A review of the ZUMA-1 trial using anti-CD19 CAR T-cell therapy in patients with refractory large B-cell lymphoma and the management of adverse effects such as cytokine release syndrome (CRS) and neurotoxicity.

Transcript

Bruce Feinberg, DO: Ian, I’m going to flip the gears and we’re going to get into more depth. Your opening comments was rational exuberance over CAR T. Because we had this change. We had 50 years of cytotoxic chemotherapy, some excitement with targeted therapy that unfortunately started high with imatinib and then waned thereafter. Great addition to the armamentarium but not necessarily the cure that we were all looking for in our decades of practice. Then suddenly we unleash the immune system and we do it first with checkpoint inhibitors and then we start to do it with cell and gene therapy. It is different because for the first time we have, in different diseases, survival that looks like the tail of the curve is flat and maybe these patients are cured. Tell me a about the pivotal trials in CAR T that set off this excitement.

Ian W. Flinn, MD, PhD:There have been two pivotal trials so far, a third product that’s not been FDA approved yet. The first was ZUMA-1. ZUMA-1 was a trial with Kite’s CAR T-cell, targeting CD19 on the surface of the cell, of the malignant B-cell. In this trial there was roughly 100 patients that entered into it. They all had refractory disease, and when we were a site for ZUMA-1, the patients had to have not responded to the last therapy or will relapse within a year after an autologous transplant. It was a difficult group of patients. The good news is that the majority of people were able to acquire CAR T-cells, receive the lymphodepletion and have the CAR T-cells infused.

Fast-forward, what we learned was that most patients will respond, however, the response was transient. But those patients who achieved a complete remission, most of those patients, if you looked at they had a complete remission at three and six months after the infusion of the CAR T-cells, they will remain in remission indefinitely at this time. There’s about40% of original patients at two years out are still in remission. That’s exciting news. That was way different than we ever had prior to the introduction of CAR T-cells. Before that I was just talking about hospice to patients but not about some durable long-term remissions.

We also learned along the way that there were some [adverse] events. We know that there are a variety of smaller [adverse] events, but the two that most of my patients worry about and I am sure to go through in great detail with them is cytokine release syndrome, as well as neurological toxicity. Cytokine release syndrome, I explain to patients, it’s the worst infection of your life. You can have a fever to 104, you can drop your blood pressure, you can end up in the ICU.

Bruce Feinberg, DO: That was like COVID.

Ian W. Flinn, MD, PhD:There are some similarities there. In some of the therapies that we use now have been tried, like tocilizumab have been tried in COVID as well. But we’ve gotten better about managing that with the introduction of steroids earlier with tocilizumab which is a drug that mediates some of that. But the other one that’s scary is the neurological toxicity. I remember the first time I experienced this, we now refer to as ICANS, but there’s a range of things from very moderate modest confusion to frank coma where you have to intubate patients to put them on a ventilator in order to protect their airway. The good news here is that this also is generally reversible. There’s a small percentage of people that can’t be reversed. The majority of people you can. It’s still an incredibly scary [adverse] event that happens.

We saw the same thing. The Novartis studies with their competing product is similar. There are some differences in the design of the trial that led to its approval in terms of whether you allow bridging therapy or not and how many people ultimately got the therapy. In the big picture, they’re relatively similar products. Different centers and different investigators like one versus the other. But, frankly, in the big picture, they’re relatively similar products.

Bruce Feinberg, DO: Ed, it’s worth getting deeper into what exactly is this therapy that’s introducing both this potential for cure as well as toxicities which we don’t normally associate with chemotherapy or other forms of cancer treatment. Ed, what exactly are CAR T-cells and the process in which they’re generated and how again that’s a very different process than, for the most part, we’ve experienced in the last decades of cancer management?

Edward J. Licitra, MD, PhD: Very simplistically, a CAR T-cell is a chimeric activated receptor T-cell, it’s a genetically engineered T-cell that is targeted at a specific antigen. CAR T-cells take advantage ofa very basic and fundamental process of cellular biology. Many years ago, I did a lot of work in a lab and at that time it was very interesting how receptors were modular in nature. You could take receptors and you can flip flop various domains of receptors such that you could come up with artificial activation of certain receptors through ligand engagement. And I spent a significant part of my career doing this 20+ years ago.

It’s gratifying that this basic fundamental concept of cellular biology now 20 years later is transforming the way that we take care of cancer patients. Essentially what happens is that a T-cell is taken out of a patient and then ultimately is sent off for transformation with a retroviral vector, such that a chimeric protein is introduced into the T-cell. And outside the T-cell there is a component of it that recognizes an antigen, and that antigen could be anything. In the case of the CAR T-cells that we’re talking about here for relapsed and refractory non-Hodgkin’s lymphoma, that antigen is CD19 on the surface of a B-cell in the lymphoma cell. Then, linked to that external domain that recognizes CD19 is a variety of costimulatory domains, that are artificial in some ways because they’re not supposed to reside in that particular cell. But those costimulatory domains are then linked together such that when the antigen recognizing a portion of the chimeric receptor engages with its target, it results multimerization of these receptors and then downstream activation of the T-cell.

Now you have is a T-cell removed from a patient, sent off to a lab where over a 17 to 20 day period of time it is transformed through a retroviral vector into a chimeric T-cell that is then reintroduced into a patient . And then essentially what it does is it seeks and destroys the B-cells or the non-Hodgkin’s lymphoma by engaging them, activating the T-cells. And, if you activate the T-cells right, you get the desired response. If you activate the T-cells too much, you get cytokine release syndrome and other [adverse] effects related to these.

The key is how do you activate the T-cell in the most precise way, not too much, not too little and just the right way. In the development of CAR T-cells, people spend a lot of time figuring out which costimulatory domains should be linked to one another to get that desired response. Now, it’s not perfect but if you look at later generations of CAR T-cells, they are actually better than some of the earlier generations with the ability to kind of more finely titrate the desired effect.