CAR T Cell Therapy in Relapsed/Refractory DLBCL

Brian Hill, MD, PhD: Chimeric androgen receptor T cells, or CAR T cells, are autologous T cells, T lymphocytes, that are derived from the patient. They have to be collected through a standard leukapheresis procedure at an authorized treatment center. Then the cell product in a self-contained isolated sterile container is shipped to a manufacturing center. Right now, in 2020, there are 2 FDA-approved therapies, axi-cel and tisa-cel. The 2 FDA-approved therapies are both directed against anti-CD19 on the target of B cells. And the chimeric antigen receptor is introduced into the patient’s own T cells through a viral transduction method, which is done, again, in an authorized treatment center in a manufacturing facility that works with an authorized treatment center. That viral transduction process takes a couple of weeks to take place, then those cells expand to sufficient numbers that can then be used to be delivered to the patient for therapeutic benefit.

Andre Goy, MD: In our center we have been involved quite a bit in CAR T cells with the NCI [National Cancer Institute] for 7, 8, 9 years ago now. When the patients who are candidates for this with the approved CAR T cells are in third-line setting, there are a number of ongoing trials that they are trying to look at if we can take advantage of this approach early on in the disease.

But what’s really important to summarize is that there are 3 different products among the most advanced axi-cel therapies from the ZUMA-1 data. Now that we have follow-up with this, the tisa-cel from JULIET and liso-cel from the JCAR017 trial TRANSCENDWORLD, they’re slightly different in terms of the signal CD28 for axi-cel and 4-1BB for tisa-cel and liso-cel. There’s a slight difference in the population of relapsed/refractory, the dosing process, the bridging therapy allowed on that. What is interesting is that the response rates went from 52% to 83% and the CR [complete response] rate from 40% to 58%. In a population that really has no option, this is quite considerable. And what is interesting in that setting is that there is some late delayed response. Up to 20%, 30% of patients can have a late response. Sometimes it can take up to a year, and that’s really important. Typically patients respond very rapidly, but it can take a while because it’s a live therapy. This is very important.

With our long-term follow-up, what is interesting also is that particularly in the ZUMA-1, where we have the longest follow-up, we’re at 27 months and close to 40% of the patients are doing really well and half the patients are alive. This is very impressive, and potentially a good fraction of these patients can be cured. One issue is the durability of the remission in this population, because the relapse is still definitely an issue, and the salvage after CAR T is very difficult. The patient who has CNS [central nervous system] involvement, for example, is also a significant issue.

There are some data—not a lot of data, particularly on tisa-cel—looking at patients who had known CNS disease, including disease with some durable responses. But overall, there’s not a lot of experience, and it could be a challenge, particularly toxicity from T cells. Toxicity from the CRS [cytokine release syndrome] and the neurotoxicity are very well known now. But we can manage this toxicity much better preemptively with tocilizumab and then with steroids. One of the questions that comes up is, what’s the best timing and the best combination that you can build on CAR T cell and how we overcome the resistance to CAR T? Those are the issues that I can see in CAR T.

Julio Chavez, MD, MS: How does CAR T-cell therapy affect patient outcomes and costs? We currently have 2 CAR T-cell products approved for relapsed/refractory diffuse large B-cell lymphoma, tisagenlecleucel and axicabtagene ciloleucel, but there has not been a comparison head-to-head. In clinical practice, there are some differences in terms of toxicity and efficacy. They both have the inherent risk of CRS and neurological events. There is probably more toxicity with axi-cel than tisagenlecleucel. But in general, both carry the same risk, so the patient has to be monitored closely in CAR T-cell therapy centers.

One of the challenges is some patients live far away from the centers, so they have to relocate into the cancer center, and that adds cost. They need a caregiver to stay off work for 1 or 2 months, and that’s another type of cost that families endure with the CAR T-cell therapy. I’m not talking about the cost of the treatment. CAR T-cell therapy is a very expensive treatment. There are also the management of the adverse effects, the use of tocilizumab on admission to the hospital, the use of an intensive care unit bed. Those factors increase the cost. For these reasons, cost and logistics, some patients may decide not to do CAR T-cell therapy, even though it’s a curative option.

Transcript Edited for Clarity