Ezra Cohen, MD, Associate Director of Translational Science, Moores Cancer Center at UC San Diego Health talks about a new way to possibly treat metastatic cancer.
Interview conducted by Ivanhoe Broadcast News in January 2019
The precision treatment with the T cells. Tell us a little bit about that.
Ezra: What we designed was essentially a truly individualized vaccine therapy for patients with cancer. Let me take a few steps back. And talk about how all this started. It really began with a current knowledge that everybody’s cancer is different. Even though we might see two patients and say that they have breast cancer, we know at a molecular level, in terms of the mutations and the different changes that those cancers have, that they are different. They are really completely different. That was the first realization: every single person’s cancer is different. The second was that everybody’s immune system is different and the immune response to that individual’s cancer is going to be different. We put those two pieces of knowledge together and realized that if we were really going to take the next big steps in cancer therapy, if we were going to think about curing patients with metastatic disease, with advanced cancer, then we had to design therapies that were really individualized, that were going to be for a specific patient because that is what the biology was telling us. With that in mind, we began thinking, “Well, how do you figure this out?” The sequencing part that analyzes cancer mutations was becoming routine practice and certainly routinely available in oncology. The other part of it was a lot more challenging. How do we ask a person’s immune system what that system is responding to with respect to the cancer? Well, that took us about four years. That’s really the novel part of what we are doing. We have set up a methodology that takes the cancer, analyzes it, takes a person’s blood, takes the immune cells out of that blood and puts them together in a functional assay that reads out what that person’s immune system is responding to. That took a little while to develop. We finally got it to a point where it was reliable, where we could get reproducible data. What was interesting was that what we found was everybody’s immune system was responding to their cancer in one way or another. The responses were different. There was some consistency to them. But there was a response there. The last part is how do you take that into a therapy because, at the end of the day, we want to make this applicable to patients. That is where the vaccine came in. We started talking to different vaccine manufacturers. We finally settled on a vaccine platform that we were convinced could induce an immune response. The immune response we wanted. We started working with that collaborator to now create the first truly individualized vaccine for cancer that was based on neoantigens. These mutations that are producing immune responses.
How far into the trial are you and have you seen any results yet?
Ezra: It is still early days in terms of the clinical study. The clinical study opened just a few months ago. It will enroll 10 patients in total. The third patient has just been enrolled. It is really too early to see clinical results. We realize that what we are trying to do is activate the immune system to activate against the cancer. That takes time. Vaccines take many months to start working. We have to be patient. Inherent in this entire process is that it takes time to understand the neoantigens. To identify them, it takes time to create the vaccine. It takes time for the vaccine to work. Right now, we are at a stage where we need patients whose cancers are not progressing very rapidly. We hope that one day this will be applicable to everybody even if their cancer is rapidly progressing. We do have to take time for the entire process, and eventually the clinical results to manifest.
And there’s a Keytruda component to this too.
Ezra: The other component that we are putting into the study is a drug that activates the T cells. The vaccine we think will stimulate those T cells, that the T cells are really the critical part of the immune system that we want to activate. The vaccine we think will boost those T cells that exist, and we have good evidence that the vaccine will do that. But when those T cells get to the tumor, the tumor is going to try to put them to sleep. That’s where the other drug comes in. The drug is called pembrolizumab or Keytruda. We are getting it through a collaboration with Merck, and what Keytruda does is that essentially it keeps those T cells from falling asleep once they get to the tumor. Hopefully once that happens, those T cells destroy the cancer.
So, it sounds like great teamwork between those two – the vaccine and the Pembro
Ezra: It really has been teamwork on many, many aspects. Exactly these are two different mechanisms, two different drugs. The vaccine and the pembrolizumab, the antibody that should work in concert to help fight the cancer.
And you said it’s for metastatic cancer, all kind of cancer?
Ezra: We are looking for patients who have metastatic disease. The nice part about this approach is it applies to every type of cancer, as long as the cancer has mutations. Every cancer has mutations. Our ability to identify these neoantigens, what the immune system is responding to, cuts across every cancer that we will see.
How is this different from current T cell research that’s going on?
Ezra: It is really a different therapy in multiple ways. The first is that every vaccine that we produce is meant for one person. It is truly, truly individualized. The other is the T cell therapies depend on some type of engineering outside the person’s body. Whether it is just infusing T cells, so we call that T cell therapy. That involves growing the T cells outside of a person’s body. If it is a CAR, T cells so a chimeric antigen receptor T cell, that involves taking the T cells from a person and actually engineering in a receptor that will be against the cancer and then putting those T cells back in the person. There are other types of T cell technologies as well. But all of them involve some sort of manipulation of the T cells. Here we are not doing that. We are taking the patient’s own immune system, and we are boosting that immune system based on our understanding of what the immune system is responding to. We are really depending on the natural process, and the immune system is pretty sophisticated. We have got something, you know, we have a process that is pretty good to rely on. We are really relying on that immune system sophistication to boost and eliminate the cancer.
So when you say it takes a long time, from the day that a patient enrolls to the day that they’re actually getting the vaccine how long?
Ezra: From day one, from the ability to get a tumor biopsy and begin the whole process until we’d actually do the vaccine injection is anywhere from three to four months. It is long and we realize that. In that three to four month period, patients can get treatment so that we can keep the cancer at least at bay. And in the future, there are many ways that can shrink that timeline. I think we can get it down to even six weeks which, I think would be acceptable for most cancer patients if not all cancer patients, but we are just starting the process. This is the first step. We are about three to four months.
Is this something that you anticipate will take off or will cost of treatment and research, there’s going to be some kind of crossroads?
Ezra: We thought about the scalability of this quite a bit. The whole purpose of doing this was to make an impact on patients. Even if the science was extraordinary and we could do all this, but at the end of the day if we could not make this scalable, then we are wasting our time. But there are ways to make this scalable. There are ways to make this widely applicable. First of all, the manufacturing will get faster, more efficient, and it will get better. This is the first time we are doing it and so we are honestly still learning, and we are still working out the kinks. That will get faster. The other thing is that we are beginning to recognize patterns as we see more and more patients, and we take more and more tumors through this process that I described. We are beginning to understand that there are some mutations that keep coming up as neoantigens, as something the immune system is responding to. What I can envision in the future is that we will get the patient sequencing, and that now takes two weeks at the most, we will identify certain mutations that we have seen before. For example a certain mutation keeps coming up and we know with 90 percent/ 99 percent certainty the immune system is going to respond to that mutation. You can imagine a day where we are going to create a few different versions of the vaccine. The first one that we can create in just a few weeks might be against the mutations that we are pretty sure the immune system is going to respond to. Come back with a second and third dose down the road with the truly unique mutations in that person’s cancer. I think in the future we will have a hybrid of something that we can apply quickly to get that immune system going and then individualize it completely that takes a little bit more time.
Have you seen any side effects so far in patients?
Ezra: We have seen good side effects. The side effects that we were hoping to see. Remember, we are trying to stimulate an immune response. What we have seen so far is that the place where we inject the vaccine hurts. To me, that is producing an inflammatory response. That is producing an immune response. I am viewing that as a good thing. I would be worried if it did not hurt at all. The other side effects we have seen have been relatively minor. Fatigue, some joint pains, things that we would expect. But so far it is been very, very well tolerated. We expected it to be because it is so individualized. Of course, time will tell if anything else comes up. The fact that the person’s arm is hurting after we put in the injection, to me I think that is a good thing.
Tamara she’s so excited about participating in this trial. Tell us a little bit about her case whatever you can.
Ezra: Tammy is amazing. Her story is really fantastic on multiple levels if you think about it. She’s a young woman who was diagnosed with a relatively rare cancer called pancreatic neuroendocrine tumor, and underwent curative therapy with surgery and was doing well. Unfortunately, the cancer came back. She had surgery again. Cancer came back. She had a third surgery. Cancer came back. She was at a point where really surgery did not make sense anymore. Unfortunately, with metastatic disease, the available therapies are not curative. We began talking to her doctor, Dr. Paul Fanta, who is fantastic, about this approach that is truly individualized. That helps to stimulate the immune system, and she understood it. She was fully on board. In many ways, she is the ideal patient to start with. She is healthy. She is young. Her cancer is giving us time. It is not rapidly progressing. And scientifically, pancreatic neurendocrine tumors have a very low mutational burden. What I mean by that is that as opposed to say melanoma or lung cancer where those cancers have a lot of mutations. Her cancer actually just has a few mutations. And for us, the identification of the neoantigens that we think works in every cancer and one of the advantages is that it works even in patients whose cancers have only a few mutations. Not only was Tammy an ideal patient, but even the cancer that she has was an ideal proof of principle for us to apply this.
Awesome. What haven’t I asked you that would like to include in the story?
Ezra: The other critical and key component of all this has been a collaboration with La Jolla Institute and specifically, Dr. Steven Schoenberger. I met Steve at the beginning of this process about four years ago, and we began talking in general terms how can we take immunotherapy to the next big step. That big step for us was actually curing patients. I remember this conversation like it was yesterday. We sat in his office. We started making notes on his whiteboard, and a diagram of what we would need to do to be where we wanted to be. We didn’t take a picture of it, unfortunately. But that’s exactly what we did. What we drew out that day about four years ago. I am privileged to be working with an exceptional scientist in the field, and we really leveraged both our skill sets with me in the clinic and with him being a world class immunologist to try to bring this therapy to patients. It has been a pleasure.
When you were talking with Tammy in the room downstairs you mentioned that lack or less cells.
Ezra: Right now, Tammy has gotten all three doses of the vaccine, and she is receiving the pembrolizumab. What is interesting is that on the clinical study, we do a second tumor biopsy after the third dose of the vaccine. We do that primarily to see what is going on in the tumor, and if there are now T cells in the cancer where there were not before. What we noticed in that biopsy were two very interesting things. The first is there are T cells there, which was very encouraging. The right types of T cells as well. The second was that there were not a lot of cancer cells. I do not know what to make of that yet. Obviously, time will tell. But the fact that we did not see a lot of cancer cells when we did the biopsy, right now, leads me to be cautiously optimistic.
END OF INTERVIEW
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