November 07, 2018
By Julie Gould
Podcast Series: In this episode, Steven Albelda, MD, professor of medicine at the University of Pennsylvania, Pulmonary Division, discusses a $10 million grant that Penn Medicine recently received from the National Cancer Institute and explains how a team of researchers hopes to expand the use of CAR-T therapy and improve outcomes for patients with solid tumors.
First Report Managed Care: To get started, can you tell us a little bit about your background, current position, and research focus areas?
Dr Albelda: I'm a professor of medicine at the University of Pennsylvania in the Pulmonary Division. I've been interested in lung cancer and the other chest disease, mesothelioma, for most of my career, and have worked for many, many years trying to develop new treatments based on, initially with gene therapy treatments.
That morphed over the years to immunogene therapy treatments. That is inserting genes into the tumor or into other cells that would then activate a patient's own immune system to get rid of the tumor.
The initial work we did was primarily focused on treating the tumors themselves. This was in the mesothelioma tumors, which are tumors caused by asbestos, that affect the lining of the lung but enables us to put a small tube in and inject different types of medications, cells, or gene therapy.
The first big project that was funded by the National Cancer Institute starting in 1995, injected a gene that caused tumor cell death but also activated the immune system. I've actually been working on that project for almost 20 years.
We switched our gene therapy cargo at one point. We were able to complete a relatively large study for one institution with 40 patients, and showed that our treatment could prolong the survival of previously treated patients with mesothelioma.
That trial is actually going on to an international phase three trial that's going to start within a few months. That was the original focus of this program project that started in 1995. When Carl June arrived at Penn in early 2000, we started shifting our direction a little bit toward CAR T‑cells since that was a big interest of his.
Again, the program project supported his project that focused on trying to use the CAR T‑cells for a solid tumor rather than the leukemias and lymphomas that he'd been working on and had been so successful.
Those projects took advantage of the fact that there's a specific protein on the surface of most mesothelioma cells called mesothelin. That served as our target. He created CAR T‑cells that could recognize that particular protein which is not expressed very much elsewhere in the body.
For many years, we worked on animal models of the CAR T‑cells. About five years ago, we felt we'd gotten to the point where we could actually try this in patients. We began clinical trials using very short‑acting gene therapy techniques. If there was any complications, the gene would disappear quickly. We didn't see complications with that.
We moved to infecting the patient's own T‑cells with a virus we derived, but not infectious of course, from the HIV virus, called the lentivirus, and completed a clinical trial with that without complications, and have recently, in collaboration with Novartis, started doing a bigger trial with a new virus and a new CAR that's much more powerful than the original one.
That's the basis of this new program project, which in many ways is just an extension of the other one, but this one focuses exclusively on the CAR T‑cells. In addition to the trial targeting the tumor, this new program project also has a big project where we're targeting the support structure of the tumor.
In a given tumor, it's not just tumor cells, sometimes more than half the cells are support structure cells. One of the most important are called fibroblasts. Fibroblasts are the cells that make scars, and in a tumor, they provide basically the scaffolding and protect the tumor cells from attack.
The second big project that was just funded is to develop a clinical trial using a whole different type of CARS to target the structure, rather than the tumor itself, with the ultimate goal of probably combining that with other therapies or with two different types of CARS, one to target the tumor and one to target the structure around it.
First Report Managed Care: Can you give a brief description of how CAR T works?
Dr Albelda: I think a good way to think about it is if you think about transplantation. If you were given a kidney, a lung, a liver, or a heart, from a mismatched donor, your immune system would recognize that tissue as foreign and within days would destroy the entire graft. Our immune systems are really well‑tuned to target foreign proteins.
Unfortunately, as we develop tumors, tumors also have different proteins, but because it takes a long time for the tumors to develop, the tumors have ways of evading the immune system, sort of hiding from the immune system even though they still have some differences from normal tissue.
The idea with CAR T‑cells is to artificially engineer your own T‑cells so that they could now recognize those foreign proteins on the surface of tumors. For example, the one I just gave you, mesothelin, that's a normal tumor but our own immune systems don't react to it very well. It's even worse in the patients that have big tumors that suppress the immune system.
By making T‑cells, and we do this by genetically changing them, we put in a protein that enables them to target whatever we choose them to target. A CAR T‑cell, in the case of the leukemia, targets a protein that's only found on the B cells. Those are the antibody cells. That B cell antigen, it's called CD19.
[laughs] Immunologists have a whole numbering system of things, but you might have heard of CART19. That's the thing that works so well with lymphomas and leukemias because the only cells that have that are the tumors and our own B cells. Carl's group targeted T‑cells to attack that particular antigen.
In fact, it does knock out your normal B cells, but it also wipes out the tumor cells also. By taking the cells out, exposing them to a virus that enables them to have a new targeting system put in, we can then put those cells back in. Theoretically, they'll circulate around the body like a normal lymphocyte would. When they see their target, they'll stop, they'll start to grow, and they'll start to kill the tumor cell.
That's worked very well in what we call liquid tumors, leukemias, and tumors of the blood system. As you know, there's a been a number of FDA approvals now for these CAR T‑cells, these genetically targeted killer cells in those diseases, but so far, it hasn't worked nearly as well for what we call solid tumors, the more common tumors, lung cancer, colon cancer, ovarian cancer, pancreas cancer etc.
That's really what we're trying to do, is get the same type of success that has been achieved in these blood tumors in the solid tumors.
First Report Managed Care: Can you explain the grant that the National Cancer Institute awarded to Penn Medicine and how Penn Medicine will utilize that over the five years?
Dr Albelda: This grant was given to us by the National Cancer Institute. They have a number of divisions down there. This grant went to the division that's focused on clinical trials. They try to fund new and exciting clinical trials rather than more basic research.
This grant, as well as the previous grant, is centered on conducting a clinical trial. With these kind of cellular therapies, the first time they're going to people, it's quite expensive to do that. Making those viruses and making the T‑cells can cost up to $100,000 per patient.
This grant is focused on the main project is a clinical trial. We're finishing off this mesothelin CAR T‑cell I told you about, and then we plan to start the new trial that's targeting the fibroblasts. The accompanying projects are closely linked to that.
One project is using animal models to see if we could improve what we're doing, test some of these new therapies regarding the fibroblasts, looking at interesting combinations that might work. The third project is focused on trying to analyze what happens to the T‑cells and the tumors after we inject them into the patient.
One of the things we're trying to do is actually stimulate a patient's own immune response to attack the tumor. One of the big problems with solid tumors is, not every tumor cell has the target on it. Let's say, and this is very common, 80 percent or even 90 percent of the tumors might have the target of the CAR T‑cell, so even if everything went perfectly well, you would still be missing 10 percent of those cells.
What happens in cancers is, there's a selection where you kill the cells that are susceptible and the other ones then just continue to grow and overgrow. We need to develop ways to get rid of that last 10 percent.
One of those approaches is that, we hope that when there's an active immune response, that then wakes up the resting immune system that we have. That's able to then kill the remaining tumor cells which have their own changes, but don't involve the target of the CAR T‑cells but are foreign to the body.
One of the big things that's been discovered in the last five years is that when you get tumors, there's many mutations. It turns out that those mutations make new proteins that the body has never seen before, so it creates an immune response against those proteins.
That can be activated by, you probably heard of the checkpoint inhibitors, KEYTRUDA for example, and we've taken advantage of that. What we're hoping to do is to develop ways to make the CAR T‑cells also activate the body's own immune system to get rid of the remaining tumors.
It's a clinical trial with two sister trials that are focused directly on the findings that we have. These program projects have what are called corps, that support the main project. There's an administrative corps, there's a corps where we analyze some of the blood tests and things from the patients. Then we have a corps that is involved with the statistician and analyzing our data.
First Report Managed Care: You just covered some of this here. What exactly is needed in order to use CAR T in solid tumors? What are the challenges?
Dr Albelda: It turns out there are a lot of challenges. One of the main ones is just what I told you, so that not every tumor cell has your target on it. That's what we're trying to do. We call it a bystander effect. We're trying to induce a response that will kill those non‑targeted tumor cells. There are many other problems.
For example, the T‑cells are injected intravenously usually into the bloodstream. They're very inefficient in finding the tumor cell and staying in there. Less than one percent of the injected cells end up going into these tumors, partially because, as I mentioned, they usually have this encasement of scar tissue around them that makes it very hard for the T‑cells to actually go in there.
The targeting, unlike a blood tumor where if you inject the CAR T‑cells, the blood tumor cells are right there, they don't have to worry about that. That's one of the issues.
The second issue is, inside of a solid tumor, unlike the blood, the environment inside of a tumor is very inhospitable for the T‑cells. By that, what happens inside of a tumor, the sugar levels are very low, the nutrient levels are very low. It's very acidic inside the tumors. That tends to inactivate them or kill them once they get inside.
In addition to that, the tumors have developed methods to escape the immune system. There are some cells that are inside of the tumor that can inactivate the T‑cells. They also secrete different chemicals that are very much able to prevent the T‑cells from working.
That's a toxic brew that makes it hard for the T‑cells to work. In addition to that, it turns out that our own T‑cells are programmed to turn themselves off after they're stimulated.
If you think about it, if you developed a virus, let's say a cold, and your T‑cells came in to get rid of the virus, if they don't turn themselves off relatively quickly, you'll get a tremendous damage to the tissue due to this unrelenting immune response.
That's what happens in some of these so‑called autoimmune diseases where the immune system doesn't turn itself off. That works well in an infection because you can knock out the infection relatively quickly. The T‑cells are programmed to turn themselves off and everything goes back to normal.
In the tumors, the T‑cells get activated all the time. There are so many tumor cells that you can't get rid of them quickly, and so what they end up doing is turning themselves off. Again, that's one of the ways this KEYTRUDA works is, it targets at one of these receptors that helps the tumor cells turn themselves off.
Between the trafficking, the not having the target on every tumor cell, the inhospitable environment, the chemicals that are released that turn off T‑cells, and the fact that the T‑cells turn themselves off, it's really made it difficult on the solid tumor side compared to the liquid tumor side.
A lot of what we're doing is working on, how do we overcome each of these potential problems? One way, a simple way, is actually to directly inject the T‑cells into the tumors themselves and you can overcome some of these trafficking issues.
For some of the tumors that we're interested in like mesothelioma, where you can actually just put a small tube in where the tumor is and inject cells, and there's a trial actually in Sloan Kettering that's doing that. It's looking pretty promising.
For the lung cancer, instead of giving them by vein, we could actually inject right into the tumor cells, and we'll be looking into that kind of thing. Of course, giving in two different types of CAR T‑cells is a way you might be able to get around the fact that not every tumor cell has the target on it.
It's a tall order, and there's a number of people working on it. To date, I've just recently reviewed all the clinical trials, there's been a couple of hundred patients reported. Very few patients have had responses, a handful maybe, at this point.
Of course, seeing the incredible paradigm‑changing results in leukemia and lymphoma has really energized the immunology community and the CAR T‑cell community to say, "Yes, this is possible. We just have to figure out how to overcome some of these obstacles."
First Report Managed Care: How many more patients will benefit from CAR T therapy in solid tumors versus the current approved method that it's for the blood cancer?
Dr Albelda: There's 10 times, 20 times more patients with solid tumors than these leukemias and lymphomas, which are relatively rare.
I don't really have the numbers in front of me, but I would guess there's less than a hundred thousand new cases of these blood tumors a year, whereas there's many, many hundreds of millions of patients with the common tumors, breast cancer, ovarian cancer, lung cancer, head and neck cancer, pancreas cancer, etc.
If we could crack that nut ‑‑ and that's why everybody is working so hard, and that's why the NCI is willing invest in this even though to date we haven't had success ‑‑ it would be huge. I would just add that having been in this business for a long time and seeing things, sometimes it takes a long time and a lot of work to overcome obstacles.
The best examples I think are probably monoclonal antibodies, which were discovered in the late '70s, early '80s, and generated a huge excitement, but it's taken 20, 25, 30 years to really develop a handful of those that are very effective therapies.
The same thing, I've been in the gene therapy business since the early '90s and it's just now, 25 years later, that the first approved gene therapies for cancer, and CAR T‑cells are the first one, that have been approved.
The problem is, everyone gets very excited. Often there's a little bit of hype about a new approach, and then if it doesn't work right away, people get very discouraged and, "This is never going to work, why should we bother with it?" That's not probably the best attitude. [laughs]
There needs to be a group of more hard‑core, stubborn people, and I guess I'm one of them, and some vision, and the NCI to keep funding these kinds of things to let us have the time to work out some of these kinks. I've gotten responses on grants recently about the CAR T‑cells that they just say, "Well CAR T‑cells don't work, so why should we fund any more grants?"
I have to argue. I said, "Well, I would say it would be the opposite type of thing. You know, the proof of principle is already there. Why wouldn't you want to double down rather than fold your hand at this point?" [laughs]
That's the grant philosophy that, luckily for this program project, the people that reviewed it had the latter philosophy rather than saying, "Oh, this is never going to work. I don't want to waste any more money on it."
I'm grateful for the NCI, some foundations, and some companies for funding it. Carl had a very difficult time getting NIH funding initially for his work. People just thought it was crazy type stuff, but as they got more and more information and he convinced people, there's many more people in field now.
First Report Managed Care: Finally, overall, is there anything else you'd like to add about your future research, CAR T therapy or just solid tumor treatment in general?
Dr Albelda: I think I've mixed that in pretty much with what we've talked about. As I said, it's been daunting so far, but people are chipping away at it. I hope we'll be able to make that kind of a breakthrough.
One of the things people are thinking about in the future is trying to develop more off‑the‑shelf type of cells that wouldn't have to be individually made for each person. If you can imagine, it's a very time‑consuming and expensive process to do this.
The patient has to come in, they have to be screened to see if they have the target. They have to agree that they want to do this. They have to come in and have their blood, not just a blood tube, but they have to get a lot of blood taken out in a special machine. Commercially now, it has to be sent, for example in Nevada, it has to be sent to New Jersey.
They have to have the virus. They have to make the T‑cells. They have to do quality control. It has to be shipped to the hospital. The patient has to come back in, and that can take weeks, come into the hospital.
They're given drugs to lower their own lymphocytes so that the T‑cells have a better chance to grow. They're infused, and then there are side effects after that. It's very time‑consuming and very expensive.
One of the goals of the field is to try to see if we could figure out ways to make cells that we could give to everybody, so it's a more off‑the‑shelf type of approach. I know Carl's team has really been working on that in terms of the blood tumors where they already have some success.
Our lab is working on that also, finding a cell line rather than an individual person's own T‑cells, where we could make multiple changes and potentially give multiple does of the drug, which I think might certainly be less expensive and maybe more efficacious.