September 20, 2007
Rare People Have Extreme Anti-Cancer Immune Cells
At the the third conference for Strategies for Engineered Negligible Senescence (SENS) Dr. Zheng Cui of Wake Forest University reported on impressive progress of his research team toward use of immune cells to defeat cancer.
Attendees at SENS3 heard first-hand about an extremely exciting approach to cancer treatment that has not yet hit the scientific literature or the press. In 2003, Dr. Zheng Cui and his colleagues at the Comprehensive Cancer Center of Wake Forest University reported the discovery of mice with immune cells that rendered them invulnerable to cancer: they had been intentionally giving mice cancer by injecting them with virulent cancer cells as part of a separate study, when they discovered a single mouse in the colony that was completely immune to the invasive cells.
His curiosity piqued, Dr. Cui went on to show that it could resist multiple rounds of such injections, and were so impressed that they used him to father a whole colony of mice, all of whom shared this remarkable invulnerability to cancer. Based on that ability, he calls them spontaneous regression/complete resistance (SR/CR) mice.
Last year, Dr. Cui electrified the world when he showed that the new strain's cancer-fighting abilities were caused by a particular subset of their immune cells -- members of a class of white blood cell known as neutrophil granulocytes.
You might be among the lucky few who have immune systems with especially high competence at defeating cancer.
At SENS3, Dr. Cui presented the next logical step in his research: work demonstrating the existence of, and characterizing, high-potency cancer-killing granulocytes in humans.
Dr. Cui's team first went looking for the existence of potent cancer-killing granulocytes in a group of healthy volunteers. This was done by testing the volunteers' granulocytes' ability to destroy cancer cells in a petrie dish. They found that, unlike in mice (who seem to have an all-or-nothing effect), there appears to be a classical bell-shaped distribution of cancer-killing ability in the granulocytes of people in the population: a few people have white blood cells extremely weak cancer-killing activity, the great majority have an 'average' competence, and a very small group of outliers have the kind of overwhelming search-and-destroy activity (at least in a test tube!) that is seen in the SR/CR mice.
Winter gives you cancer by weakening your immune system.
Surprisingly, they found that the ability of peoples' granulocytes to kill cancer is very sensitive to the season. Looking at the efficacy of granulocytes drawn at samples taken year round, he found that the activity is strong in the sunnier months (May to September) and falls off dramatically in the gloomier ones (November through April). The reason for this effect is unknown, but it could be connected to other things that vary with the number of hours of daylight and that are connected to cancer risk, such as the circadian-rhythm hormone melatonin or the "sunshine vitamin," vitamin D3.
He also found that the cancer-killing capacity could be "abolished" by stress: in one anecdote, a grad student from his lab at Wake Forest had been tested just after making his first presentation at a scientific conference, and the normally high level of cancer-fighting activity in his granulocytes was severely depressed. Re-testing him several days later, the activity of his granulocytes had bounced back to normal.
Stress is bad. Stress gives you cancer. But then that only makes sense. As Joe Jackson sang "Everything gives you cancer".
An immune method to defeat cancer would be great. Cui's about to start a clinical trial on 22 humans to try to see if immune system components from people with super immune systems can defeat cancer when separated out and injected into people with cancer.
The difference in potency of cancer killing cells between people is enormous.
Cui took blood samples from more than 100 people and mixed their granulocytes with cervical cancer cells. While granulocytes from one individual killed around 97 per cent of cancer cells within 24 hours, those from another healthy individual only killed around 2 per cent of cancer cells. Average cancer-killing ability appeared to be lower in adults over the age of 50 and even lower in people with cancer. It also fell when people were stressed, and at certain times of the year.
Maybe most of the increase of cancer with age is due to weakening immune systems. Immune system rejuvenation would probably reduce the incidence of cancer. Also, these people who have super anti-cancer immune systems have something that can be replicated in other people. Maybe gene therapy or vaccines could tune up our immune systems to make them more like the immune systems of the rare few whose immune systems are especially aggressive against cancer.
Cui's group is giving a "GIFT" (Granulocyte InFusion Therapy) to the rest of us.
Neutrophils and macrophages, as major components of infiltrating leukocytes, migrate to the site of cancer cells, capture the cancer cells by making tight physical contact with the cancer cell surface and destroy them via cytolysis. The leukocytes of these cancer-resistant mice can be used as therapeutic agents to cure several forms of highly aggressive cancers in wild type mice without any sign of adverse side effects. This leads to the apparent question of whether we can find cancer-resistant humans to test a similar cancer treatment via allogenic innate white cell transfer. Using a newly developed in vitro assay to measure the ability of white cells to kill various cancer cell line targets, we surveyed human volunteers and found that a significant number of healthy humans have cancer-killing activity (CKA) similar to that of cancer-resistant mice. There seems to be a bell-shaped distribution of CKA in the population of healthy humans. The CKA average appears to be lower in older human populations and to be even lower in human cancer patients. The CKA can also be abolished by stress and change of seasons. Based on these findings and the ability to screen for cancer-resistant humans as allogenic white cell donors, we proposed a new cancer treatment strategy, termed "GIFT" (Granulocyte InFusion Therapy), that will soon enter phase II clinical trials.
I recently had a NK-cell test which showed relatively high activity, though not the highest measured in the group. That belonged to an outdoorsy type with high aerobic training lifestyle. I however, outranked all the sedentary folk, and I have my own significant training regime.
It would be interesting to see the impact of excersize on these granulocytes, and whether or not classic aerobic training improves/worsens the impact of the granulocytes. Is the limit of activity genetic?
Can we shift the granulocyte activity level with drugs? Obviously Vitamin D studies are an absolute must now.
I used to ascribe much of the benefit of training to the cancer-killing effect of peroxidized lipids... but clearly other factors are at work. Maybe a longitudinal study in a crop of athletes? Or Marine trainees?
It just occurred to me: If the distribution is bell-shaped, it means the central-limit theorem is at work, which means many factors are causal in the granulocyte activity -- this opens a wide-door of hope that we can find factors that we can use to radically shift the activity level.
On his web site he says this immune system characteristic is inherited. But they can't find a place on a chromosome to pin it down to and suspect it is either jumping around or not on a chromosome.
This is the coolest medical research result I've posted about in months. Maybe this'll be the cure for cancer?
But killing 97% of cancer cells sounds good,it is obvioulsy not enough (many chemo agents will kill 99+% but are unableto cure the disease).
Perhaps in conjunction with other therapies and surgery etc.
Agreement with Randall. This is some of the best news I've read in months.
I think one of the best ways to provide the immune system boost is before there is any cancer.
Just as there is 80% survival for stage 0 cancer versus 2% survival for stage 5, getting the GIFT boost
as a form of vaccination could prevent cancer from getting a toe hold.
Are there any down-sides to injecting other peoples granulocytes into you though?
You wrote in a previous post.
" the arguments of evolutionary theorists Gregory Cochran and Paul Ewald that the role of infections in causing chronic illnesses has been much underestimated."
Could this anti cancer technique be used to dramatically improve peoples immunity to infections too and therefore have a massive effect on human health?
Yes, boosting the immune system before getting diagnosed with cancer is certainly preferable.
One risk is that other immune cells could, in small numbers, come over with the granulocytes and attack host tissue.
We need two things here:
1) Techniques for rejuvenating the immune system. These granulocytes are just part of the total picture. Immune system aging puts old folks at risk of death from influenza and many other pathogens. Plus, an old immune system can attack the wrong stuff.
2) An understanding of what genetic differences make granulocytes from some people so effective against cancer. With that knowledge gene therapy crafted to deliver those genetic differences into one's own granulocytes might provide a better way to protect us all from cancer before we get diagnosed with cancer.
If the distribution is bell-shaped, the central limit theorem is at work and human granulocyte activity must be regulated by more than the genetic factor alone. We cannot extrapolate from mice to men in this case. It might be an x+1 case, where you need an extra gene to get the super-killer effect.
But this opens so many possibilities, including, but not limited to, re-engineering a progenitor cell line to give people this super-cancer-killer. It should be well within the current technological grasp to grab the extra genes off mice and pop them into a harvested cell line. Not saying it's easy, but it should be doable by those schooled in the art.
In terms of immediate therapy, photopheresis just before infusion could be utilized to damnpen graftvshost response against the GiFT.
Anyway, this is all very exciting and let's hope the FDA doesn't test this into oblivion like so many other promising therapies.
"If the distribution is bell-shaped, the central limit theorem is at work and human granulocyte activity must be regulated by more than the genetic factor alone. We cannot extrapolate from mice to men in this case. It might be an x+1 case, where you need an extra gene to get the super-killer effect."
Well, according to Robert Plomin, the IQ bell curve is the result of multiple genes will small effect and with a small dose of environmental factors. Hopefully, in this case, these genes would have a relatively large effect so the QTL would be located with less effort. Regarding IQ, not many QTL has been found because current tests.
"Progress towards identifying quantitative trait loci (QTLs) for complex traits like intelligence and common disorders like mental retardation has been slower than expected. An important factor is that most QTL effects may be much smaller than expected—not just 1% effect sizes but perhaps effects as small as .1%. If so, this would mean that studies have been seriously underpowered to detect and to replicate QTL effects. We have used microarrays to genotype DNA pooled for groups of low versus high intelligence in order to screen very large numbers of single nucleotide polymorphisms (SNPs) on very large samples in the quest for QTLs of very small effect size: We find no effect sizes greater than .5%. Microarrays with 500,000 SNPs are now available that facilitate genomewide scans which will make it possible to identify nearly all SNP associations that account for 1% of the variance of intelligence—if there are any QTL effect sizes as large as 1%."
meant to say "...current tests do not have a large enough sample size":
Thousands of genes are expressed in the brain and
null findings are common. Moreover, a sample of 496
(or even the 644 available for the entire sample)
provides only 95% power to exclude an association that
accounts for 2% of the variance. Given that genetic
effect sizes turn out to be extremely small, typically
0.1%, and contribute interchangeably and additively
(Plomin et al. 2006), most studies have been seriously
underpowered to detect and replicate effects. Association
studies of many markers in thousands of individuals
may be required to identify appropriate genes.
Let's not forget epistatic variation too.
"One risk is that other immune cells could, in small numbers, come over with the granulocytes and attack host tissue."
In reading all of the published studies - so far - it has been shown that, in the mice subjects, no negative impact whatsoever on the receiving host's cells occurred. Further, the research since 1999 has shown that even if the granulocyte transfusion is at a site distant from the tumour or ascite activity, they will track the cancer cells and kill them at the distant site.
You may find these studies of interest:
what, if any, are the specifics of an adult immune to cancer and his immune cells injected into a cancer prone patient. I am seventy six year old male and searching back through my paternal and maternal families there are no records of any cancer deaths or diseases on either side. I was only able to trace back three generations. Do you have any data on families such as mine? And would this be of any benefit in cancer immunity research? I have developed emphysema and COPD but never any cancer. i was a heavey cigarette smoker up to 25 years ago.
Any progress since their first discovery? Did they do in vivo studies? I can't find any recent articles on their work.