The Innate Immune System
The innate immune system is one of two limbs of the human immune system. It is comprised mainly of natural killer cells (NK cells), macrophages and eosinophils. The other limb, the adaptive immune system, is comprised of T and B cells. Dendritic cells and T cells, which reside between the two limbs, facilitate cross-talk between the innate and adaptive immune system. Both the innate and adaptive immune system are important in controlling cancer; however, 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 our bodies make precancerous cells. Our ever vigilant immune system seeks these abnormal cells. When an NK cell contacts a precancerous cell, it kills it. This process, called Immune Surveillance, keeps us cancer free. An NK cell must come in direct contact with the cancer cell to kill it. The NK cells secrete granzyme into the cancer cell, which causes holes in the cell membrane and kills the cell.
The Cause of Cancer Relapse
NK cells play a critical role in killing cancer cells that are remain after surgery/radiation and/or chemotherapy, so-called “residual disease.” Modern cancer therapy can effectively eliminate most of cancer in a patient. To eliminate all cancer cells, the patient’s immune system needs to do its part and kill the residual disease. For instance, patients with AML often receive an induction chemotherapy regimen called 7+3 (7 days of cytarabine and 3 days of daunorubicin). Of these patients, 40% are cured (“survivors”) while 60% relapse (“relapsers”). The difference between a survivors and relapsers is the patient’s immune system. The NK cells of the survivors kill the residual disease while the NK cells of relapsers do not kill the residual disease. The failure of the immune system to eliminate residual disease is the cause of the cancer relapse.
Nearly 20 years ago, Prof. Mark Lowdell began research to better understand the difference between the NK cells of survivors and relapsers. The scientific community assumed the issue was one of immune cell function – a defective NK cell. That is, the NK cells in relapsers did not have the ability to kill the residual cancer cells.
Prof. Lowdell showed that NK cells of survivors and relapsers have an equal ability to kill cancer cells. The difference was the AML cancer cells from survivors prime the resting NK cells, initiating the NK killing mechanism. In contrast, the AML cancer cells in relapsers failed to prime the NK cells and they remained at rest. Without NK-mediated killing, the residual AML cancer cells in relapsers grew and the leukemia returned.
This important observation by Prof. Lowdell led to the discovery that while the killing and targeting ability of survivor and relapse NK cells were the same, the relapsers’ cancer cells had undergone changes to evade NK surveillance. That is the relapsers’ cancer cells were hiding in plain sight! The NK cells could kill the cancer cells if primed, but priming did not occur due to some evolutionary trickery on the part of the cancer cells. So the problem was with the cancer cells, not with the immune system!
The problem with relapsers’ cancer cells is they evade patients’ NK cells by making themselves effectively 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 activated NK cells to kill cancer cells. To prevent uncontrolled killing of normal cells, multiple signals are required for this conversion. We have shown that these signals are divided into two stages of activation. Stage 1 (S1) moves the resting NK cell to a state of priming that makes it ready to be triggered by a cancer cell. Many cancers fail to provide the signals need to prime. Once primed the NK cells need further signals to move to Stage 2 (S2) and trigger the killing mechanism. The signalling molecules need to drive the NK cells to S1 and S2 are located on the cancer cell. These are the sets of molecules expressed by a survivor’s cancer cells and why the patient’s immune system can eliminate residual disease.
Cancer cells are simply normal cells that have mutated to lose the ability to die naturally. The vast majority are killed by chemotherapy or radiotherapy, but some acquire more mutations that make them resistant. A common mutation is to downregulate the priming molecules on the cancer cell surface. When the patient’s resting NK cells fail to receive priming signals, they never achieve S1 of activation. As such, they cannot progress to S2 and kill the cancer cell. The cancer cell could equally mutate to retain the priming signals but lose the ability to trigger lysis (S2), in which case the cancer would still evade killing. For reasons that we don’t understand, most cancer cells retain triggering ability but fail to prime NK cells. In this dichotomy lies the opportunity….
The obvious solution is to replace or artificially provide patients’ NK cells with priming signals. This converts an NK cell that needs two signals from a cancer cell to an NK cell that needs only triggering signals to initiate cancer killing. More importantly, it eliminates a major mechanism by which cancer cells evade a patient’s immune system.
This obvious solution is not simple, but it is exactly what INmune Bio is doing. INmune Bio is developing an S1 therapeutic product that can be infused into the patient to move the resting NK cells to S2. We call this product INKmune™.