Promising Results Shown With CAR T Cells for MCL and Indolent Lymphoma

The treatment landscape for patients with relapsed or refractory mantle cell lymphoma (MCL) has changed positively over the past few years, primarily due to ithe ntroduction of chimeric antigen receptor (CAR) T-cell therapy, namely of brexucabtagene autoleucel (formerly KTE-X19; Tecartus).

Brexucabtagene autoleucel is a CD19 autologous T-cell product. The approval was based on the ZUMA-2 study (NCT02601313) which looked at patients with relapsed refractory mantle cell lymphoma who were exposed to chemoimmunotherapy and Bruton's tyrosine kinase inhibitor (BTK). All patients had to be BTK exposed, and it was a high-risk group of patients.

In the high-risk population tested, a very high overall response rate was demonstrated at 93%. Additionally, 67% of patients achieved a complete remission. To see if there was any sign of relapse, a follow up took place at 12.5 months after the study and concluded 78% of patients who responded to remain in complete response.

The results of the ZUMA-2 trial in addition to other lymphoma therapies and studies are promising and advancing at a rapid rate, according to Lori Leslie, MD.

In an interview with Targeted OncologyTM, Leslie, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, discussed the CAR T-cell product, brexucabtagene autoleucel, and its influence on both MCL and indolent lymphomas.

TARGETED ONCOLOGY: Can you discuss brexucabtagene autoleucel and the impact that it's had over the last year?

Leslie: Brexucabtagene autoleucel is a CD19 autologous T cell product that is approved in relapsed/refractory mantle cell lymphoma. It has really helped start to change the treatment landscape for these patients. It was approved based on the ZUMA-2 study which looked at patients with relapsed refractory mantle cell lymphoma, who had been exposed to chemoimmunotherapy and BTK. All patients had to be BTK exposed, and it was a really high-risk group of patients. About a third of patients had very advanced blastoid mantle cell lymphoma, 88% of the patients were actively relapsing through their BTK inhibitor, which we know is a high-risk patient population with poor outcomes that really don't respond well to subsequent line of therapy. In this high-risk population, there were very high overall response rates for a single infusion of brexucabtagene autoleucel CD19 CAR T-cell, the other name is KTE-X19, with an overall response rate above 90 at 93% and 67% of patients achieving a complete remission.

With mantle cell lymphoma, treatment is more of a marathon such that these patients can relapse later. With the follow up, which was at a median of just over a year, 12.5 months, very remarkably, 78% of patients who responded remained in complete response. This is a very promising therapy that's given a 1 and done type of approach for high-risk patient population and responses seem to be durable. It really has changed the landscape for these patients with mantle cell lymphoma.

What do you hope to see from the ongoing ZUMA-2 analysis?

There are a few different cohorts ongoing in ZUMA-2 looking at brexucabtagene. We've got a cohort looking at BTK-naive patients, we have a cohort that's expanded access that allows bridging therapies and more of our real-world population, and then there's a cohort where you can get access to cells if they're out of specification.

I think these data along with data that's emerging from real world experience with brexucabtagene in mantle cell lymphoma, show us that what we see in clinical trials is translating to our real-world population. I'm hoping these data will help convert the accelerated approval into a full, long term FDA approval for this CAR T-cell product in patients with relapsed mantle cells. I think moving forward too, it will be investigated in earlier lines of therapy as we're doing with other CD19 CAR T-cell products across B-cell lymphomas.

Are there any studies or novel CAR T cells that you have your eye on right now?

There's a lot of other studies looking at CD19 CAR T cells across different B-cell malignancies. We've got ZUMA-2 which looked at indolent lymphomas and led to an approval in follicular lymphoma based on overall response rate of 94% and a complete response rate close to 80% in patients with relapsed/refractory disease. I think further follow up from ZUMA-5 [NCT03105336] will let us know if this is a potentially curative option for our patients with the more indolent lymphomas, they can have relapses 10, 20, even 30 years down the line.

We have CD19 CAR T approved in DLBCL and that is being investigated in earlier lines of therapy. Recently published in a New England Journal of Medicine is the ZUMA-7 [NCT03391466] study that looked at CD19 CAR T-cell therapy axicabtagene ciloleucel

[axi-cel; Yescarta] as second line therapy compared to standard of care, high dose therapy and autologous stem cell transplantation. This was the first initiated and first to meet its primary efficacy analysis among many different studies in this space trying to transform second line DLBCL therapy, away from high dose chemo and consideration of autologous stem cell transplant, particularly for patients with chemo-sensitive disease and instead sparing patients the toxicity of high dose chemo and transplant and allowing them to go straight to CD19 CAR T-cell therapy in the second line setting.

We are taking the CD19 CAR T cells and adjusting the types of lymphoma where we can use them and the lines of therapy where we can use them. Moving forward, what's probably transforming this space the most are potentially CAR T-cell products that target different antigens on the tumor cell, but also dual targeting CAR T, so these targets CD19 and there are other CAR T products that target more than 1 tumor antigen. Instead of autologous products, there are allogeneic off the shelf or their cell therapy products that may be T cells, they may be NK cells. There are some other ways of conjugating an antibody to an effector T-cell to have a CAR T-like effect with a more simple and potentially less expensive manufacturing process. There are a lot of ways that this space is moving forward quite rapidly in a way that's incredibly hopeful and promising for our patients.

What are some of the highlights from your presentation?

I presented the updates on CAR T-cell therapy in patients with mantle cell and indolent lymphoma, and currently mantle cell lymphoma. We have CD19 CAR T brexucabtagene approved for relapsed refractory disease based on the ZUMA-2 study, showing an overall response rate of 93% and a complete response rate of 67%. In indolent lymphomas, we have CD19 CAR T-cell therapy approved for patients with relapsed refractory follicular lymphoma based on the ZUMA-5 study, and that shows an overall response rate of 94% a CR rate of almost 80% and durable response with the latest follow up.

Another thing that was highlighted in the presentation is that studies are ongoing with other CAR T products across mantle cells and follicular lymphoma. And 1 very interesting combination type of approach that's moving forward in mantle cell lymphoma is the combination of BTK inhibitor, particularly ibrutinib [Imbruvica] with CD19 CAR T, ibrutinib may enhance the activity of CD19 CAR T-cell therapy or CAR T-cell therapy in general, because it shifts the immune response towards a T-helper 1 type response, which is involved in cytotoxic effector response against cancer that in combination with an impact on the immune microenvironment may help make CAR T-cell therapy more effective and potentially mitigate cytokine release.

There's a lot of interesting things going on in the mantle and indolent lymphoma space to take our current CAR T products, hopefully expand where they can be used, move them into earlier line settings and move forward with rational combinations to make our therapies more effective and less toxic.

What are your thoughts on the current landscape for mantle cell lymphoma and how the future looks?

I would say it is a exciting time in cancer in general and lymphoma therapies are advancing at the most rapid rate we've seen since I've been in medicine. It's really a very promising time for our patients. Even as a lymphoma specialist, it's hard to stay up to date sometimes because things are changing so rapidly. I feel very hopeful, our patients have all the reasons to feel very hopeful, and as we harness the power of the immune system, I think things are only going to continue to get better.