CAR-T Therapies in R/R DLBCL

Transcript:

David Miklos, MD, PhD: In 2016, we presented the ZUMA-1 work. This was exciting because of the complete response rate of 58% and overall response of 82% in patients who were relapsed and refractory to 2 lines of chemotherapy or more.

Quickly, we saw Novartis with the tisa-cel [tisagenlecleucel] agent, and not as quickly but very effectively, the JCAR17 initially through Juno, then Celgene, then Bristol Myers Squibb. There’s now what we call liso-cel [lisocabtagene maraleucel]. We wouldn’t be doing ourselves a favor if we didn’t discuss the differences in the model CAR [chimeric antigen receptor] in regard to antigen binding, the motor—I like a fast motor, the ability for the cells to persist, and the killing in the transmembrane domain.

What’s remarkable about these 3 early commercially approved, FDA-approved therapies is that they all have the exact same binder. They bind to CD19 using a remarkable monoclonal antibody that Laurence Cooper and others developed called FMC63. We’ve been discussing the same Pac-Man binding site, which is remarkable. Yet we’ve been discussing the differences through how they’re produced with selection retrovirus or lentivirus, or how they’re driven with costimulatory domains, and even the transmembrane domain. I’m sure we don’t want to go into the details of the small differences. The point I want to make is they’re remarkably the same, and all 3 were effective. All 3 were desperately needed by patients to bring forward a therapy with enough capacity for individual cell manufacturing and personalized care across what was estimated to be 10,000 to 15,000 patients with relapsed/refractory large cell lymphoma annually.

We commented for the last 3 years about the underuse of the therapies, initially about the costs and whether Medicare would pay for it. Most of those conversations have gone away. We’re left asking, are they persistent? Do they provide durable response? Is this 1-and-done? Remarkably, it has been. We’ve talked a little about redosing; we’ve done a good number of studies of that. We’ve talked a little about dose escalation, but we never dose escalated. Four years later, with a lot of experience at many centers, we’ve come back to whether we can do this with less toxicity, out of the hospital, and with durable, enduring responses.

The historical perspective on CAR T isn’t the fine differences, but the remarkable difference that is made in patients’ lives, the dramatic shift in the care of the patients. Now we’ll discuss whether we could do the same thing with T-cell engagers, endogenous binding, amplification of payload on monoclonal antibodies. But the bar for relapsed/refractory lymphoma moved from 12% 1-year overall survival to greater than 50% overall survival at 2 years, and now 37.2% at 5 years.

Jason Westin, MD: The word cure is something we all want to use when we talk to our patients. One thing I’d like to highlight from the long-term follow-up from the ZUMA-1, JULIET, and TRANSCEND-NHL-001 studies is that we’re seeing what I consider to be a plateau, so I use the word cure when I talk to my patients. When patients are more than 6 to 12 months out, we don’t have a lot of events that occur at those late time points. That shows the power of the immune system, that we’ve gone from a disease where the curve kept dropping and patients kept relapsing and dying of their cancer to where we’re curing at least a subset. Clearly, we need to do better, but this is a new era where we can cure patients with chemotherapy-refractory disease.

Grzegorz S. Nowakowski, MD: There’s no question that this is a transformational therapy for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma, and we’re all extremely enthusiastic about this. But like with any progress, it creates new opportunities and challenges. We still have to remember that over half the patients will relapse after this therapy, and we don’t know how to approach those patients. I always joke that if you ask key opinion leaders, everybody is going to say, “clinical trial.” Good luck with that.

At ASH [American Society of Hematology Annual Meeting], 1 of our colleagues at Mayo Clinic, Dr Pizarro, 1 of our fellows, presented the data where he applied common inclusion criteria to relapsed/refractory studies to patients at the time of post–CAR-T-cell relapse, and only half those patients based on those criteria were eligible for clinical trials. Half weren’t eligible because of prolonged cytopenias and organ dysfunction, and those patients had a median survival of only 3 months.

We’re excited about this progress, and by no means am I trying to undermine it—it’s a great development and we’re extremely excited—but as we’re seeing more patients post–CAR-T-cell therapy, we have to learn how to deal with those patients and how to develop novel therapies. We need to come together with novel inclusion criteria for clinical trials in those patients. We can’t accept the standard ones because we’re leaving many people behind. They almost require leukemic-like protocols. You may have very low counts, and there’s going to be a high risk and higher infectious risk, but we have to accept it and embrace it to move forward.

In the meantime, I’m very excited about all these strategies appearing with the novel CAR T cells and trying to build on the CAR T cells and increase response rate. Because ultimately, this will probably be the way to greatly reduce this problem with post–CAR-T-cell therapy. There’s no question that this is a major breakthrough across the lines of therapy for diffuse large B-cell lymphoma.

David Miklos, MD, PhD: Giving a therapy that at best has a 20% 1-year mortality risk has to be the therapy of last resort after we’ve tried a few of these other therapies in our armamentarium. Cost and time are other issues. The patient is committing to an allotransplant. In the case of CAR T, the discussion of staying in the hospital for 7 to 14 days would be criticized. We’ve forgotten how far we’ve come from requiring patients to stay in the local area for 3 months. I’m piling on. But we just had a feel-good discussion not for ourselves but for our patients on how far care has come in large cell lymphoma, not only in up-front induction therapy but in the hijacking of the immune system in order to put it to work.

I was struck by the work of Novartis, the shortened 2-day production to use the CAR that’s targeting CD19.

Jason Westin, MD: YTB323, the T-Charge program.

David Miklos, MD, PhD: Thank you. Jason, who gave that talk in the ALL session?

Jason Westin, MD: I don’t know regarding the ALL session, but Dr Ian Flinn gave the talk for lymphomas. It shows this incredibly short manufacturing time and almost off-the-shelf–like products. It still hasn’t worked out to be quite as fast as they claim it can be, but it’s clearly intriguing. We shorten that manufacturing time.

David Miklos, MD, PhD: It was remarkable work. We’re using the same constructs without a lot of innovation into multitargeted binding, but to turn out a product in 2 to 3 days would be a life changer for patients.

Transcript edited for clarity.