Development of CAR T Cells in Multiple Myeloma

Keith Stewart, MBChB: Let’s discuss our favorite topic of CAR T-cells, Noopur has the most experience of all of us in using CAR T. Do you want to just give us a lay of the land, Noopur? Where are we at with these, and what’s your impression as we’ve get more experience?

Nooper Raje, MD: We were waiting on cellular therapy for myeloma and we now finally have them. We have several different products. All of them in the myeloma space are targeting the same protein, BCMA. And there are different products out there, including one from Janssen, one from Juno, one from bluebird, and one from Celgene. And the big differences are the way they are creating the CAR. All of them are using a very similar post-stimulatory domain, which is 41BB. And this is required for T-cell expansion. CAR T-cells, unlike what people really talked about with bela and maybe the BiTEs, which we will talk about later, this is not off-the-shelf. This requires collecting cells from patients, getting those cells back to whoever is producing the CAR, and from collecting the cells to creating the CAR T-cells, it can take anywhere between 3 and 4 weeks right now. And then once those CARs have been generated, we get the patients back. And they do need to be hospitalized, at least for right now.

This might change in the future. We’ll have to wait and see. But most patients will receive some conditioning chemotherapy, and we typically use a combination of Cytoxan with fludarabine, and following 3 days of that, 2 days of rest, and then you give back these CAR T-cells to patients. The most important toxicities associated with cellular therapy are twofold. One is neurotoxicity, and the second one being cytokine-release syndrome. And these occur because of the CAR T-cells being active. Once the CAR T-cells finds your treatment cell, they destroy the tumor cell, produce a lot of cytokines, and that results in cytokine release syndrome. And the second one, neurotoxicity, which is less well understood, is again because of the CAR T-cells and whether or not it’s because of crossing the blood-brain barrier or whether or not it’s because of some of these acute-phase reactants, it’s still not completely clear.

The most important thing we’ve learned from CAR T-cell technology in the last couple of years is the fact that they work. We can generate them in very end-stage myeloma patients. They work with extremely high response rates, north of 80% in whichever clinical trial you look at. And it’s manageable toxicity. Most of the toxicity we’ve seen is cytokine release syndrome. And we’ve been able to manage that quite well. And we’ve seen very little in the way of neurotoxicity with these cellular products. It’s a really exciting space. We’re just at the beginning of cellular therapy in myeloma. And at least the initial look at this has been quite encouraging. The data looks quite exciting.

Transcript edited for clarity.