DR LOVE: Maybe you can begin with the background of what CAR-T therapy is, where it’s being utilized and what we know about it, Noopur, in terms of myeloma.

DR RAJE: It’s been very exciting over the last couple of years because of all of the press it’s gotten in the hematologic malignancy space. We’ve seen potentially curative treatments in ALL patients with a CD19-directed CAR T-cell approach. And all of that work has largely come from Dr Carl June at Penn and his colleagues.

And what it really means is you collect cells from the patient. And you engineer T cells from these patients. You put into these T cells certain factors, which make them, one, grow, and also make them immunologically more functional, but also able to recognize a protein which is present on the tumor cell. And in this case, most times for leukemias and lymphomas, they’ve used CD19-directed CAR-T cells because that’s the protein expressed on these malignancies.

In myeloma, I think we’re still in the early days of working with CAR-T cells. There was a late-breaking abstract at ASH. And there’s been work from Ed Stadtmauer’s group at Penn, wherein they have used both CD19 in that case. Ed had used CD19-directed CAR-T cells in myeloma patients and had seen some success with that.

More recently, the NIH has used a BCMA-directed CAR-T cell. And at least the data with the late-breaking abstract was about 12 patients, but there were patients who’d had a PR or a VGPR. I’m not sure what the follow-up on that has been because it’s still early studies.

So based on that, we are also using CAR-T cells now. It’s in the context of a clinical trial. In myeloma specifically, I think most of us believe that we should be using a BCMA-directed CAR-T cell because BCMA — it stands for B-cell maturation antigen — it’s pretty much present on all myeloma cells. The degree of expression can be different for different myeloma cells. And these T cells are generated so as to recognize BCMA-positive cells.

Typically what is being done is patients are admitted, get a little bit of chemotherapy, which we refer to as lymphodepletion. And that’s essentially similar to all heme malignancies. The drugs we commonly use are fludarabine and cyclophosphamide. And then give back those CAR-T cells. Again, the trial we are doing, we’ve treated close to 12 patients now. Again, the follow-up is quite limited.

But what we have seen is it’s tolerated. We haven’t seen the things one worries about with CAR T-cell therapy: You can get something like a cytokine response syndrome, and that needs to be treated appropriately because patients can get extremely sick, so much so that they can go into an ICU, need pressor support, might need intubation and all kinds of specialized care. So recognizing that is important.

And the other thing which has been seen with these T cells is you can get neurotoxicity and, therefore, monitoring all of this. So it’s not trivial, this treatment. And patients have to be selected appropriately. And they’re to be followed in a specialized center.

DR LOVE: Rafael, any comments on this strategy and the data that we have so far?

DR FONSECA: I think it’s fair to say it’s probably one of the most exciting areas of research right now, alongside PD-1 inhibitors. I think there is a next step that we will see soon, which is the bispecific antibodies. That will obviate the need for cells. The CAR-T cells, you have a designer link between the T cell and the target cell. But you could say, “Could we do that just by infusing the link?” And that’s what the bispecific antibodies are. So they bring together a T cell; they bring together a target cell. So I anticipate we’re going to see a lot of that as well.

DR LOVE: And have there been these types of agents produced yet?

DR FONSECA: There’s not a lot of activity yet in myeloma, but it’s anticipated it will happen at some point soon. I think this is going to completely change how we think about cell therapy. Cell therapy for the last 30 years has been allogeneic approaches.

I think we should capitalize on that expertise of our colleagues who do transplant. In my opinion, I think that should be the group that should be doing most of the CAR T-cell therapy. They’re more familiar with the cytokines, et cetera. And it actually will give them better tools. It’s just a different tool for the same group of physicians caring for cell therapy-based approaches to patients. So I do anticipate we’re going to see more.

I wanted to mention, there’re other groups that are working on SLAMF7. There’s a group out of Wurzburg that received funding through a crowd initiative. So everything’s new. There was a myeloma crowd initiative which is a new group that’s run by a patient advocate, Jenny Ahlstrom, who uses this crowdfunding approach, and it’s funding clinical trials now. And one of them is this one in Germany, looking at SLAMF7 CAR-T cells.

Now, if there’s a patient listening to this, I can tell you this is probably the most common question I get in the clinic after we go through the options is the one about CAR-T cells. There was this article in the Parade magazine that talked about CAR-T cells. And we all got copies of that article from the Parade. I didn’t know there was a magazine called Parade. But, anyway, there’s such a magazine.

But patients need to know that as much as we have great excitement for that, it’s still early on. There’s significant toxicity. It can be curative, but it’s not a walk in the park. And it’s really reserved for more advanced stages at this point.

DR LOVE: I’ve heard the term “off-the-shelf CAR-T cells.” What’s that? And is that kind of like the bispecific antibodies?

DR FONSECA: Well, no. With all the advent of this DNA-modifying technology, like with CRISPR, you could envision a future where you don’t even need to collect the T cells from the person, but you have T cells that are pluripotent, meaning they could work on any individual. And they already have T cells that are going to be primed against BCMA. And it doesn’t matter that they didn’t come from the person because you can eradicate some of the antigens that would make them be rejected.

So those would be like assassins that are ready there for the myeloma cells without necessarily having to be harvested from the person. Now that’s very exciting because then that would mean off the shelf, right away, you can get repetitive courses for that. I think what we need to know is just how to control them once they’re in the person’s body, which is one of the biggest challenges.

DR LOVE: You were mentioning the neurologic toxicities that have been seen. What specifically?

DR RAJE: Patients can get seizures. Patients can get changes in their mental status. And part of the problem is we don’t understand exactly why that happens. So it’s still ongoing work to try and understand this better, but this is something we need to be following over time.

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