Obstacles to Using CAR-T Therapy in Hematologic Malignancies

Transcript:Ian W. Flinn, MD: CAR-T therapies have got some obstacles. It’s a customized product. It has to be developed for an individual patient, and sometimes there’s some difficulty in collecting those cells. There’s a period of time when you collect the cells and when you’re able to deliver the therapy. And so, some patients can progress during that time. There are all the different constructs that Fred was talking about. So, Krishna, is there anything to this, the 4-1BB, the CD20, the retrovirus, and the lentivirus? Does it make any difference? Do we know the differences?

Krishna V. Komanduri, MD: Good questions, and I think this is something that we’re all trying to understand. So, just to go back to that basic biology, we know that signal 1 is delivered through the T-cell receptor, and we have that CD3-zeta intracellular domain that’s common to all these. But, typically, there’s a second domain that’s fused, and the two that are in place in the early generation of trials are CD28 and 4-1BB. These are both, again, things that normally would be a receptor on the T cell that would receive a second signal through a unique ligand. But in the context of the CAR, they’re basically artificially delivered through the same genetic construct. For example, the Kite Pharma KTE-C19 trial uses a construct that has the CD28 intracellular domain, and that’s also true of the Juno JCAR015 trial which is in place for acute lymphoid leukemia. The JCAR017, which is the second trial in the setting of non-Hodgkin’s lymphoma, actually uses the 4-1BB domain. And the Novartis trial, the first trial, is also using a 4-1BB domain.

Theoretically, the kinetics of engagement of the second signal through these receptors can vary. And, therefore, when you deliver it artificially, the cell can react differently. So, there are some data that suggest that perhaps that CD28-based secondary signal will give you an earlier expansion and then the 4-1BB signal may be slightly later and perhaps lead to greater persistence. I would still say, although there’s obviously strong basic biology behind these concepts, right now, we have almost 200 patients that will be treated in the context of these early stages of clinical trials. All these companies have very smart individuals who are really doing very extensive correlative studies. And those correlative studies include the measurement of CD4 and CD8 cells, B-cells, dendritic cells, monocytes, and other cells that may affect the expansion. And then secondly, they’re looking at a whole range, typically 30 to 40 analytes in the serum, to look at serum biomarkers. While we can speculate, we will soon know which constructs, and in the context of which patients and what happens in the cells in the serum, will expand. So, I think we’ll have that data soon.

Andre Goy, MD, MS: I think it’s important for our audience that we summarize what’s happening when we give the CAR-T cell, besides the production; the biology behind it. What’s fascinating is that we actually inject those cells and they’re very well tolerated for the first few days. And then a few days later, very often, the patient develops fevers and chills. That’s called the cytokine release syndrome (CRS) and that can be very impressive. We try to not use steroids because we don’t want to impair the expansion of the T cells, which can be very, very impressive and very quick. But then eventually some of these patients can become comatose, have to be intubated, have seizures and speech problems, communication issues and all that. So, it’s very impressive clinically, but this has to be done in centers that are very familiar with this approach and the context of high-dose therapy and transplantation. But, what is interesting is that we have tositumomab, an anti-IL-6 receptor, that really helps control CRS. And it was serendipity that it happened initially at University of Pennsylvania in this young girl that was treated, was having very severe toxicity, and when in the ICU, did very well once they gave her tositumomab. She’s in remission.

So, I think this is very important to realize: that as we’re learning that if you have a patient that is refractory to standard therapies—and you definitely have a center nearby—this is something that needs to be looked at for a patient. Because it gives opportunities. We have, among the first responders, the first three refractory follicular lymphoma patients that are all heavily pretreated and have now been in remission for more than a year.

Ian W. Flinn, MD: So, Fred, let’s get back to what Andre was talking about a second ago in terms of centers that do this. You put together a group at Moffitt Cancer Center that just specializes in immunotherapies, a special group of doctors and nurses that take care of these patients. Clearly, this isn’t something that’s coming to the average community hospital in the near future. But talk to that a little bit.

Frederick L. Locke, MD: There are two reasons for that. First of all, these therapies are cellular therapies that require collection of the cells from the patient, an autologous cell therapy product. You need access to apheresis and the ability to schedule that. In addition, as Andre mentioned, this can be a very toxic treatment.

Cytokine release syndrome is seen with all the different constructs that we’ve mentioned. The timing of that cytokine release syndrome may be variable depending on the constructs or even the disease or the disease burden. But what we do see is those high fevers, chills, hypotension, and hypoxia. And so you need a specialized team that’s familiar with those toxicities. What we did at Moffitt Cancer Center is we got together with the hematologic malignancy physicians and the transplant physicians, like myself, to really pair up to create a team, as you mentioned, that could focus on these toxicities. And the administration of this treatment from the start to the finish is not unlike hematopoietic stem cell transplant.

So, as anti-CD19 CAR-T cell therapy becomes more widely available, it’s likely that we’ll see its use in centers that have familiarity with hematopoietic stem cell transplant. And we’ve used that same paradigm. We call it the Immune and Cellular Therapy program (ICE T), and it’s caught on. We actually now have seven or eight different clinical trials that we have on that program. We have a specialized clinical service to care for those patients. And it not only includes CAR-T cell therapy, but T-cell receptor therapy, which is slightly different than CAR-T cell therapy, but is also on the horizon for solid tumor and hematologic malignancies.

And I also want to speak to the other toxicity that Andre mentioned, which is neurologic toxicity. We talked about cytokine release syndrome, but generally a little bit later than a cytokine release syndrome is a neurologic toxicity. The pathophysiology of this remains really undescribed as to what’s causing it. We do know that the CAR-T cells can be found within the central nervous system or within the CSF (cerebrospinal fluid). The cause of that is being looked at, but the neurologic toxicity is very unusual. It’s most similar to the neurologic toxicity seen with blinatumomab, the CD19-targeted BiTE antibody where patients can get a locked-in syndrome where they’re awake, they appear alert, but they can’t answer questions. And so, again, you need a specialized center that becomes familiar with these treatments and is able to manage them. Because these toxicities are generally completely reversible.

Transcript Edited for Clarity