Dr Azab Highlights Nanoparticle T Cell Engagers for Patients With AML

Kareem Azab, PhD, Associate Professor, Department of Radiation Oncology, Department of Biomedical Engineering, Washington University, St. Louis, Missouri, highlights nanoparticle T cell engagers for the treatment of patients with acute myeloid leukemia (AML).

Transcript

Hi. My name is Kareem Azab. I'm an associate professor at the Department of Radiation Oncology and at the Department of Biomedical Engineering at Washington University in St. Louis.

The beginnings started from the CAR-T therapy studies that showed beautiful data and response. However, we're also aware of how expensive and how complicated that is to make. The general theme in my lab is we take existing medical/clinical problems, and we try to solve them, which is what we call translational medicine.

We wanted to start thinking about solution to improve immunotherapy, CAR-T cell-mediated immunotherapy, in a way that can simplify and make this therapy more accessible to people because, currently, CAR-Ts cost about a million dollars per patient. That's a lot of money. Therefore, we see that a lot of companies, other companies, not only us, pharmaceutical companies and other researchers and universities, started to think about alternative to CAR-T cells.

One of them was bispecific T cell engagers. In the bispecific T cell engagers, you don't genetically engineer T cells out of the body, like what's done in CAR-Ts. We rely on the T cells that are already inside, and we give them a molecule to direct them into the tumor. The se are the bispecifics.

With CAR-Ts, we take cells from a patient. We genetically engineer them to express recognition molecule that recognizes cancer cells with lentiviruses outside the body. It needs a lot of QA—It needs a lot of work to purify and clean these cells, just from a safety perspective. Then we ship them back to the hospital, and we give it back to the patient.

These T cells will recognize the cancer cells and kill them. The bispecific T cell engagers don't take any T cells out. We give a bispecific antibody. It is like a molecule that has 2 sides. One side that binds the T cell, one side that binds the cancer, and they engage them together.

In that case, the T cells will now be in a close proximity to the cancer cells, will get activated and kill the cancer cells. This sounds great. The only problem with that is that at least the first generations of this technology, it had bad pharmacokinetics. It means patients needed to be on an infusion continuously for weeks.

Some pictures we saw of patients having backpacks of infusions on them. We said, "OK, that's not a good way to give things." From here, we started thinking about how can we improve this to still have the good component of the bispecific engagement, but have a much better kinetics or a dosing regimen.

There was another problem that still exists now for both CAR-Ts and for the bispecific T cell engagers, which is that each 1 of these is targeting generally 1 molecule on the surface of cancer. We pick 1 receptor that we know it's highly expressed on that cancer type. We design our therapies to target.

This is great in a way because it makes it specific—less side effects. However, with what we know now about cancer more and more, that cancer is not monoclonal. The idea that we had 10 or 20 years ago that cancer is one cell that starts dividing and dividing, and making the tumor, is totally not correct. Now we know that cancer is actually a polyclonal disease, or at least a multiclonal disease. In every tumor, we have more than 1 clone. Some cells will express more of that receptor, less of that receptor. Cells which will have a lot of it will be killed and cured. We started to notice with these therapies that after a while, we will have recurrences of what we call antigenless tumors.

We get rid of all of these cells that have this specific antigen, but then this therapy will stop working because the tumors will lose this 1 specific antigen. The idea of solving these 2 problems led us to that project.

We described the problem, now we will describe the solution.

What we have is we got a nanoparticle that looks like a sphere. Imagine a sphere. On that sphere, we stick from 1 side an antibody that recognizes the cancer. From the other side, an antibody that recognizes the T cell and activates it.

In that case, we still maintain that this molecule will hold the T cell in 1 hand, the cancer cell in 1 hand and put them together, just like the regular bispecific T cell engagers. But, because we have this big nanoparticle, now the pharmacokinetics in the blood will depend mainly on this, not on the small recognition areas like in the bispecifics.

Instead of a half-life of 2 hours that the early bispecifics had, now we have a half-life of 1 week. It means the patient can take this once-a-week injection, instead of having it every day several times or a continuous infusion.

The other great thing about it, that there is a big surface on that nanoparticle that we can not only put 1 and 1, we can put 1 antibody that engages the T cells, and then put multiple antibodies that target multiple clones of cancer.

Say, we have a tumor that has 3 clones. Now we can stick 3 different antibodies on the surface, and this 1 therapeutic entity can now treat all the 3 different antigens or the 3 different clones of cancer. In that case, we will have way much less tumor recurrence. There is much lower chance for what we call antigenless tumor escape, which are cells that have no specific antigen that the treatment is designed against.

We have shown that when we combine more than 1 antigen, the results are much better compared to targeting a single antigen at a time. This is not a new idea to the field. People doing CAR-Ts have been trying to do that—people doing T cell engagers have been trying to do that. Unfortunately, unsuccessfully because of the technical problems.

For example, in T cells, when you want to add 2 genes, it's much harder than adding 1 gene. If you add 3 genes, it's even harder and harder. In that case, because we have a big surface of that nanoparticle, we literally pick and choose antibodies, and we stick them very simply. It's a process that takes 3 hours.

As a principle, if you come to me today and you say, "Hey, I have a cancer patient that has this specific antigen on the cell," and we have already an antibody for that, I can make the therapy in 3 hours. It can be very personalized.

What surprised us was how easy this could be done and how effective it can be.

As a principle, we have an IP rights on that. We have that pending now. We are planning to develop it as a therapy.

We are going in 2 routes. The first route is to have it per disease. The way we are thinking about it in a more general way, which is to open it to not necessarily against a specific disease, but make it more of a platform which will be matched to per patient.

The idea is we have these liposomes ready to use. These nanoparticles are ready to prepare. We can have them as ready products to sell in the pharmacy against specific molecules or against specific diseases, or we are thinking also to have it as a service per patient where we will design therapy exactly in correlation with the biological features of every patient. We will have a biopsy from the patient. We will screen which epitopes are there. Then we will design the therapy specifically for each patient, which I think will make the therapy much more effective.

There is a lot of things to do down the road. One is to expand to other diseases, specifically in terms of solid tumors. Right now, CAR-T cells technology and bispecifics are very limited to solid tumors. There's plenty of it in hematologic malignancies but, right now, much less for solid tumors. We will try to expand there, especially that nanoparticles can specifically accumulate in solid tumors for many biological reasons, so it will even enhance the specificity of these in solid tumors. That's one direction that we are taking it to. Hopefully, we will be able to do that.

The other big direction that we're trying to work on is to have 1 universal bispecific T cell engager for all cancers, but this is in a much earlier stage. We're going 2 opposite directions. We're going into specifying it for individual patients and we're trying also to expand it to be just a pan-cancer therapy, and all the things in between.