Cancer: Avoiding Cytokine Catastrophe
To focus on cytokines is in reality to focus on Quality Control issues. Why? Because cytokines are the most frequently used, yet least understood of the raw material components now being utilized in immunotherapy. Whether it be the testing for the presence of cytokines, the quantification of cytokines, or the up and down regulation of cytokines, there are no hard and fast rules on just how to perform these tasks properly. No scale of quantification to appreciate if we've used too little or too much and too little or too much can have disastrous effects. Interrelationships between cytokines can occur without any intent of cooperation or modulation. Overall, the most serious quality control issue regarding cytokines is what to do when cytokine production requires we intercede and assume control immediately before it’s too late. As has been past experience, intercession usually only occurred after the effects were already being manifested.
The Cytokine Storm
In normal cases of illness, cytokines are released to control the immune response, but in some situations, the release of cytokines will further exacerbate the illness and may possibly result in death. When uncontrolled release occurs it is referred to a term you may have already encountered in newspapers; 'cytokine storm'. Recent deaths from Avian flu are believed to have been caused by cytokine storms as the body's immune system overreacts to the presence of the virus. Therefore, these glycoproteins and peptides that we so easily add to immunotherapy products in that laboratory have the potential to cause a response 180 degrees from that intended. Therein lies the greatest challenge to quality operations and quality control; achieving a balance that is not only efficacious but presents no risk to the patient. A task that on several occasions has proven to be most elusive. In order to achieve this goal, it is essential that one first understands the function and purpose of cytokines, as well as their interplay with other cytokines, since most do not reach their potential effect alone.
The term ’cytokine storm’ brings vivid images to mind, especially after the TGN 1412 fiasco which saw six patients on a Clinical Phase 1 trial almost die and even though they did survive, all will probably die prematurely from a variety of organ and immune dysfunctions. These six were healthy volunteers, that felt the close to $5000 gift of appreciation was well worth the risk. I'm certain they think otherwise now. Cytokine Storm is a term that captures the imagination, raising images of a body destroying itself from the inside, visually typical of any science fiction horror movie we've watched. The reality is somewhat different. Though the concept of an uncontrolled release of pro-inflammatory cytokines is not that hard to grasp, the actual events that precipitate the molecular events are not really known. Nor is there any counter strategy to either counteract or prevent the storm from occurring. As mentioned, it is the recent spread of Avian Flu which has brought the term into the public forum, and news media have certainly overdramatized its prevalence, but nonetheless, it is still a mystery to the scientific researcher. Though storms resulting from therapeutic intervention have been relatively rare, these create a far greater public interest and hysteria than do the more common cytokine storms as a regular outcome of disease and illness. In general, the storm is the result of the up-regulation of multiple cytokines and the multiple molecular events that subsequently follow. But in order to prevent or treat the storm, it is first essential that we study and learn everything we can about its mechanism.
Riding Out the Storm
Since any one cytokine can have a combined paracrine, autocrine and/or endocrine response, terms that basically mean cellular, neural or hormonal responses, without total appreciation of the fact that the addition of cytokines may have effects far more extensive than those we have intended will ultimately lead to disaster. In other words, we may get the desired cell proliferation but at the same time we may be triggering a massive immune or even cardiovascular response. How a single cytokine can have multiple and unrelated functions is not yet known but it is understood that these multiple effects are the result of interactions or the failure to interact with other cytokines. In a sense, it is the combination to trigger multiple receptors simultaneously that determines exactly which effect the cytokines will have. Therefore, in order to prevent the ‘storm’ it is necessary to have advance knowledge of which cytokines interact and ensuring that those others are either present or absent depending on the desired effect we wish to effect.
There are several classes of cytokines which interact. The interferons play a central role in innate immunity to viruses and microbes. The interleukins function primarily in immune cell differentiation and activation. They can be either pro– or anti-inflammatory and they are produced by a wide variety of cell types. Chemokines are the largest family of cytokines. These are classified into four groups baased on the spacing of their cysteine residues. Primarily, they are chemoattractants, controlling the migration of cells.
CSFs are Colony Stimulating Factors, and they tend to increase the number of cytokine secreting macrophages. Therefore, any stimulus to CSFs that causes them to continue to increase macrophage numbers will promote a cytokine storm.
TNFs or Tumor Necrosis Factors are proinflammatory cytokines that originally were indentified as inducing tumor regression but now we know they also play a role in acute viral diseases and are responsible for chronic inflammation and autoimmune diseases. TNF inhibitors will improve the wellbeing of patients with inflammatory bowel disease, psoriasis and rheumatoid arthritis.
Therefore, reduction of risk of a storm requires advance knowledge of which cytokines will dampen the immune response if a storm is triggered. At first, IL10 ws thought to be the answer, being an anti-inflammatory cytokine but then it was found that it caused fibrosis in the lungs. The correct balance between pro– and anti– inflammatory cytokines is not yet known and what we are doing for the time being is applying best guess. Not what should be considered a satisfactory solution.
Since our knowledge at present is still very limited, exactly how to turn an immune cascade ‘off ’ is still beyond our current capabilities but attaining this knowledge is simply a matter of time. Meanwhile, by studying the interactions between cytokines, it is possible for scientists to make educated guesses regarding the likely effects of combining specific cytokines and through this approach possibly prevent a storm before it ever happens. Events of the TGN1412 trial were preventable had their Quality Department performed to a level that would be expected. When asked to review the course events for the Scott Committee, there was sufficient pretrial data to show that there was reason to fear such a 'storm' could occur. Evidence from the cynmolgus monkey trial suggested a storm was possible. The animals on the trial demonstrated a limited cascade, which considering the monoclonal being used was a hybrid of mouse and human should have immediately suggested that the reaction going back into humans would have been many times more severe as the monkey was an abnormal host. I have always argued that if you're going to do animal experimentation, then it should only be conducted by people that are actually knowledgeable and experts in animal experimentation so that the results are properly interpreted and the use of animals has not been in vain. Sadly, such misuse of animal experimentation only caters to the radical Animal Rights activists that insist mistakenly that animal experimentation is of no value. Enforcement of the protocol properly by QA would have never allowed six people to suffer in this manner.
Dr. Allen Goldenthal
Avrom Aryeh-Zuk Kahana
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