company Abivax, which is funding the current trial.
And, this time, patients will also receive doses of the checkpoint inhibition drug nivolumab. Not yet invented in the 1990s, the drug has the potential to achieve a certain kind of synergy with ABX196, increasing the odds of a strong response when natural killer T cells activate other immune fighters, Kronenberg said.
It is a combination approach, noted Kronenberg, himself a recognized expert in the basic science of natural killer t cells, that has increasingly become part of the research process. If it works, he said, it will be a significant addition to the existing immunotherapy arsenal. Effective treatments for liver cancer, after all, have been far and few between.
Stimulating other types of T cells is a trickier process because the process requires interfacing a special presentation molecule called “MHC” that differs from person to person. Natural killer T cells also require a separate molecule to be activated, but it does not vary from one human to the next. So, while it is currently the case that cancer vaccines must be designed for each individual, that’s not likely to be the case for compounds capable of activating natural killer T cells.
“It won’t have to be personalized; it will be off-theshelf, and that’s the power of NK T cells,” Kronenberg said.
The trial is still open to new enrollees. Those diagnosed with hepatocellular carcinoma can call (858) 554-5269.