Immunotherapy Use in Advanced Lymphoid Malignancies - Episode 10

Recent Trials of CAR-T Therapy

Transcript:Ian W. Flinn, MD: There is a lot of talk with CAR-T therapies. It’s a really exciting field. There are three major manufacturers of this and many others that are in the wings. Fred, you’re involved with the Kite trials, especially the ZUMA-1 study. How’s that going? I know there’s a phase I trial that’s been completed and now moved into the phase II trial.

Frederick L. Locke, MD: It’s going very well. So, the ZUMA-1 study is sponsored by Kite Pharmaceuticals. They have licensed the same construct that Jim Kochenderfer and Steve Rosenberg developed at the NCI. They provide centralized manufacturing for those CAR-T cells. We collect the T cells by apheresis and ship them out fresh to a centralized manufacturing facility, where the CAR-T cells are manufactured, frozen, and shipped back. The results of the phase I portion of that ZUMA-1 study have been released. Essentially, seven patients were treated, and that was enough to determine that the fludarabine and Cytoxan dosing and the number of CAR-T cells administered were safe. All patients who had T cells apheresed had successful manufacture of their CAR-T cells, so that’s important. And the turnaround time for those CAR-T cells was relatively short, just over 2 weeks. So, we’re getting the cells back relatively quickly. Out of those seven patients treated on the phase I portion of the ZUMA-1 study, there was one dose limiting toxicity. However, that patient died of an intracranial hemorrhage. It was deemed by the investigators to not be due to the CAR-T cells, but related to the lympho-depleting chemotherapy and also how quite ill this patient was. That patient also had a sepsis at the same time when he passed away. For the other patients, all the toxicities were reversible, including both cytokine release syndrome and neurologic toxicity. And all patients, 100%, did develop some neurologic toxicity. There seems to be a dual peak in the neurologic toxicity and early neurologic toxicity, which occurs within 1 to 3 days after infusion of the CAR-T cells. This is probably related to the cytokine release syndrome occurring at the same time, which is high fevers and chills and then a later neurologic toxicity, 7 days around that time, which is this well described locked-in syndrome or aphasia that’s seen with all the different CAR-T cell constructs. And, again, these neurologic toxicities were reversible.

As far as efficacy, it’s only seven patients. But, out of those seven patients, there were five responders and four CRs, and three of those patients have durable CRs out to 9 months and counting. What’s really important about understanding this trial, if I didn't mention it, is it’s for patients with diffuse large B-cell lymphoma, as well as primary mediastinal and transformed follicular lymphomas. But, what’s really important about this trial is that only patients with truly chemotherapy-refractory disease were enrolled.

And, as presented here at ASCO recently, the SCHOLAR-1 study, really we all know as clinicians that a large-cell lymphoma patient who doesn’t respond to the last chemotherapy has a very poor prognosis. But, by collecting data from four different large databases or two prospective clinical trials, the SCHOLAR-1 study showed that the overall response rate you can expect from a patient who didn’t respond to the last chemotherapy or who relapsed within 12 months of an autologous hematopoietic stem cell transplant was 28%, 30% and showed a CR rate of like 8% to 10%. Here we have a trial using that same criteria to enroll large-cell lymphoma patients, and three out of seven had CRs. So, it’s pretty remarkable! And the phase II trial portion is ongoing and enrolling.

Ian W. Flinn, MD: I think one of the other impressive things about that study and the other studies that are going on is not just the clinical results, which are fantastic, but also just the logistical advancement that we’ve had in terms of taking these out of single center academic, and being able to do it in large trials across the United States. Krishna, you’re involved in the Juno trials.

Krishna V. Komanduri, MD: That’s right.

Ian W. Flinn, MD: What’s your experience there?

Krishna V. Komanduri, MD: We’ve been involved in both the Kite and the Juno studies. The Juno ROCKET study is looking at the same principle, basically a CD19-directed CAR in the setting of ALL. There are a few differences in terms of the design. Actually, the antibody recognition fragment is the exact same as in the Kite study. There is also a CD28 costimulatory domain in the JCAR015 product, again, which is the focus of the first ALL study. The Juno B cell lymphoma study actually uses a 4-1BB domain. Juno has decided that they would pre-select the cells. And with the JCAR015 product that’s in the ROCKET study, they’re a CD3 selection as opposed to an unselected product following the expansion of those cells. In the lymphoma study that Juno will be doing actually, they’re going to select both CD4 and CD8 cells as opposed to just doing total CD3, which is a generalized marker of CD3 cells.

Again, there are some other differences in the Juno ROCKET study. There are two planned infusions of the CAR-T cells. So, you have basically a dealer’s choice chemotherapy or supportive care once the patient is enrolled during the time that the manufacturing happens. And then you have lympho-depleting chemotherapy, which right now, the backbone is basically fludarabine and cyclophosphamide for most patients. Then there’s an infusion of the cells, again, assuming that the patient has acceptable performance status and toxicity. With the first cellular infusion, there’s a dose escalated second infusion. That is a little bit different than the design of the Kite study. So, there are two infusions that are dose escalated.

Transcript Edited for Clarity