Cancer Immunotherapies Tim Pierpont Regan Stephenson September 2018 The goal of our talk is to give a brief overview of what immunotherapies are, and highlight some of the more exciting treatments with a little bit about how they work. We’ve prepared about a 20 minute talk, but I believe we have plenty of time for questions so feel free to interrupt with either question or if either of us say something you don’t understand Immunotherapies have been increasingly in the news, some of you may have either had them or know someone who has

One of the most well known headlines happened about3 years ago when Jimmy Carter was diagnosed with metatstic melanoma, Stage 4, spready to brain and liver Radiation and immunotherapy Complete remission Stage 4 melanoma survival rate is not great, especially among older patients, and he’s currently 92 and still building houses. Immunotherapies hold a lot of promise for actually curing cancers, but I’m not sure they’re often defined very clearly

What is immunotherapy? Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. So what is cancer immunotherapy? ACS definitions.. This is pretty accurate. But it doesn’t actually explain how we use the immune system to fight cancer

Immune system: Infections So what makes immunotherapy have so much potential? The best analogy I’ve heard so far is a reference to how well it fights off infectious disease. Animated here, a cell infected with a virus will get recognized by the immune system and killed. The ability to find and eradicate infections all over the body is impressive and emphasized by the point that people with severely compromised immune systems can’t fight off any infection and will almost certainly be killed by it anything you or I could fight off. I think everything can relate to that idea, but what might be less known is that our immune system already does a pretty good job of fighting cancer on it’s own

Immune system: Transformed cells When a cell acquires mutations and starts heading towards becoming a cancer, the immune system already has the ability to detect and kill those cells, although we don’t really know how often it happens.

Immune system: Transformed cells But one of the hallmarks of cancer is that it gains the ability to evade the immune system.

Immune system: Cancer This can happen in many ways, some of which I’ll tell you about later, but once the immune system can no longer target and kill a transformed cell Or at least not sufficiently, It is then able to go on growing until it becomes a real problem

Immune system: Immunotherapies Immunotherapy works in two general ways to tackle this problem One, is to help the immune system recognize or target the cancer cells again. The other, is to bolster the immune system to be able to target or kill them Or some combination of these two concepts Although most therapies is highly tailored to a specific cancer, the idealistic hope is that we can use some combination of these therapies to cure most, if not all cancers, with as few side effects as possible. If you go back to the analogy about how efficiently our bodies fight off foreign disease, you can appreciate why there’s a lot of hope in the potential of cancer immunotherapies.

Monoclonal Antibodies So, I’m going to talk about one class of immunotherapies called monoclonal antibodies, and Regan will talk about… Monoclonal antibodies generally work by helping the immune system recognize cancer cells better

Anti-cancer monoclonal antibodies I wanted to highlight two monoclonals here that I thought were most relevant.

How do monoclonal antibodies kill cancer cells? So how does an antibody kill a cancer cell? The honest answer is that we know how it can happen, but we don’t entirely know which methods are important clinically, although evidence for all the mechanisms of killing are found. It’s generally believed that NK cells are the most important facilitators of mAb response. They recognized the bound antibody and release factors that kill the target cell. Macrophages also recognize bound antibodies and phagocytose the cancer cell Components of the compliment system also recognize bound andiodies and form what’s called a membrane attack complex which pokes a big hole in the cell membrane, these cells die due to the compromised membrane. What’s presumed to be the least important factor in most cases are direct cell killing. Here, through mostly unknown mechanisms, just the binding of the antibody to the cell can cause the cell to trigger its own death. Finally, a totally different mechanism can be used by conjugating the antibody to a toxin and having that antibody bring the toxin to the cancer cell. Just to emphasize the complexity of immunotherapies and what is still left to be figured out. Most of my work right now is actually trying to understand how rituximab is really working to kill cancer cells and what factors control or predict how well it works. And that treatment has been in use for 20 years now. ADCC ADP CDC Direct Conjugated

Monoclonal Antibodies Manipulating them in vitro, either actually changing them or at least expanding their population And then reintroducing them to the patient. In case you haven’t heard of a T cell before… Adoptive cell transfer (ACT)

T cells eliminate disease sources in the body, but have a hard time fighting cancerous cells. Bacterial infections Fungal infections T cells are an multi-talented immune cell that can fight off bad stuff including bacteria, fungi, virally infected cells, and parasites. They even fight some early pre-cancerous cells, but they can’t always eliminate cancer cells because tumor cells have evolved ways to hide. T cell Viral Infections Parasites

Adoptive Cell Therapy – CAR-T Engineered cancer-killing immune cells One way to use immunotherapy to target cancer is to take out the patient’s T cells, genetically engineer them to have a cancer-finding protein on their surface, and then put them back into the patient. Since T cells already have the mechanisms to kill cells ,now that they have the finder protein called a CAR they can seek and destroy cancer. Patient’s T cell Cancer-specific CAR-T cell Genetic engineering

CAR-T cell therapy Engineered cancer-killing immune cells 3:29-5:07 minutes CAR-T therapy is very expensive so it’s usually reserved for very advanced cancers and as the last possible option. Here is a success story video. Notice how sick Emily is before treatment and how quickly she rebounded with this immunotherapy

Monoclonal Antibodies Checkpoint Blockade Inhibitors Another important immunotherapy is checkpoint blockade inhibitors. Like I mentioned, immune cells can recognize cancer cells on their own and kill them. However, cancer cells evolve to survive and one way is to express a marker that tells T-cells not to kill it. There’s a lot of interest in developing drugs that target those receptors to block that interaction so that the T-cell will kill the cancer cell. Adoptive cell transfer (ACT)

Checkpoint Blockade Inhibitors Turning on T cells T Cell PD-1 PD-L1 The key players of this hiding mechanism are PD-1 on T cells and PD-L1 on tumor cell. When they find eachother, the T cell is relaxed and doesn’t recognize the tumor cell as dangerous. ________________________________________________ Yervoy >> (CTLA4 – T cell activation )melanoma Keytruda>> (Pd-1) non-small cell lung cancer, Hodgkin lymphoma, gastric cancer, melanoma, cervical cancer, head and neck squamous cell cancer, urothelial bladder cancer, primary mediastinal B cell lymphoma Opdivo >> (Pd-1) non-small cell lung cancer, small cell lung cancer, metastatic melanoma, renal cell carcinoma (kidney), hepatocellular carcinoma (liver), advanced bladder cancer, advanced Hodgkin Bavencio >> (PDL-1) metastatic Merkel cell carcinoma Tumor Cell

Checkpoint Blockade Inhibitors Turning on T cells T Cell T Cell PD-1 PD-L1 Now some immune checkpoint inhibitors are antibodies that can block the interaction between these surface proteins Yervoy >> (CTLA4 – T cell activation )melanoma Keytruda>> (Pd-1) non-small cell lung cancer, Hodgkin lymphoma, gastric cancer, melanoma, cervical cancer, head and neck squamous cell cancer, urothelial bladder cancer, primary mediastinal B cell lymphoma Opdivo >> (Pd-1) non-small cell lung cancer, small cell lung cancer, metastatic melanoma, renal cell carcinoma (kidney), hepatocellular carcinoma (liver), advanced bladder cancer, advanced Hodgkin Bavencio >> (PDL-1) metastatic Merkel cell carcinoma Tumor Cell Tumor Cell

Checkpoint Blockade Inhibitors Turning on T cells T Cell T Cell PD-1 PD-L1 And when the interaction is blocked, the T cell is active and ready to fight the tumor cell. I some of these blockade inhibitors block at Pd-1 others and PD-1 or another molecule called CTLA-4 on T cells that works in the same way. I have included the names of some FDA approved immune checkpoint inhibitors here that are FDA approved for many cancers, since this interaction is not cancer type specific. _______________________________________________________ Yervoy >> (CTLA4 – T cell activation )melanoma Keytruda>> (Pd-1) non-small cell lung cancer, Hodgkin lymphoma, gastric cancer, melanoma, cervical cancer, head and neck squamous cell cancer, urothelial bladder cancer, primary mediastinal B cell lymphoma Opdivo >> (Pd-1) non-small cell lung cancer, small cell lung cancer, metastatic melanoma, renal cell carcinoma (kidney), hepatocellular carcinoma (liver), advanced bladder cancer, advanced Hodgkin Bavencio >> (PDL-1) metastatic Merkel cell carcinoma Tumor Cell Tumor Cell

Monoclonal Antibodies Checkpoint Blockade Inhibitors Now we are at the last immunotherapy that we are going to discuss. It is referred to as BCG (because it’s French sounding) and is approved for Bladder cancer. It’s an immunotherapy that uses a safe bacteria to activate the immune system. While this seems like a wild idea, there is a lot of history to back it up. Adoptive cell transfer (ACT) BCG

Using bacterial “foreign” signals to jumpstart the immune system to fight cancer Dr. William Coley was an American bone surgeon who successfully treated a man with a throat tumor by injecting the bacteria known to cause erysipelas repeatedly into his tumor. The man previously had just weeks to live, but Coley gave him 8 years. Dr. Coley went on to ambitiously inject many tumors, but had no idea why it worked and had very inconsistent success and many bad outcomes. He later used bacterial toxins instead of the live bacteria to induce the same effect and it was produced from 1899 to 1951 by Parke-Davis and Company until the FDA officially outlawed it in 1962. Later, his daughter worked to better catalog the successes of her father’s work and research the mechanism. For that , we have the budding field of immunotherapy and some better understanding of how this next immunotherapy works. http://discovermagazine.com/2016/april/11-germ-of-an-idea Dr. William Coley 1862-1936 The Cancer Resource Institute Carl Engelking, Discover Magazine, April 2017

BCG for bladder cancer Immune Cells Bacillus Calmette–Guérin An immunotherapy for bladder cancer that uses a different and safe bacteria with mild side effects to activate the immunes system in the lining of the bladder. These bacilli are engulfed by the cancer cells and processed by the immune cells then recruit more immune cells for an increased response. This new localized army of immune cells in the bladder out-compete the cancer cells and eliminate them although the direct mechanisms are still unclear after nearly 50 years of use in the clinic. _____________________________ Potential mechanisms of action Cancer cell phagocytose the BCG Present BCG like an APC Adapted from the American Cancer Society

Thank you Monoclonal Antibodies Checkpoint Blockade Inhibitors With that we would like to thank you for your attention to our talk on cancer immunotherapies. We are both happy to discuss these topic further if you have any more questions or thoughts on the subject. Thank you. Adoptive cell transfer (ACT) BCG