The Innate Immune System
The innate immune system is one of two basic arms of the human immune system; the other being the adaptive arm. Like adaptive immunity, the innate immune system consists of a variety of cells and soluble factors and the principal cytotoxic cell is the natural killer (NK cell). These cells are essential for survival and, in addition to directly killing infected cells and cancer cells, NK cells facilitate cross-talk between the innate and adaptive immune system by interacting with dendritic cells and secretion of immunostimulatory cytokines. 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 circulating 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 and bind tightly in order to kill it. The NK cells kill target cells by two mechanisms, first by secretion of perforin molecules which create holes in the cancer cell membrane and allow entry of NK-cell secreted enzymes called “granzymes” into the cancer cell, which kills the cell. This is called “NK cell degranulation”. The second killing mechanism is by binding to “death receptor” molecules on the surface of the cancer cells and signalling to the cell to commit suicide by a process called “apoptosis”.
Cancers arise because the immune response fails to detect them, or the cancer cells are resistant to killing or, simply because the cancer cells grow more quickly than the immune response can deal with them. Chemotherapy and radiotherapy reduce the tumor burden but it is unlikely that either is curative alone; we probably need an immune response to eradicate the disease.
The Cause of Cancer Relapse
NK cells play a critical role in killing cancer cells that 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. It is well established that cancer patients usually have NK cells which are less functional than those of healthy people so 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.
Working with AML patients, Prof. Lowdell showed that, although their NK cells were less active than those of healthy donors, the NK cells from AML patients after chemotherapy were able to kill AML cancer cells. He looked at patients who survived more than 2 years versus those who relapsed and found no difference in their NK function. The difference was the AML cancer cells from the two patient groups.
AML patients who survived had AML cancer cells which were killed by NK cells from either patient group. In contrast, the AML cancer cells from those patients who relapsed were resistant to NK killing. 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 normal NK surveillance.
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 and these are delivered by the cancer cell to the NK cell at the point of contact between the two cells; known as the “immune synapse”.
We and others have shown that multiple signals are required and the outcome of the signalling is dependent upon the type of signal, the strength of the signals and the stability of the immune synapse. Failure of any of these leads to inadequate NK cell activation.
We have a model of NK cell activation which moves from “resting” through a “primed” state to “triggering” and have studied the first transition from “rest” to “primed” in great depth. NK-sensitive tumor cells rapidly prime resting NK cells and initiate the process of killing. Most NK-resistant tumors are susceptible to NK lysis, but only if the NK cells are primed by some other factors such as IL-2, IL-12, IL-15 or cancer binding antibodies such as Rituximab or Herceptin.
None of the cytokines which activate NK cells are specific to NK cells so the risk of off-target effects is very significant, as seen in the early IL-2 and IL-12 trials. We have taken a different perspective and studied the cell membrane signals delivered by tumor cells which move the NK cell from “resting” to “primed” state. We hypothesized that some tumor cells might be able to activate NK cells but be resistant to NK-mediated lysis and thus create an NK cell which is physiologically “ready to kill” but hasn’t received the triggering signals.
This obvious solution is not simple, but it is exactly what INmune Bio is doing. INmune Bio has created a therapeutic product that can be infused into the patient to move the resting NK cells to primed state without initiating NK cell degranulation. We call this product INKmune™.
INKmune™ is a biologic delivery system that allows for the delivery of essential priming signals to patients’ resting NK cells. INKmune™ is delivered by IV infusion. Once in the patient’s system, INKmune™ comes in contact with resting NK cells. The interaction converts NK cells to “primed NK cell” (pNK) similar to an “on-off” switch. pNK then remain primed until they contact and kill cancer cells. Importantly, we have shown that INKmune™ primed NK cells form much stronger immune synapses with cancer cells and this is essential to deliver the lytic payload and death receptor signals to cancer cells which are resistant to resting NK cells.
Are NK cell-directed therapeutic strategies important for the control of cancer?
Yes, the most clinically effective immunotherapy programs for cancer are focused on targeting and activating NK cells. For example, Rituximab™ and Herceptin™ are currently some of the world’s largest selling immunotherapy drugs and both are monoclonal antibodies targeting tumor antigens. These therapeutic anti-cancer antibodies do not kill cancer cells on their own, they require NK cells to bind the fragment crystallizable (FC) portion of the antibody for effective cancer killing. Put another way, INKmune™ helps NK cells target and kill the tumor cell using a different method than these anti-cancer monoclonal antibodies, but with the same results. Unlike Rituximab™ and Herceptin™, INKmune is not antigen-specific so there is no need to identify the specific tumor antigen.