The Innate Immune System
The innate immune system is one of the two limbs of the human immune system. NK cells, macrophages and eosinophils are the principle cells of the innate immune system. The adaptive immune system is comprised of T and B cells. Dendritic cells and γδT cells sit in between and facilitate cross-talk between the innate and adaptive immune system. Both the innate and adaptive immune system are important in controlling cancer, but the interplay between the two is very complicated and not completely understood.
The NK Cell
NK cells of the innate immune system have two primary functions: to kill virally infected cells and to kill cancer cells. We focus on their role in killing cancer cells. NK cells play an important role in preventing cancer. That is, every day we make precancerous cells. Our ever vigalant immune system is looking for these abnormal cells. When an NK cell comes in contact with a precancerous cell, it kills it. This processes, called Immune Surveillance, keeps us cancer free. To kill a cancer cell, an NK cell must come in direct contact with the cancer cell so it can kill the cancer cell by granzyme mediated cell killing. The NK cells secrete granzyme into the cancer cell that causes holes in the cancer cell membrane so the cancer cell dies. We call this the “kiss of death”.
The Cause of Cancer Relapse
A more modern role of NK cells is to kill the cancer that is left over after surgery/radiation and/or chemotherapy. Modern cancer therapy can effectively eliminate most of the cancer in the patient. To eliminate all of the cancer, the patient’s immune system needs to “do its part” and kill those remaining cells called residual disease. For instance, pateints with AML receive an induction chemotherapy regimen called 7+3 (7 days of cytarabine and 3 days of daunorubicin). 40% of the patients are cured (“survivors”) while 60% relapse (“relapsers”). The difference between the “survivors” and the “relapsers” is their immune system. The NK cells of the “survivors” kill the residual AML that remains after the induction chemotherapy. The NK cells of the “relapsers” do not kill the residual disease. The failure of the immune system to eliminate residual disease is the cause of the cancer relapse.
Almost 20 years ago, Prof. Mark Lowdell wanted to understand what was different between the NK cells of the “survivors” and “relapsers”. Everyone assumed the problem was a problem with immune cell function – a defective “kiss of death”. That is, the NK cells did not have the ability to kill the residual cancer cells. To everyone’s surprise, Prof. Lowdell showed that NK cells of “survivors” and “relapsers” have an equal ability to kill cancer cells. The difference was the “survivor” NK cells could see the cancer cell so they could target the cancer cell for a “kiss of death”. The “relapsers” NK cells could not see the cancer cell. NK cells cannot kill what they cannot see! Without the “kiss of death”, the “relapsers” NK cells could not eliminate residual disease and their cancer progressed.
That important observation led to the “discovery”. Prof. Lowdell discovered that the killing ability and targeting ability of the “survivor” and “relapse” NK cells were the same. The difference was that the “relapser” cancer cells had undergone changes to evade NK surveillance. That is, the “relapser” cancer cells were hiding in plain sight! The NK cells could kill them if they could see them, but they could not see them due to some evolutionary trickery that the cancer cells undertook. So the discovery was that the problem was with the cancer cell, not with the immune system!
The problem with “relapser” cancer cells is they evade the patient’s NK cells by making themselves invisible. Because the patient’s immune system cannot see them, it cannot kill them. Understanding the problem, requires a deeper understanding of NK cell biology. In nature, resting NK cells must become an activated NK cell to give the kiss of death. Two signals are required to convert the resting NK cell into an activated NK cell. We call these S1 (priming signal) and S2 (triggering signal). S1 and S2 are on the cancer cell. When a cancer cell comes in contact with a resting NK cell and the NK cell binds to both S1 and S2, it becomes an activated NK cell that gives the “kiss of death”, killing the cancer cell. This is what we see with the “survivor” cancer cells and why the patient’s immune system can eliminate residual disease.
Cancer cells aren’t dumb. Their goal in life is to survive. Unfortunately, their survival comes at the price of the patient’s. One of cancer’s primary evolutionary strategy is to mutate so they can evade the immune system. A common mutation is to downregulate S1 off their cell surface. Now, the patient’s cancer cells only have one signal, S2, on their cell surface. When the patient’s resting NK cell comes around, it only sees one signal (S2) and goes away. With only S2 on the cancer cell, it is invisible and quietly grows with disasterous consequences. The cancer cell could easily downregulate S2 and leave only S1 on its cell surface. This too would be invisible to the patient’s immune system. For some reason more than 98% of cancers down-regualte S1. In this dichotomy lies the opportunity….
The obvious solution is to replace or artificially provide the patient’s NK cells with S1. This converts an NK cell that needs two signals from a cancer cell to give the “kiss of death”, to an NK cell that needs only one signal (S2) to give the “kiss of death”! More importantly, it eliminates a major mechanism by which cancer cells evade the patient’s immune system. This obvious solution is not a simple solution, but it is exactly what INmune Bio is doing. INmune Bio is developing an S1 therapeutic product that can be infused into the patient. We call this product INKmune™.