Cancer: From Accurate Diagnosis to Appropriate Treatment
Most will be familiar with my articles written on religious topics but for those that know me personally, they recognize the conundrum I represent. Being involved in cancer treatment and therapy as both scientist and quality evaluator of the treatments, to most would seem to place me in a position of conflict with leaving matters in the hands of God but personally I don't see the conflict at all. In fact, I believe God gave us all special talents and insights to make this a better world, and in my particular case it was a gift for science and medicine. So, this time I'll introduce you into my world and we'll look at the science of targeting cancer. For immunotherapy to achieve its goals of curing disease, scientists must learn to target the therapy more specifically, focusing only on the disease component and not causing any collateral harm or damage to the surrounding tissues, organs or systems. The approach is in a steep learning curve, still not 100% fully comprehending how our bodies’ mechanisms work and that creates a precautionary element to everything we do since the opportunity for risk and disaster is just as high as that for medical success. This learn as we go component has pushed the immunotherapeutic industry to develop faster than any other breakthroughs in medical history.
From Accurate Diagnosis to Appropriate Treatment
There are certain bioethical, political and fiscal roadblocks which need to be considered as immunotherapy progress towards its goal, not limited to patient privacy, regulatory issues, health care reimbursement and ownership of intellectual property but also the fact that the science is in its infancy and not fully comprehending the mechanisms of the immune system. In addition to the identification of potential diagnostic applications, there is a major focus on identifying new treatment targets, and/or improving therapeutic strategies involving existing treatments. Patient variation, with respect to treatment response (efficacy and toxicity), is a well documented phenomenon. Through the capturing of clinical data and pertinent samples across a large patient population that exhibits variable treatment response, retrospective statistical analysis of the integrated clinical, experimental and molecular data could reveal the underlying causes of this variation. Until we understand this variation, allogeneic treatments are still only a future pipedream.
Any appropriate treatment has to first overcome two difficulties. The first being, how to sustain sufficient T cell numbers after the infusion and how these cells once maintained can be directed and percolated into the tumor. Currently, our approach is to pump in a large number of cells, knowing that they are going to last only a few days and hope that sufficient numbers actually locate and penetrate the tumor cells in that short time. The second issue is how to get cells which do locate the tumor to proliferate on contact so that there are large numbers of T-cells available to kill the cancer cells.
Fortunately recent research has shown that by injecting IL7 and IL15 into the patient, a homeostatic expansion occurs in the body, increasing T-cell numbers by 100 times. At the same time, the T-cells become engrafted into the host’s lymphoid department and start to become self-generating.
Of course, any new therapy regime is not without its risks. If by using certain cytokines the cells can be turned on to replicate within the body and become engrafted, then there must also be a mechanism to turn them off in case something goes terribly wrong and cells other than the ones infused begin to expand rapidly as well. Therefore, it is not simply a case of injection and watch what happens because a company must be prepared to remedy any situation that turns bad as well.
Therein lies the dilemma, because our understanding of the science is still in the infancy, and just like a child, we may be able to take something apart but that does not necessarily mean that we know how to put it back together again. Until we do, each procedure must be undertaken with due caution and a full appreciation of the risk management required.
The use of cytokines is not new. In fact the story of cytokines goes back to the 1950’s with the discovery of interferon. Recently our knowledge of this family of small to medium sized polypeptides and glycoproteins has increased dramatically with more than 200 of them identified and their regulatory functions documented. Several of them overlap in function and besides not knowing why that occurs, their feedback mechanism is also a virtual unknown. Theories abound, but these still remain unproven.
Within the family of cytokines are the chemokines, chemical attractants that draw the T-cells to the lesion or tumor. Key to effective treatment is finding the balance of these chemical agents through knowing how to administer how much and how often.
For example, IL2 treatments of the patients will improve the treatment of certain cancers by 15-20% but the IL2 has also been shown to have toxicity towards all vital organ systems. It has been postulated that ineffective cancer treatments have really been the fault of not knowing the dose and interaction of cytokine and anti-cytokine therapies. Since it is unlikely that any single cytokine will be the key to treating cancer, then fully understanding the relationship between these chemical modulators is essential. Every cytokine must be approached as if it were a double edged sword, capable of great beneficial actions but also serious detrimental ones as well. In some cases the detrimental effects have been recorded as being worse than the primary disease being treated. For example, IL1 can cause ischemic brain injury and can actually promote the metastatic spread of tumor cells. IL6 has been shown to protect nervous tissue but at the same time may cause anemia by preventing the uptake of iron into red blood cells.
The enhancement of immunotherapies is therefore only going to be fully realized through the development of even more complex and novel strategies.
There is no question that the future of medicine revolves around individualized treatments made possible through immunocell therapy. The problem is that we still don’t fully understand the mechanisms of the immune system and until we do, we still place each patient at risk with every treatment because of complications that we may not be fully aware of.
In my next article we’ll look at the cocktail mix that is now possible with our limited understanding of chemokines, lymphokines and cytokines. Selecting the right mixture can be the difference between a major breakthrough in fighting cancer and a lethal and painful brew that is worse than the disease it was intended for. With so many activators, regulators, and potentiators to choose from, finding the correct combination is no longer a simple process. Therefore, an understanding of current technologies is crucial.
Dr. Allen Goldenthal
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