OncoResponse is an immunotherapy company that leverages its proprietary human antibody platform to discover novel targets and identify fully human monoclonal antibodies. The mAbs can be used as therapeutics for the treatment of cancer and extending cures to the greatest number of patients who otherwise would not respond to immunotherapy.
The company shares a broad strategic alliance with MD Anderson Cancer Center that is enabling them to discover antibodies from Elite Responders to cancer immunotherapy that target and modulate immune cells in the tumor microenvironment (TME).
OncoResponse’s Chief Medical Officer, Bob Lechleider, M.D., discussed the nature of cancer, immunotherapy, and the company’s proprietary drug OR2805 with SCINQ.
What goes wrong in a person’s body and DNA that causes cancer in general?
Cancer is an aberrant outgrowth of normal cells. It’s important to distinguish that it can happen two ways. We all have benign tumors. Those are tumors that are aberrant growths of cells but don’t really cause you any trouble. Think about a wart or a freckle. Sometimes people get little fatty deposits out of their skin called lipomas. Those may be cosmetically unattractive but they’re not going to kill you. They’re benign growths.
Cancer is one of those benign growths that one runs out of control and could invade local tissues and potentially move to distant sites. The way I think about cancer, I like to divide it up into two very big families.
One is the hematological malignancies, the blood cancers. Leukemia, lymphoma, myelodysplastic syndromes, things like that. The other are the solid tumors, which is everything else. It’s important to remember that cancers all come from a single cell. The original cancer, whatever it is, is a clonal growth. It’s derived from one cell that becomes abnormal and is allowed to grow. That’s both true for blood cancers and for solid tumors.
We all have a lot of cells in our body and many of them are dividing all the time. Think about skin cells constantly replenishing themselves, the cells in your gut constantly replenishing themselves. The cells in your blood are constantly replenishing themselves.
Other cells don’t grow as often — neurons, muscle cells, certain bone cells, things like that. Every time the cells replicate and make a copy of themselves, there’s the possibility for introduction of error in the DNA. It happens all the time, and we have normal mechanisms to repair that error.
There are molecules within yourself that look after your DNA and make sure that the DNA that’s been replicated is a faithful copy of the original. However, you can get errors introduced into the DNA. Most of the time those errors are going to be benign. Sometimes those errors introduce changes into the cell that allow it to first, grow uncontrollably. Second, go to spaces it should not normally go to. That’s really what it is, in a very basic sense, what makes cancer.
There are a lot of different causes for that introduction of error, there are environmental factors, the best example probably being tobacco smoking.
Normally, every time you replicate, there’s so many base pairs that must be copied faithfully, that their errors just happen every now and then in a very low event, but it can happen.
Why doesn’t the body essentially correct those?
It does almost all the time. There are viruses or other things that can cause those errors. Almost all the time your body corrects it.
Occasionally, what happens is that you get an error in the DNA. There are good examples where it’s just a single mutation and a cell starts to grow uncontrollably. It has the ability to move outside its normal space, and your body fails to recognize that and kill that cell. That’s when you get cancer. There are many other mechanisms involved in the biology of cancer, such as building new blood vessels, and other things that have to accumulate in the cancer to make it work. But that’s the basic part of it.
Does it snowball off that single cell?
The single cell accumulates enough changes to be able to grow and move. That cell just keeps growing. This is a very simple explanation. It’s way more complex than that, in reality. Breast cancer is a great example.
In breast cancer, you can get a group of cells that are growing more quickly. They’ll show up on a mammogram, sometimes, and you can take those out, and they’ll be what’s called ductal carcinoma in situ. And what that is, is a set of cells that stay where they’re supposed to be, they’re not going anywhere, but they’re growing too much. It’s like a wart on your skin. There are too many cells. but they’re not going anywhere. They’re just staying right there. They’re just going to grow, maybe they’ll get bigger right there, but they’re not going to move up your arm or into your eyeball, or anything like that. They’re just going to stay right there.
Now, these ductal carcinoma in situ cells, they can grow and grow. They can recruit other factors that allow them to then invade into the surrounding tissue. Then you get an invasive carcinoma, and that’s where it starts to get dangerous.
Normally, your body recognizes those cells very early on, but sometimes they have what’s called immune evasion, and they’re allowed to grow. They accumulate other changes that allow them to move around to other parts of the body and can cause real damage. But they all start from one cell.
Is there something genetically that sort of determines whether a tumor goes from being benign to malignant? Is there something that triggers that shift?
There are a lot of factors that go into that. Some of those are based on the host such as genetic factors; others are environmental factors.
There are a whole host of factors such as how quickly it’s proliferating and what the mutations are that are originally acquired by the cell, what the degree of immune surveillance is, where it is. All kinds of things go into determining whether something’s going to grow and stay put or grow and move or not grow at all. There’s no one thing.
Does cancer immunotherapy vary between person to person and how their immune systems respond to therapy?
One of the big issues in cancer drug development, and it has been for a long time, is that we know that some people respond exquisitely well to any particular cancer therapy, whether it’s a chemotherapy or an immunotherapy or radiation therapy, that some patients will have cures, and other patients will have no response whatsoever. Some patients will respond great. Most patients won’t respond at all. On the other hand, some patients will have an in between response.
What are the factors that influence those responses?
What things that the patient either has inherently or develops during the course of therapy can help us understand how patients respond or don’t respond to therapy. It’s a huge question in oncology right now. And has been for a long time.
Can you just give a background into what immunotherapy consists of, for those unfamiliar with it?
Your body has a normal surveillance mechanism to identify and weed out cells that are different such as damaged cells, cells that are potentially cancerous. Under most circumstances, that works well. Your immune system is composed very broadly of two components – a lymphoid component and a myeloid component. They both contribute to the identification and elimination of potentially harmful cells, and they have a whole host of other normal things they do such as fighting off infections and helping with wound healing.
Cancer immunotherapy has really focused on the activity of T cells. T cells are important because a class of T cells can identify and kill specific cells. They do the same thing with viruses, right? So, T cell response is very important in viral infection, but they can identify and kill cells that are funny. During normal human development, your immune system learns to recognize itself. It learns to recognize you because it doesn’t want to attack you.
Normally, your immune system recognizes you, when it sees “not you”, when it sees a virus, or it sees a cancer cell that has a funny look to it – that’s not the technical term – specific T cells can identify that cell and kill that cell directly. That’s an adaptive response. There are other cells that have a more generalized response that they can kill any cell if it’s got particular characteristics that don’t have to be generated.
So, for example, macrophages. If they see a cell that’s coated with antibody they can bind to that antibody and kill that cell. Cancer immunotherapy up till now has focused on the T cell. It probably started out with the identification that there were T cells within tumors called tumor infiltrating lymphocytes. If you took them out and grew them up, this was a lot of work that Steve Rosenberg did at the National Cancer Institute, if he took the cells and grew them, and then put them back in patients, some patients would respond that they would have a shrinkage of their tumors.
This is over the course of decades of work, identifying the mechanism of how those T cells worked, or didn’t work. What we found was that in tumors, those T cells were turned off. They had maybe started to do their job, and then just stopped. They were still there, in many cases, but they didn’t really do anything. What was found was that there was a set of molecules called checkpoints on the T cell that, when they were over activated, would turn off the T cell. So there is a normal response.
Now, let’s go back to the normal immune response and think about that for a minute. What happens if you cut yourself, right? Aside from fixing the blood vessels, you have an immune response. It’s a wound and the T cells come in and clean up the bacteria and anything else that’s in there.
But you really want to turn that off, otherwise, you’re going to have this inflamed wound that’s going to go on forever. The T cells come in, they’re active for a while, and then they get turned off by other cells that come in and help turn them off. Under normal circumstances, that process works well, you get a cut, it’s a little bit inflamed for a day or two, and then it goes away. Because that’s a normal response.
It’s nice to think of the cancer as a wound that basically isn’t healing. The reason for that is that the T cell response has been turned off before it’s done. The T cells come in, maybe they start to attack the tumor, but the tumor makes factors that shut off that T cell.
The big idea in cancer immunotherapy was to say, okay, what are those receptors on the T cell or those molecules on the tumor that are turning off the T cell? And can we turn them back on? Those are checkpoints. And there’s a lot of you know, this is a very kind of simplified version of this work that’s done over decades that led to the Nobel Prize.
The first of those have made it into clinic with an antibody against CTLA-4. The next example was drugs which target either PD-1 or PD-L1. And you’ve heard of Keytruda and Opdivo. Those are drugs that are approved for therapy that are directed against the T cells. What those molecules do is they reactivate those quiet T cells. Now, again, they don’t work all the time. If they work well, they work really well. They’re great. They revolutionized cancer therapy, but not everybody’s cured and not everybody even responds at all.
When we talk about immunotherapy, by and large, what we’re talking about are, PD-1, PD-L1, and CTLA-4 (to some extent to it’s used in a few and marketed for a few cancers). PD-1 and PD-L1 are the big players. We’re really talking about checkpoint inhibition or immune checkpoint inhibition. So, you’ll see it abbreviated either ICI or CPI. Those are the mainstay of cancer immunotherapy.
The whole question now, in my mind in Cancer Immunotherapy is: how can we get PD-1s or PD-L1s to work in everybody? Why are they not working with some patients? And what can we do to get them to work for everybody? I think, now, there may be some other molecule like PD-1 that’s out there that we haven’t yet interrogated that may be as good as – but I doubt it. I think that’s probably the key player, and we need to work off that key player.
The real question is, what can we do to the T cell? What can we do to the other cells in the tumor microenvironment? That is not just the tumor itself, but the cells around the tumor because tumors are very complex, kind of like organs in a way. What can we do around those other cells to help the T cells do their job? Because they’ve already been told, hey, get turned on; you’ve given them an anti-PD-1, and they’re like, hey, get active.
But then something else in some patients and most patients is preventing them from really doing everything that they can do. How can we get at that and help them kind of work through where they should?
What is a tumor microenvironment? What does it consist of?
When we talk about the tumor microenvironment, what we really mean is everything in the tumor that is really supporting its growth and is potentially usable to target against the tumor itself. The tumor microenvironment consists of the blood vessels that need to grow into the tumor. So, if you think about a tumor, once it’s above a tiny little speck, it needs its own blood supply. Tumors have their own vasculature; they have their own structure to keep them going with nutrients and oxygen exchange, many things like that. There are what we call stromal cells, which are cells that help support the tumor. Different tumors have different amounts of each of these things.
Some tumors are highly vascular, some are not so vascular. Some have a lot of these stromal cells like pancreatic cancer, some have relatively few. These stromal cells we’re learning now have a role in supporting the tumor. They secrete factors that allow the tumors to grow. There’s kind of a symbiotic relationship. That they’re “normal cells.” They’re not, they can’t grow independently, they’re not transformed to be able to grow in a petri dish like cancer cells are.
The tumor promotes their growth, and they promote the tumor’s growth. Then there’s a whole host of immune cells. There’s T cells, or macrophages, there are NK cells, there are B cells, there are myeloid derived suppressor cells. All these cells have been recruited by the tumor and influenced by the cancer cells to help support the tumor growth and/ or to suppress an immune response.
Does the tumor microenvironment have mechanisms that expel toxins?
If you think about it, it’s a complex organ, right, and it’s different for every tumor, which makes it incredibly hard to study. The tumor itself changes the metabolism. Some tumors are very rich in vasculature. They can exchange metabolic products. It is exquisitely designed to promote the growth of those cells, right. If you can influence the microenvironment such that it doesn’t work as well, you have a greater ability to kill the tumor. The best example of that right now is Avastin.
Avastin is a drug that was developed to target angiogenesis, new blood vessel growth. By doing that, preventing the tumor from getting the nutrients and getting rid of the toxins that it produces, and potentially killing it often works partly that way, it works in other ways to help it work. When Genentech developed it, they thought this is going to be it, we’re going to kill all tumors. It’s more complex than that and tumors have ways of getting around it.
Avastin is a very important drug in the arsenal though. It’s an important concept to think that if you can attack the microenvironment of the tumor, including the vessels, you can potentially shut down the tumor.
So how does OncoResponse’s platform fit into all of this?
Everyone wants to identify ways of potentiating the immune response. OncoResponse said, the best culture dish for understanding how patients respond to PD-1 therapy is actually the patient.
The idea is, we could look at patients who had really, really, good responses to checkpoint inhibitor therapy, that is to cancer immunotherapy, and see if they would give clues as to how to get other patients to do the same thing. The idea was that these patients – we call them Elite Responders – were making antibodies that help them to respond to checkpoint inhibition.
What we set out to do was, first, identify those patients. That’s not that hard. Get some samples from them, serum and blood. That’s a little bit harder, and then screen against targets in the tumor microenvironment that we thought might be important for regulating that response. That’s the harder bit.
The premise is Elite Responders are making factors – in this case, antibodies – that are helping them potentiate the response to the PD-1 therapies. We sought to identify what those factors were.
We thought because the patients are doing it, they’re the best test tube. Other people do it by looking and understanding the immune system and using model systems like mice and in vitro systems and identifying the pathways and then saying, okay, we’re going to target that.
We went right to the heart of the matter and looked functionally at what these elite responders are doing that is allowing them to do so well with checkpoint inhibition therapy?
The first target that we looked at was, what are called M2 macrophages. Their normal role is in wound healing to help turn off that immune response. We talked about that earlier. T cells come in, they clean everything up. Macrophages come in, they clean everything up at some point. Somebody has to turn that off. These M2 macrophages get signals from the environment and then start to turn down the immune system.
Now, it’s good in a wound because you don’t want to have that inflammation. It’s bad in the tumor, because you want that inflammation to go on to kill the tumor. These M2 macrophages, they’re in the tumor, and they suppress the T cell response.
The idea was, are there patients who’ve had really good responses, who have managed to keep those macrophages active? Have they managed to turn off those immunosuppressive macrophages and make them be more stimulatory? That’s how we started out to look at the tumor, the tumor microenvironment and how patients might respond to it with their potential therapies, based on that.
The drug that you’re developing is called OR2805. What is the mechanism for its activity?
The way that the screen works is we identify a patient. We have target cells, M2 macrophages. We want to see antibodies bound to M2 macrophages in their blood. We have technology that allows us to grow individual memory B cells at clonal density. We can take the supernatants from each of those clones, which have a monoclonal antibody – so a single antibody – and then screen those supernatants against our target.
We can look at up to about 200,000 different individual clones, which should cover most of the B cell repertoire and look and screen each of those individually against our target using high throughput robotic screening techniques. We do that and then we find out, aha, there’s a bunch of antibodies that potentially bind to our target. We do a negative screen. We’ll ask if they bind to M1 macrophages, and those that do we throw away, and then we have a set that binds to the M2 macrophages. That just tells us one thing so far. That just tells us that they bind.
The second question is, are they functional? What we can do then is take those antibodies and look and see whether they altered the phenotype of those M2 macrophages. Some of them are just going to bind to some target and not do anything. Others are going to bind and change the phenotype of the M2 macrophages and make them more immunostimulatory.
That’s how we got to OR2805. We knew the target was on the cell, but we didn’t know what the molecular target was of that antibody. We didn’t know that it was CD163. We found that out later when we characterized the antibody that we got. We had this antibody that bound to M2s and did not bind to M1s, changed the phenotype of those M2s to make them more M1-like.
There’s a lot of plasticity in the macrophage differentiation pathway and they move more towards an M1-like phenotype but importantly, they have characteristics that allow them to stimulate T cell growth and activity.
Then we did all the biochemical work to try to understand what it bound to, what was the affinity, what was the epitope, all that kind of work. But this is from a patient who made this antibody that alters the activity of M2 macrophages to make them more immunostimulatory.
Now, one question that comes up as kind of an aside, but always comes up is: why are cancer patients making antibodies to their own proteins? It’s a normal protein. It’s not one of those funny proteins I told you about earlier that’s mutated. So it gets recognized right away. It’s normal protein. Cancer patients have an altered immune response. They lose the ability to recognize self, so to speak. It’s called breaking tolerance. They’ll start to make antibodies to self-antigens. Normally that’s prevented, but in the context of the tumor that is allowed to happen. So it’s well known that cancer patients make antibodies to a lot of things that normal individuals do not.
What are your next steps for companies for testing?
Cancer drug development is really straightforward, right? I mean if you think about it the right way. We must determine the safety of the molecule. That’s the most important thing.
I spent a year at the FDA and the FDA cares a lot about safety, as they should. That’s totally appropriate. The first thing I have to do is establish that it’s safe and then the, the next big thing is determine whether or not there’s any activity as a monotherapy.
We would predict based on our preclinical data, that OR2805 will have activity on its own in some tumor types. We don’t know which and we don’t know how good that activity will be. But we predict that we will see some degree of activity when OR2805 is used as a monotherapy. As I told you, previously, almost every cancer patient is treated with a PD-1 or PD-L1. We really want to understand what it looks like not only as a monotherapy, but also as a combination with PD-1. This is important for a variety of reasons.
First, the FDA wants to know what your monotherapy activity looks like. Investors want to know, scientists and clinical investigators want to know and you really need to establish that and understand how that works. The combination is also important because you’re going to want to combine with the PD-1 drug because that’s going to give the biggest bang for your buck. It’s probably some combination. Combination therapy is common in oncology. We always use combinations; we hardly ever use a single drug. So that will be what we’ll do.
For OR2805, the next step is after we establish a safe dose will be to go forward and look at various specific tumor types for monotherapy activity and combination therapy activity to try to understand the path forward for development.
Then we’ll just do the hard work to demonstrate that we have a safe and effective drug. That’s the path for OR2805.
We think it is given that OR2805 is targeting a novel target in the myeloid compartment, which we know is important for regulation of immune response. We think OR2805 is a shining star for the company.
Our second product going into the clinic will be an antibody to LILRB2. LILRB2 as a known target on macrophages. There are other companies that are in the clinic with a LILRB2 antibody. One of them, Merck, has published results that show that there is a modest degree of single agent activity and good activity in combination with Keytruda.
We know that cancer patients make antibodies to LILRB2 so that’s probably an important target. We decided to develop a better antibody. We’ve published some poster presentations at AACR, data that suggests to us that we have something that is better than what’s out there.
The company has a great platform. We have the ability to interrogate patients who had great response to their cancer and we are now in the process of going back and doing that, again, looking at different cell types. I can’t tell you exactly which cell types, but we feel like we’ve done a good job with macrophage biology. We’re going to go back and look and understand other types of cells in the tumor microenvironment that may be important to target to help potentiate PD-1 responses.