Insights From: Michael Wang, MD, The University of Texas MD Anderson Cancer Center
Michael Wang, MD: I will never be able to forget the 2019 ASH [American Society of Hematology annual meeting] when I presented the ZUMA-2 clinical trial with CAR [chimeric antigen receptor] T-cell therapy targeting CD19 that has induced prolonged remissions in some of the patients. In this clinical trial 68 patients, nearly half of the patients, have more than 2 years follow-up. In fact, at The University of Texas MD Anderson Cancer Center, we have follow-up up to 3 years. Some of these patients have p53 mutations. Some patients have blastoid and relapsed mantle cell lymphoma. Those patients after BTK [Bruton tyrosine kinase] resistance, they don’t really have a survival of more than 8 months. But the fact I can see some of them reach 2 years, 3 years without further relapse is so encouraging.
I used to lose those patients, and it’s very sad. But now I really see some hope. So, I will never be able to forget how eventful 2019 was for me, my career, and my patients. With my colleagues, together we made this trial happen. The trial has a response rate of 93% with a CR [complete response] rate that’s the highest among all the reported CAR T-cell therapy in lymphoma. We are very hopeful this therapy will be approved by the FDA and will be published in a good journal. Therefore, it will be used worldwide, not only in the United States, but in Europe and all over globally so it can save some patients’ lives. I think that this trial gave me hope that a fraction of patients might be cured. That can only be proven to be true with more time to follow up. That’s the KTE-X19, CAR T-cell therapy that you just mentioned.
In the past 10 years we have a theme that therapy for lymphoma, and especially for mantle cell lymphoma, has migrated from chemotherapy mainstream to targeted therapies. Targeted therapy is powerful, but it cannot cure just anybody because the resistance comes very fast. So there has been chemotherapy, targeted therapies, and now we’re in the cell therapy era. Cell therapies have the potential ability to lead to the cure of some of the patients. Again, only more follow-up time will prove my point to be true. The CAR T-cell therapy is the combination of genetic transfer, manipulation of T-cells, and immunotherapy…and chemotherapy. This is because we have to use chemotherapy to prepare the body to accept the CAR T-cells we’re going to infuse. It’s a combination of all.
CAR T-cell therapy, or cell therapy, is so promising, but there is toxicity that comes with it. The adverse effect profile so far is pretty bad. For example, the CRS, cytokine release syndrome, the patients’ fever can be as high as 104 degrees Fahrenheit. When the patient’s fever is this high and it’s seen for many days, some of the patients become very ill. They may have to be transferred to the ICU [intensive care unit]. Sometimes we have to put a tube down their throat to help them breathe. So sometimes the toxicity can be very difficult. Another even worse toxicity is neurotoxicity. Some patients would slide into a coma with grand mal seizures, and they are not able to recover on a ventilator for a week or two. Those are very life-threatening therapies. In this clinical trial, there were 2 patients who actually did not make it due to infections, and infections are another major issue.
While CAR T-cell therapy is bringing the major change and also the potential to cure certain lymphoma patients, so far, the toxicities are very heavy. But I think we have the first-generation CAR T-cell product where we’re using it and while we’re using, we’re learning how to use steroids, how to use the interleukin-6 antibody to totally kill the CRS, it’s very effective, and high-dose steroids. While we’re learning all this, we’re also improving the second-, third-generation CAR T-cell product that would have fewer adverse effects.
For example, you can use different costimulatory molecules, the CD28 costimulation, and the Juno Therapeutics product, which is not approved yet. We also reported some of the mantle cell lymphomas use 4-1BB, which is generally associated with fewer adverse effects of CRS and neurotoxicity. I lead the MD Anderson Moon Shots Program among B-cell lymphomas with Richard Champlin, MD, and Christopher Flowers, MD. In this Moon Shots Program, we are using CAR NK [natural killer] cells; instead of using T-cells, we use CAR NK cells. CAR NK cells so far are very effective in... the efficacy, but natural killer cells are part of the immune system. CAR NK cells do not induce CRS or neurotoxicity.
Science is moving so fast, right? Of course, for CAR NK cells, we need more time to see whether the response will be as durable as the T-cells. We still don’t know all the good things about the CAR NK, but at least we are now innovating. We are finding new approaches. It’s an exciting time for lymphoma, especially for mantle cell lymphoma. With my generation, I think we shall be able to cure some patients.