What are checkpoint inhibitors?

What are checkpoint inhibitors? I have to ask when we talk about immune checkpoints is, if you're in a car on a highway and I tell you to go faster, how do you go faster? And everyone will say, that's easy, you step on the gas. And what if I said, no, no, no, just take your foot off the brake. And that's the entire philosophy behind immune checkpoints, that our body is constantly cranking to attack viruses, cancer, bacteria. But if that system was allowed to run free, that's what autoimmune disease is. It's antibodies attacking things they shouldn't. So our body has a natural brake system to stop the immune cells from going crazy. Checkpoint inhibitors are basically the brakes of the immune system. And so I think when you think about how a T cell works, you need to think about it as an automobile, where there's an accelerator and there's a brake. And what happens in cancer is that the brake is on through a series of immunosuppressive mechanisms that are present. And many of these brakes or these checkpoints are molecules such as CTLA-4, PD-1, LAG-3, TEM-3 to mention a few of them. And there have been antibodies that have been developed to block these blockers or block these brakes. And so the end result is if you block a brake, you can actually turn the cell on. Checkpoint inhibitors have shown to be very, very effective in many solid tumors. Melanoma, the skin cancer, lung cancer, to mention the top two probably. And in liquid tumors, Hodgkin's lymphoma has shown to work very effectively. Checkpoints inhibitors are getting approved for almost all cancers there. The results from checkpoints inhibitors are really encouraging. Basically what it means is when it literally when our immune system shakes hands with a The cancer cell tell the T cell to back off and leave the cancer cell alone. The checkpoint inhibitor is we inhibit this process so the cancer cell cannot turn off our T cells and therefore our T cells will go and or our immune system in general will go after the cancer cell. In simple terms, it's an immune therapy that will empower our immune system to recognize cancer cells and act on this recognition by killing those cancer cells. Checkpoint inhibitors are a potential way to boost the immune response and the way they work is that when an immune response is developing, checkpoint receptors also go up as the immune response is gearing up. And it's a natural brake on the immune system so that you don't have an overly robust response that could actually cause damage. In the setting of cancer where you want to really turn on the immune system a little Blocking that negative pathway is a potential way to boost a response. How that fits into myeloma therapy is still under study right now. The normal immune system has a system of checks and balances in order to make sure that the immune cells like T cells only respond to the four antigens that are foreign and not respond to your own body's antigens. And one of the checks that we have is called checkpoint molecules, which a variety of them have been described, including the PD-1, PD-L1, as well as others. The PD-1, PD-L1 axis appears to be the one that has been targeted for a lot of the cancer therapies. So what can happen is over time, one of the mechanisms for the tumor to escape the immune mechanisms or the immune surveillance in humans is to employ these checkpoint blockade. So essentially what it does is the T cell will no longer act against the tumor cell because it engages this axis. So by blocking the interaction between the checkpoint or interaction between the PD-1 and the PD-L1, what can happen is now the T cells are becoming more active or they are more capable of recognizing the tumor and going after it and killing it. So it's one way to get over the apathy that sets in with respect to the immune cells. When it comes to immune checkpoints that are being explored, think about that a lot of these interactions are like a lock and a key, and you can block the lock and key either at the lock side or at the key side. So the lock and key is called PD-1 or PD-L1, and PD-L1 is the key and PD-1 is the lock, and basically those are the two big areas where you want to block it, and there's PD-L2, so there's two different types of keys. Do you block one key or both keys or just block the lock? For a lot of diseases we don't know that one is better than the other, blocking the lock or the key, but in some diseases it's starting to emerge. Maybe if we block the lock, that's better than blocking only one key. How have checkpoint inhibitors been used in myeloma? A while back there were a number of trials that were being run with a drug called Pembrolizumab, also called K-Truda, and all of the studies that were done with K-Truda were called Keynote. Keynote 1, Keynote 2, Keynote 85, bajillion. I believe it was Keynote 155 and 153, or 185 and 183, but essentially there were two Keynote studies that were done. One was lenalidomide and dexamethasone versus lenalidomide, dexamethasone, and Pembrolizumab. The other was pomalidomide and dexamethasone versus pomalidomide, dexamethasone, and Pembrolizumab. And in both studies we saw an increase in adverse events, an increase in immune-related toxicities, and no improvement in outcomes. So as a result of that, a lot of the studies were stopped because it was felt that checkpoint inhibitors, particularly with immunomodulatory drugs like Revlimid, may be toxic and not provide a good benefit. However, there's a reinvigoration of looking at checkpoint inhibitors in myeloma for two reasons. There's a subset of myeloma that has an IGH-Maff rearrangement, or 1416, and those patients tend to have more genomic instability or a higher genomic burden, and those patients may benefit from checkpoint inhibitors. And the really cool thing is CAR-Ts. People who relapse from CAR-Ts, one of the mechanisms of relapse may be through the PD-1-PDL-1 axis. Remember, we're giving activated T cells and they're not getting the job done enough, so maybe taking the foot off the brake to allow CAR-Ts to work better may be an answer. So even though they've been a little bit of a no-no, I think there's a big future for checkpoints in myeloma.