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Interviewee: Zheng Cui, Wake Forest Univ. Baptist Med. Center
Human Study Approved
In 1999, Wake Forest University cancer researcher Zheng Cui repeatedly subjected a seemingly ordinary laboratory mouse to injections of huge doses of cancer cells that unfailingly killed other laboratory mice at lower doses. He discovered that this unique mouse had the previously unseen ability to remain cancer free. Cui and his team bred the amazing mouse, and learned that this cancer resistance was passed on to the mouse’s offspring in an autosomal dominant pattern, meaning it is likely due to a mutation in a single gene.
They still haven’t found that gene, but that hasn’t stopped Cui from pursuing treatment implications, because it made sense to him from day one that this resistance must also occur in people. “We occasionally run into the stories of someone who had a cancer, and then, a few months later, it disappeared for no obvious reason,” he said in 2003. “But in medical research, you cannot go back to the patient and say, ‘What did the body do to get rid of these cancer cells?’”
In mice, you can ask that question
They identified the cancer-killing cells as white blood cells, or leukocytes, part of the innate immune system, and observed that they seek out cancer cells, surround them, and burst them.
Cui, his colleague Mark Willingham, and their team bred a large colony of cancer resistant mice and decided to transfer these cells from the cancer resistant mice to normal mice afflicted with advanced cancers. The infusions cured the cancers in the ordinary mice “100 percent of the time,” Cui said.
“Cancer cells had already developed a large tumor in the mice, and at a different place [than] where we put the immune cells in,” says Cui, “That would require the immune cells to find them at a different part of the body and then track them down to the site and destroy the cancer cells.”
Additionally, these immune system cells only harm cancer cells, allowing the mouse to remain perfectly healthy.
Time to try it in people?
After learning of this exciting new discovery, many people requested that Cui attempt this procedure in humans. Cui said he felt a moral responsibility to push for human tests.
“If we can identify cancer resistant humans, why not just do the same thing as we did in the mice without knowing the mechanism and to find out whether it will work or not?”
They now have approval to try it. As Cui will describe at a conference sponsored by the Methuselah Foundation, they have developed a test to identify these cancer-killing cells in human blood, and their studies have shown that individual genetic make-ups, different seasons, different ages, and emotional stresses greatly affect these cancer-killing cells.
Furthermore, individuals whose cells have low cancer-killing activity are most often cancer patients. Given this information, it appears that an injection of granulocytes, the part of white blood cells that has the highest cancer-killing activity, from healthy cancer-resistant people to cancer patients would work.
First human trial starting
The pilot study will now begin to recruit as many as 500 potential cell donors to be screened for cancer resistance. They will select donors by testing whether their white blood cells show this same ability to kill human tumor cells in the lab. Their cells will then be used to treat 22 patients with advanced cancers.
Cui notes that this transfusion program is not at all unusual, pointing out that it’s similar to the bone marrow transplants that are used in medicine. He says, “If we can offer some clear clinical benefit, it’s just like another arrow in the quiver, so to speak, that can give us more weapons to fight against cancer.”
Different from mice
Willingham, a pathologist, says, “This kind of transfer of white cells in mice is somewhat of a different kind of strategy than it is in people, because in the mice we use in the laboratory they’re very closely matched genetically, and so as a result, when you transfer any cells from mouse to mouse, it’s basically like transferring cells to an identical twin. So the result we saw in the mice when we did that is that anti-cancer activity survived for a very long time, but that’s not going to happen in human patients because we’re all genetically different from each other in a great extent, so those cells will not survive.”
But that’s a good thing
“The observations in the mice suggest that this activity that kills cancer cells occurs very quickly, so these transferred cells only have to survive for a few days, and in fact they do survive for several days, in order to be effective against the cancer,” Willingham says. “Consequently if they’re not still there, say, a week after they’re given, they can’t produce the side effects that one sees when you have those kind of cells surviving for a long period of time. So as a result it’s a safe strategy.”
He adds that there might be other unknown differences between mice and people that could make the therapy fail. “This is an experimental study,” he emphasizes.
Mouse experiments repeated
Meanwhile, the mouse studies continue in the search for an understanding of the mechanism. Cui has offered to share his cancer-proof mice with other labs so results could be independently tested.
A new study confirming the mice’s cancer resistance is now soon to be published. Klaus Reineck, a clinical immunologist at the Blood Bank, Copenhagen University Hospital, in collaboration with professor Jann Hau and his group at the Department of Experimental Medicine, University of Copenhagen, Denmark, confirm they have a paper in press in the journal In Vivo, replicating the initial Wake Forest experiments.
“The findings independently lend support to Dr. Cui’s discovery” that the mice “are indeed resistant” to cancer cells, Reineck wrote in an email. “The findings, however, should be further substantiated. We are very grateful to cooperate with Dr. Cui on this exciting mouse model.”
Clinical trial details
The researchers plan to begin by recruiting patients who have insurance, as North Carolina is one of the states that has a law requiring insurance providers to pay for clinical trials.
Willingham says this trial will be considered a Phase II trial by the FDA and the Independent Review Board (IRB) that will oversee the trial, so it falls under the state law.
As for the donor screening part of the study, he says the funding has not been finalized.
They hope some private funders will step up to the plate, willing to support a potentially life-saving innovation.
“Usually, science doesn’t like innovation at all, because it jumps over the incremental steps that science can’t go ahead without,” says Cui. “Often, scientists don’t like our studies because we don’t understand the gene or how it works.
“But, pretty much the tradition of medicine is about innovation. If it works, we don’t really care about how,” he says.
Wake Forest plans to launch a new website with more information about the new trial, called Leukocyte Infusion Therapy, or “LIFT”.
You can also find this trial here.
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