Successful Manufacturing of Lisocabtagene Maraleucel for Patients With CLL

Tanya Siddiqi, MD, City of Hope, CA, shares results and insights of the TRANSCEND CLL 004 study of lisocabtagene maraleucel, a CD19-directed CAR T-cell therapy for patients with CLL.

Transcript
CLL (chronic lymphocytic leukemia) is a slow growing, incurable type of B-cell non-Hodgkin lymphoma and patients can live a very long time on or off treatment periodically with this disease. However, there is a subset of patients who tend to relapse and progress faster, especially if they have certain porous genetic features of their CLL.

If these patients progress through some of the newer treatment options that we have available for them, like BTK inhibitors and BCL-2 inhibitors, for example ibrutinib and venetoclax respectively, then the treatment options for them are more limited. Our goal was to be able to find a type of treatment that would get them into a long-term remission after having failed some of these novel treatment options. CAR T-cell therapy provided that basis to do research in that realm to see if, much like the success we've had in aggressive lymphoma, then we translate that with CAR T-cells in CLL or lower grade lymphomas as well, and that's what led to this trial.

The TRASCEND CLL 004 study is a phase 1/2 trial of relapse or refractory (R/R) patients with CLL who have progressed after two or three different lines of therapy, including in everybody a BTK inhibitor. The type of genetic abnormalities or the high risk features of their disease really determined whether they needed to have gone through two prior lines of therapy or three prior lines of therapy but all of them needed to have failed prior BTK inhibitor. As it turned out in the phase 1 portion of this trial that we published and presented on, there were about 23 patients and all of them had prior ibrutinib therapy.

These 23 patients were treated across two different dose levels with the liso-cel CAR T-cells. Everybody underwent a collection of T-cells and, while the CAR T-cells were being manufactured in the lab over three to four weeks, patients were allowed to have salvage therapy or continue with their prior treatments if they needed to do that to control their disease. About 75% of patients did continue with some therapy or needed some salvage therapy while waiting for their CAR T-cells to be manufactured. Once the cells were manufactured, everybody basically underwent three days of lymphodepletion chemotherapy with fludarabine and cyclophosphamide, got a couple days rest, and then got the infusion of their CAR T-cells or liso-cel CAR T-cells uniformly across the board.

What we found in the ensuing period over the next month, we kept a very close watch on them, we found that grade 3 or higher toxicities with these particular CAR T-cells in CLL was not that high at all, unlike what we see in aggressive lymphomas or unlike what we see with other CAR T-cells in aggressive lymphomas. Reassuringly, there were only a couple patients who had grade 3 cytokine release syndrome (CRS) and no grade 4 or 5 toxicities with CRS. As far as neurological side effects are concerned, there were only about five patients who had grade 3 or 4, out of them only one was grade 4 but, there was a total of five grade 3 or 4 neurological toxicities and none grade 5, so it was very well tolerated.

Then, at the end of the month when they got their first disease assessment, a response assessment, we found that about two-thirds of them were already in a remission with undetectable minimal residual disease (uMRD), and another quarter of them, over time, developed improvement in their response. If they were partial remission went to complete remission (CR), or if there was stable disease went to partial remission (PR) or CR. But a majority of them, up to 75% of them, were able to enjoy an uMRD state fairly quickly and durably after CAR T-cells either in the blood or the bone marrow. This was very reassuring and now we follow them over time. The longest I've had a patient now go without relapsing with their CLL has been about four years.

One of the things that was a little surprising was that there were a handful of patients, maybe three or four, who had uMRD for their CLL. Their CLL had gone away but sometime after CAR T-cells they relapsed with Richter's transformation. It turns out that more of the people who had Richter's transformation after CAR T-cells were in the group of patients who had progressed, not just after ibrutinib but also after venetoclax therapy. Those are the particularly bad acting CLL patients who are waiting for longer term data. Also, the rest of the phase 2 portion that's already been enrolled but we're waiting to analyze the data.

Ideally, we all want to see if we could bring some of this stuff in even earlier lines of therapy, meaning instead of waiting until people have progressed after two or three lines of therapy and progressed after BTK inhibitors and BCL-2 inhibitors and those kinds of things, can we try to do CAR T-cell therapy after maybe the first relapse or earlier in the lines of therapy so that, especially if they have high risk disease like Deletion 17p unmutated IGHV, et cetera, or complex carrier type, if we treat them sooner with CAR T-cells can we get them to stay in a durable, long term remission more than pills are able or, potentially, can we even cure some of these people if they never relapse for 10 years or more? That's the holy grail, that's the hope, but that's where the research is trying to go to.

Of course, there are newer targets with CAR T-cells that we're also looking at. Liso-cel that I just described is a CD19 targeting CAR T-cells, but now we're looking at the trials. Haven't started yet but we're trying to start trials with ROS1 target, BRAF target CAR T-cells so there's newer ideas that are coming.

I do like to just recommend and advise the audience that if you have patients who you think meet the bill to need CAR T-cell therapy, then try to send them sooner rather than later so that they're in good health and good shape in order to go through this whole month-long process with us in a meaningful fashion. I just encourage patients to be sent for clinical trials as much as possible so we learn more stuff faster and we can get newer drugs approved faster.