The Next Steps for CAR T-Cell Therapy in DLBCL - Episode 2

Options for CAR-T Therapy in the Third-Line Setting

Amit Patel, BSc, MBBS, PhD, The Christie NHS Foundation Trust

A key opinion leader in diffuse large B-cell lymphoma provides a historical perspective on third-line options for CAR T-cell therapy and shares insights on both clinical trial and real-world data.

Amit Patel, BSc, MBBS, PhD: Autologous CAR [chimeric antigen receptor] T-cell therapy has been a major advance in patients with DLBCL [diffuse large B-cell lymphoma] and is commercially available for patients in the third-line space who have relapsed/refractory disease. We have had 2 products available: axicabtagene ciloleucel and tisagenlecleucel. Tisagenlecleucel is a second-generation product with a 4-1BB costimulatory domain. The binding component, the thing that binds to CD19, is derived from FMC63. That binding domain is the same domain used for axicabtagene ciloleucel. This second-generation product has a CD28 intracellular signaling domain.

These 2 products have been available after single-arm pivotal clinical trials, the JULIET study for tisagenlecleucel and the ZUMA-1 study for axicabtagene ciloleucel. There are now a few years of follow-up in the real-world setting, and there are a number of real-world data sets evaluating the efficacy and safety of these 2 products. What’s been interesting is the real-world data have shown that the efficacy is similar to the pivotal clinical trials, and it’s important to remember that the real-world data for most therapies are typically not as good as the pivotal clinical trials. However, for CAR T-cell therapy, the opposite is true, and the real-world data are just as good despite including one-third to one-half of patients who would have not met inclusion criteria for the pivotal clinical trial. In other words, more difficult-to-treat patients are included, yet the efficacy signal is maintained.

The thing that’s more heartening is that the real-world data show us that the safety of CAR T therapy is better in the real world compared with the pivotal clinical trials, in terms of both cytokine release syndrome and neurotoxicity but also other safety parameters. That’s speaking to the fact that these therapies are delivered within specifically designated CAR T centers as part of allogeneic stem cell transplant programs. There is now a critical mass of expertise and concentration of expertise in these centers that has led to these excellent outcomes.

The EBMT [European Society for Blood and Marrow Transplantation] symposium highlighted that the long-term follow-up available from the pivotal clinical trials relating to tisagenlecleucel and axicabtagene ciloleucel showed durability of response. This is a onetime therapy for patients who have relapsed/refractory DLBCL in the third-line space. After this onetime therapy, we know that 30% to 40% of patients will remain in response in the longer term, up to 4 years and that 40% to 50% of patients will remain alive in the longer term. That’s been very important. The long-term data have also shown us that immune reconstitution and full recovery are also an expectation, particularly for patients followed up with after axicabtagene ciloleucel in the pivotal clinical trial. So we know from the pivotal studies that their initial responses seen are durable, they don’t require further therapy, and the patients recover after this therapy in terms of the immunity.

Real-world data have shown us that across the globe, whether the consortia that collected the data were based in the United States, in the United Kingdom, or anywhere in Europe, the patients treated with both axicabtagene ciloleucel and tisagenlecleucel expect to have similar outcomes to those presented in the pivotal clinical trials in terms of efficacy. But what’s important is that the safety in the real world has been shown to be better than in the pivotal clinical trials. That’s important to underline because the real-world data show us the safety of this complicated, autologous, personalized, patient-derived cell product is not only logistically possible to deliver but also able to deliver it in a very safe manner in a safe environment. The inclusion of patients who would not have met the pivotal clinical trial criteria in the real world, 30% to 50% depending on the product, is also very important to highlight, making sure that patient access and broad applicability of those findings have been demonstrated.

Transcript Edited for Clarity