More than a century ago, William Coley, a surgical oncologist from New York City, had the seemingly crazy notion that the body has an immune system that can be harnessed to fight cancer.
After witnessing cancer regress in one of his patients after developing a skin infection, Coley developed a novel cancer treatment in which he injected more than 1,000 patients with a mixture of heat-killed bacteria.
The idea was to stimulate what he called the body’s “resisting powers.”
The results were positive. His approach actually caught on.
It was used by such prominent physicians as the Mayo Brothers of Mayo Clinic renown and orthopedic surgeon Henry W. Meyerding.
But the advent of radiation, then chemotherapy, and the fact that Coley couldn’t fully explain how his treatment worked, effectively killed what had come to be known as Coley’s toxins.
Today, Coley is looked upon by many as the “father of immunotherapy” and the medical establishment in the United States now embraces his philosophy.
Immunotherapy is now easily the most talked about and promising “new” idea in the cancer treatment universe.
This week, the Food and Drug Administration (FDA) approved yet another immunotherapy: a combination of Opdivo (nivolumab) and Yervoy (ipilimumab) for people with a previously treated type of colorectal cancer, according to Bristol-Myers Squibb, the manufacturer of the drugs.
At the moment, the most prominent of the treatments that utilize the body’s immune system is chimeric antigen receptor T-cell immunotherapy (CAR-T).
But now there’s talk of harnessing so-called “natural killer” cells to go after cancer.
And researchers say this CAR-NK process may be even more promising than CAR-T.
Natural killer cells
In a study published last month in the journal Cell Stem Cell, researchers at the University of California San Diego School of Medicine and the University of Minnesota Minneapolis report that modified natural killer (NK) cells derived from human induced pluripotent stem cells (iPSCs) displayed heightened activity against ovarian cancer.
NK cells, like T cells, are an integral part of your body’s immune system. They work somewhat differently than T cells, but both are effective cancer fighters when given the tools to do their job.
Dr. Dan Kaufman, the lead scientist in the NK study and director of cell therapy at the UC San Diego School of Medicine, told Healthline that NK cells may offer “significant advantages” over T cells for people with cancer.
This includes the ability to safely deliver these engineered cells in a convenient manner.
Kaufman said that unlike the CAR-T process, the CAR-NK process doesn’t require the cells to be matched to a specific patient.
One batch of iPSC-derived NK cells, which are created in a dish from mature human cells, can be potentially used to treat thousands of people, Kaufman said.
This will enable clinics to offer standardized “off-the-shelf” treatments and use these in combination with other cancer drugs.
“These are stem cells that can make all the cells and tissues of the body,” Kaufman explained. “We have defined methods to get efficient use of these iPSCs as the starting point to make NK cells.”
Previous studies conducted by Kaufman and others suggest NK cells don’t come with serious toxicities — and Kaufman’s latest study found few adverse effects in mouse models.
Moving to clinical trials
Kaufman is now collaborating with scientists at San Diego-based Fate Therapeutics to move his CAR-NK work into human clinical trials.
Fate is a pioneer in the development of universal NK cell products manufactured using a renewable iPSC line as the starting material.
Scott Wolchko, Fate Therapeutics’ president and chief executive officer, told Healthline that this approach has the potential to change the logistics of cell-based cancer immunotherapy as we currently know it.
“It is intended to overcome many of the limitations associated with patient-specific cell therapies, like the current CAR T-cell products, and to enable more patients to access revolutionary cell-based cancer immunotherapies,” he said.
Wolchko said the company’s goal is to advance its first product into human clinical trials by the end of this year.
“This would represent a very significant milestone for the world of cell therapy: the advent of an off-the-shelf paradigm that is intended to overcome many of the limitations associated with patient-specific cell therapies,” he said.
CAR-NK researchers emphasize that iPSCs aren’t embryonic stem cells (ESCs).
They’re created in the lab from mature human cells — like a skin cell or blood cell from an adult person.
“This scientific breakthrough was the discovery that you could reprogram a fully mature human cell backward in life to a pluripotent state in a dish,” Wolchko explained. “You could take a human skin cell, for example, and turn it into an embryonic-like cell.”
These iPSCs can now serve as an “unlimited source of any type of human cell needed for therapeutic purposes,” Wolchko explained.
A different approach
The University of Texas MD Anderson Cancer Center in Houston is also studying NK cells for CAR-directed therapy.
But its approach differs from that of UC San Diego.
MD Anderson’s cells are not iPSCs. They’re instead harvested from umbilical cord blood specimens maintained in the hospital’s Cord Blood Bank.
The MD Anderson approach involves taking the donated cord blood, separating out NK cells, and inserting a CAR into them that targets CD19, an antigen expressed on some blood cancers.
In a press release, MD Anderson researchers explained that they’ve also devised a way to embed a so-called “suicide gene” into the process that shuts down the cell if toxicity processes commence.
“Non-engineered allogeneic NK cells have minimal if any toxicity, but once you engineer NK cells to express a CAR and have cytokine receptors, they may end up being toxic, which is why we need the suicide gene,” said Dr. Katy Rezvani, a professor in the MD Anderson’s department of stem cell transplantation and cellular therapy.
A first-in-human phase I/II clinical trial of these cord-blood-derived CAR-equipped NK cells opened at MD Anderson last year for people with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin’s lymphoma.
“These patients do not otherwise have many options for eradicating disease that has relapsed or is not responding to therapy,” Rezvani said in a press release.
Both approaches are novel and potentially transformative.
Kaufman said the main difference between the NK technologies at MD Anderson and the work with NK cells at UC San Diego is that the NK cells at UC San Diego are derived from human induced pluripotent stem cells — the iPSCs.
Kaufman said this offers “several advantages” compared to the NK cells the MD Anderson group produce from cord blood.
“We can produce hundreds or thousands of doses of NK cells from the same starting iPSC population,” he said.
“While the MD Anderson group has stated they could scale up their process, it is probably no more than 10 NK cell doses per cord blood unit, so it is much more limited,” Kaufman said.
Kaufman noted that starting from iPSCs allows his team to carefully define the genetic modifications made to the cells, as is needed for the CAR expression.
“This adds a safety layer, as we know the genes don’t insert an area that could cause a problem with the NK cell growth or function,” he said. “In contrast, every cord blood unit is engineered separately and their methods don’t really characterize how the cells are modified.”
Kaufman said his team can also use the iPSCs as a platform for adding additional genes such as cytokine receptors and the suicide switches, as the MD Anderson group is doing.
“Again, all cells are modified in the same way and can be extensively tested to ensure safety. As we have not seen any concerns in preclinical testing with uncontrolled growth, we don’t think we will need a safety switch for these cells,” he said.
Kaufman said his team has designed and used new CAR constructs that are optimized for NK cell function.
“This is in contrast to the MD Anderson group that uses CARs designed for T cells in their NK cells. While those work OK, we have found our NK-specific CARs work better when tested in mice,” he said.
CAR-T still the star
The immunotherapy that remains on the front burner is CAR-T.
In this process, T cells — a type of white blood cell that are part of the body’s immune system — are extracted from a person’s blood and genetically modified with a chimeric antigen receptor (CAR) to bind with a certain protein found on the person’s cancer cells.
They’re then grown in large numbers in the lab and infused back into the patient.
The number of long-lasting remissions in people with lymphoma and leukemia who’ve tried CAR-T in trials, and now in clinic after exhausting all other options, is unprecedented.
Drug companies such as Gilead/Kite and Novartis already have CAR-T treatments in clinic, and several more companies including Juno, have CAR-T therapies in the pipeline that are expected to reach the clinic soon.
As powerful and promising as CAR-T is as a cancer killer, it doesn’t work for those who don’t have sufficient T cells or don’t have time to forgo treatment until the CAR-T cells are generated.
And at times, CAR-T is accompanied by a concerning level of toxicity, including something called cytokine release syndrome (CRS).
According to the , CRS is a condition caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy.
Cytokines are immune substances that have many different actions in the body. Symptoms of CRS include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing.
Most people have a mild reaction, but CRS can be severe and even life-threatening. There have even been deaths — although it’s increasingly rare.
But companies are working to mitigate those side effects. At Juno Therapeutics, for example, its leading CAR-T treatment, JCAR017, for diffuse large B-cell lymphoma, has an impressive safety profile.
In December, Juno officials announced at the American Society of Hematology convention that only 1 of the 67 patients in its JCAR017 trial experienced severe CRS.
This is significantly better than Novartis’ CAR-T treatment, Kymriah, or Gilead’s CAR-T treatment, Yescarta, which reportedly produced severe CRS in 23 percent and 13 percent of patients, respectively.
In addition, 60 percent of JCAR017 patients reportedly had no CRS symptoms at all, compared to 42 percent and 6 percent for Kymriah and Yescarta, respectively.
If severe forms of CRS can be brought down to levels low enough to be considered “safe” by the FDA, CAR-T therapies could be provided to people in an outpatient environment rather than in the hospital.
Scientists have also recently identified the origins of CRS and are working to find ways to get rid of this syndrome entirely.
In a published last month in the journal Nature Medicine, Dr. Attilio Bondanza and his team at Italy’s San Raffaele Hospital Scientific Institute identified that something called circulating monocytes — rather than CAR-T cells — were the major contributors of IL-1 and IL-6, which are the culprits that initiate this dangerous side effect in patients.
The study showed that targeted therapy against IL-1 could abolish CRS in patients.