Advances in CAR T-Cell Immunotherapy in Hematology Malignancies

An Interview with Eduardo Sotomayor, MD

Eduardo Sotomayor, MD is a renowned cancer researcher and physician scientist with more than twenty years of practice in the field of cancer immunology. As the inaugural director of the George Washington University Cancer Center (GWCC) in Washington, DC, Dr. Sotomayor serves as the program’s chief academic and clinical leader, guiding GWCC into being the premiere cancer center in the region.

Potency of T-Cells

Can you tell our readers a little bit about your role at the George Washington University Cancer Center?

Eduardo Sotomayor, MD: I am the director of the cancer center. This fresh [GW] cancer center was established in July 2015. Before that, I was chairman of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida. I was there for sixteen years, but before that, I was part of the cancer immunology immunotherapy group at Johns Hopkins. I trained at Hopkins, so that’s where I developed my interest in cancer immunology immunotherapy.

I have been involved in the field of cancer immunology for around twenty years. It is significant to mention that in the mid-90s, there was no significant interest in cancer immunology immunotherapy. There was skepticism about the value of harnessing the immune system to attack cancers. And, of course, twenty years later, there is significant enthusiasm, and that’s because of the work of many people who dedicated their lives to understanding how tumors interact with immune cells, with T-cells, with [natural killer] NK cells, and others. That work is now being recognized, given the significant success of using checkpoint blockade antibodies as well as [chimeric antigen receptor] CAR T-cell therapy.

What are the main features of cancer that makes it an effective target for CAR T-cell therapy?

Dr. Sotomayor: Let me give a little background. For many years we knew that T lymphocytes (T-cells) are capable of recognizing malignant cells. When they come in contact with malignant cells in patients, the T lymphocytes will do some harm, but not significant damage—some damage—and then the tumor cells counterattack, and basically tell the T-cells to become paralyzed. We define that concept of T-cells as being tolerant. So, that’s something we understood many years ago. T-cells can recognize tumor cells, but are not strong enough to kill and eradicate cancer cells entirely.

Then the following question was: what mechanism, or what escape mechanism, are the tumor cells using to prevent harm by T-cells? Several mechanisms were identified. One was this interaction inbetween PD-L1, PD-L2 ligand special tumor cells, and PD-1 spread on T-cells. And then we have the checkpoints [checkpoint inhibitors]. The checkpoints [inhibitors] block the interaction, and now the T-cells become activated. They recognize the T-cells, and they [T-cells] finish their job because they have the help of the checkpoint blockade.

To us, that was proof of principle that the T-cells are capable. You provide a decent environment, they are capable to kill tumor cells. We have seen in some patients that these T-cells are capable of fully eradicating tumor cells. So, right now, we are witnessing in patients with melanoma, in patients with lung cancer today with checkpoint blockade, that some of them are living longer than we were expecting—so, just providing the proof of concept about that potency of the T-cells.

CAR T-Cells in Hematology

Then we said, okay, what if we take the patient’s T-cells, and we modify them to make them better “soldiers.” Let’s train them better; let’s make them capable to better recognize tumor cells, with the capability to kill them. That’s when several groups had the idea to introduce these chimeric receptors. Basically before, the T-cells were on a mission looking for the cancer cell. Now with the CAR T-cells, they know where the targets are because they have a specific receptor that is going to permit the T-cell—this genetically modified T-cell—to tie directly to the malignant cells.

The advantage of the CAR T-cells is that they work with blood cancers. They work in the case of acute lymphoblastic leukemia (ALL) in kids. They work in lymphomas. They might work also in leukemias, as well as in myeloma. All of these are blood cancers. So, we see significant responses in patients with lymphoblastic leukemia, patients with several types of aggressive lymphomas.

The limitation is in the solid tumor field. In solid tumors, it’s more complicated because, number one, the microenvironment is less conducive for the T-cells to penetrate inwards a solid tumor, and, number two, we don’t have good targets (yet) in solid tumors. In blood cancer the target that is fairly good is called CD19. Most of the CAR T-cells, chimeric and the receptor T-cells are provided with a receptor that recognizes CD19, which is voiced in malignant B-cells. So, we can take care of the malignant B-cells.

Now, there are some data that CAR T-cells can be used in numerous myeloma. There is some interest in developing CAR T-cells in myeloid leukemias, but I think it’s going to take extra work to identify good targets in the solid malignancies field.

Combination Therapy

You’re talking about extra work to get solid tumors up to speed. Is this an area where CAR T-cell therapies are being tested in combination with checkpoint inhibitors?

Dr. Sotomayor: Yes, that’s a very good question. There are ongoing clinical trials in hematologic malignancies, some trials also in solid tumors. Your question is very significant because it highlights the importance of combination. Response rates for single-agent checkpoint inhibitors are going to be around 30% or 40%. Those are the patients that are going to react, and then the response will be durable.

In the case of CAR T-cells, we are observing better responses in hematology malignancies; therefore, it makes sense to combine CAR T-cells with checkpoint inhibitors or CAR T-cells with other target therapies that are available for several tumors. The dilemma that we have in the field is how to select the best combinations. Should we use two agents, three agents?

Just to give an example, now there is data on melanoma in which we can combine two different checkpoint blockade antibodies, and you improve the response. Should we add CAR T-cells on top of that? Should we add chemotherapy on top of that? Should we add other target agents on top of these two agents that we know are working fairly well in melanoma?

So, therefore, you are asking the question, should we do doublets, triplets with all the agents that are available? So, that creates—it’s titillating to have these opportunities—but we need to find ways we can prioritize which are going to be the most successful combinations. These are conundrums that all of us who are working in the field have in front of us. I think developing better preclinical models to test these different combinations will help speed up which combination can be taken early to clinical trials in patients with malignancies. It makes sense to combine CAR T-cells with other agents. What is significant is which other agents, and also which will be the sequence of the combinations?

Transplantation for Hematologic Tumors

Given those two pressing research questions—which combinations to attempt out and which sequence to use combination drugs—what would you say are the most significant clinical trials that are either about to kick off or have already been initiated in this area?

Dr. Sotomayor: I would say top priority will be the combination of CAR T-cells with the already available checkpoint blockade antibodies, as well as the fresh generation that is being tested in early clinical trials. That will be a priority, especially in the area of hematology malignancies. The other will be in the area of transplants. In some patients with hematologic tumors that have aggressive disease, we are using transplant.

There are two type of bone marrow transplants. One is autologous bone marrow transplant, using the patient’s own bone marrow cells. The 2nd is called allogeneic bone marrow transplant, in which we use a donor. It could be a brother, sister, siblings of the patient, but also other family members. So, combination—in some patients—of these transplant strategies, followed by adoptive transfer of CAR T-cells, will help us convert some durable responses after transplant into potential cures.

I will give you one example. Myeloma is becoming a chronic disease. When you use checkpoint blockade alone in myeloma, the response rate is zero. When you combine checkpoint blockade with immunomodulatory agents, the response rate increases to 30% or 40%. So, in myeloma in some patients we use transplant, autologous transplant, but we know that autologous transplant doesn’t cure myeloma patients. It provides a good duration of response, which is the ideal setting to take the patient to transplant, and then add these fresh immunotherapy approaches, either CAR T-cells after the myeloma transplant or checkpoint blockade.

There is a group at Johns Hopkins using T-cells that they obtain from the bone marrow. For most of the CAR T-cells, just to give an example, we took the T-cells that are in the peripheral blood. This group at Hopkins has shown that perhaps T-cells that are in the bone marrow in this patient with myeloma will be a better killer, will be better effectors. One They are conducting a clinical trial in patients with myeloma after they have received bone marrow transplants. In summary, I think top priority in the CAR T-cells will be combination with checkpoint blockade, but also use the CAR T-cells perhaps after a stem cell transplant.

Is that partly to do with the source of the T-cells? So, it’s bone marrow rather than peripheral blood?

Dr. Sotomayor: Correct. I mean that’s the question that is being asked by the group at Hopkins.

So the actual T-cell source is going to be key in refining approaches to this therapy?

Dr. Sotomayor: Exactly. I think we have, again, the proof of principle that T-cells are effective in killing tumor cells and provide good responses, durable responses, in patients with blood cancers. The question will be, which subtype of T-cells should we use? There are several subtypes: CD4 T-cells, CD8 T-cells, there are central memory T-cells, there are different subtypes.

I think that we are just at the beginning of understanding which is going to be the best source of T-cells, and also should we use cells from the peripheral blood or from the bone marrow? I think there is emerging data, and that’s where, in my view, the answers are to optimize CAR T-cell therapy.

The other area we need to understand is why it works for some patients and it doesn’t work for other patients, even however these patients express the targets—CD19, which is the target for CAR T-cells, at least for most of the CAR T-cells that are being used right now in the clinic. I think those are significant questions, and also in some patients who have a response, so after months the disease comes back. Why is it coming back? What is the tumor doing to avoid control by these CAR T-cells? Reminisce, the CAR T-cells are going to remain in the patient’s bod for months and for years, but the tumor always finds ways to attempt to escape, and sometimes the tumors are successful in doing that.

Mechanisms of Resistance

How will CAR T-cell therapy advance personalized medicine? That question is still very much part of the research agenda, and you’re just at the beginning of that process.

Dr. Sotomayor: That is correct. Those are questions several groups are attempting to response at this point. I would say one of the mechanisms, and one of the problems, is you just target one antigen, in this case CD19, and tumors are very good at doing that. The tumor is going to say at one point, okay, now I’m not going to express CD19. So, there are going to be some tumor cells that cannot express the target and, therefore, your therapy is not going to work, and that’s one of the mechanisms of resistance.

What you are going to see is an emergence of tumor cells that do not express the target. Several groups, now what they are doing is… let’s use two types of CAR T-cells: one target is CD19 and the other target is CD22. The tumor cell is attempting to escape by decreasing the expression of one of the targets, but we still have the 2nd one. So, those are the strategies being developed.

Then the group we work with here at GWU, Dr. Catherine Bollard, rather than focusing on just one target antigen, she is creating a pool of T-cells that will attack different antigens voiced by blood cancers. Two She’s doing all this work in the pediatric population at Children’s National here in Washington, D.C., and we are going to be expanding those studies into the adult population soon.

You asked me about our Cancer Center; the GW Cancer Center is going to be focusing on cancer immunotherapy. We are recruiting in that area. We are also going to expand beyond the current generation of CAR T-cells. We will be focusing on creating or using T-cells that have that the capacity to attack different target antigens.

No Thresholds with T-Cells

What do you see as the boundaries and potential of CAR T-cell therapy?

Dr. Sotomayor: I think there are no thresholds for what we can do with these T-cells. So, for example, you can take these T-cells and put several receptors that will tie to several antigen voicing tumor cells. You can attach—this is using nanotechnology—you can fasten different types of molecule drugs to the T-cells. The T-cells now are going to be the vehicle, the carrier, of whatever we want to add to the T-cells.

This is just the beginning of a promising field. Now, we’re talking about T-cells, but also now we can use NK cells, and perhaps in the future, we are going to be using B lymphocytes, or maybe neutrophils. So, there is no limit of what we can do in the future. What we are doing is manipulating the immune cells, making them more effective, and providing the devices that the T-cells need to do a very efficient job. I think the proof of principle is they can do the job, but with our help in terms of engineering and modifying the patient’s own immune cells.

We can envision the future, and we can combine different types of genetically engineered immune cells: T-cells, B-cells, NKs. There are no boundaries, in my view, for the things that we can do.

Dose Fractionation

What about toxicities and adverse events. What are you watching with CAR T-cells?

Dr. Sotomayor: The toxicities, as you know, are fairly dramatic. Patients can develop significant inflammation. They can develop [central jumpy system] CNS problems, for example, so they cannot communicate for a while. They can develop a drop in their counts. There are complications, but now there are also some emerging data when you do fractionation, so rather than give one infusion of T-cells… Let’s say that you select a number: one hundred cells. Instead of providing one hundred cells, you just fractionate, and you say, okay, day one, I’m going to do 25; day two, I’m going to do 25; and then on the fourth day, I finish my treatment. There was a publication recently that you fractionate a dose of T-cells so you can prevent, or you can decrease the strength of the side effects. Three,Four

In parallel to enhancing the efficacy, there are several groups attempting to decrease the toxicity associated with CAR T-cell therapy, and also the toxicity is mostly seen in patients with leukemia. In patients with lymphoma, I think that toxicity is less pronounced, and also it depends on what type of CAR T-cells you use, what type of technology you are using. I think we are going to make significant improvements in preventing toxicity, but you need to recall that the immune system is so powerful that it can kill the host. There are some autoimmune diseases that can kill a human being. So, we need to be careful about how to use these powerful devices we have against cancer.

That brings me to my final question, which is, you’ve talked about the technology. We’ve talked about a lot of work being done in the transplant setting. This work is at the moment in its research phase, very specialized, and it’s academic centers that are using this technology. Is CAR-T cell therapy something that will eventually be simpler and practical enough to be done in a community setting or is this something, like transplant therapy, that has to be delivered in a very specialized setting?

Dr. Sotomayor: I think that this is going to require specialized centers with physicians who have the expertise to recognize the complications associated with this treatment. Reminisce, this treatment very likely is only five to six years old, and it’s been performed in very specialized centers. I think that it is going to proceed to be delivered in very specialized centers, but then there is going to be transfer of this technology into centers that do some sort of transplant.

Collaboration among the academic institutions, continuing investment from the federal agencies, [and] from the private sector will help us to keep up this effort. As I mentioned, I was in the field at the time when minimal federal funding was available for this type of research, with no interest whatsoever from the private sector. But now the proof of principle has been provided, therefore, we should take advantage of these demonstrations that the immune system is capable of eradicating tumors, but this is associated with significant toxicity. Investment is required to speed up improving the efficiency and safety of this fresh technology.

Related movie: