CAR T for chronic lymphocytic leukemia
Kirollos Hanna, PharmD, BCPS, BCOP:Another exciting thing we saw at ASH [American Society of Hematology 2021 Annual Meeting]SELF [chimeric antigen receptor] T in CLL [chronic lymphocytic leukemia]. Dr. Perissinotti, what do you know about CAR-T cells?
Anthony Perissinotti, PharmD, BCOP: With CAR T, it took a while for CLL to come to fruition, mainly because we had so many other good, effective therapies. And CAR T is expensive. It’s laborious. And there are a lot of logistics for patients and toxicities. There were 2 abstracts at ASH that clinically aren’t going to change things but, at least scientifically, I think they’re really important. One was from Shadman [Mazyar Shadman, MD, MPH, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA] and colleagues. They were trying to show some answers in a third generation CAR T. The first generations did not have a co-stimulation domain. And then in second people [generations], we added either 4-1BB or CD28. Third generation [generations] have 2 costimulatory domains, which had 4-1BB and CD28. The idea that there is better T-cell activation and more persistence. There was only one patient with CLL in this study and this patient had CR [complete response]. Again, it’s the scientific aspect that I think will be the most interesting. The second CAR T study involved AUTO1. It was from Roddie [Claire Roddie, PhD, MD University of London, London, United Kingdom] and colleagues, presented at ASH. Again, a scientific breakthrough, I think, as opposed to a clinic at this time. Only one patient with CLL was studied in this trial. The fame of AUTO1 is that it has rapid dissociation with CD19, and so it binds to CD19 very quickly but then detaches a bit faster than our previous CAR T cells. And the idea is that, maybe , we will have less cytokine release syndrome [CRS] and less neurotoxicity. In fact, in these small numbers, we saw no neurotoxicity and no cases of CRS grade 3 or higher were reported. I think something to watch with CAR T and CLL, but at this point I haven’t seen anything in ASH that will lead to anything in clinical practice over the next year.
Kirollos Hanna, PharmD, BCPS, BCOP: I think this brings me to another exciting or promising pharmacological class: our bispecific drugs. I am thinking of epcoritamab. Looking at the epcor [epcoritamab] trial, from what was published at ASH, it’s really about looking at bispecific antibodies again. This is nothing new in oncology care. But this is, again, something new, no doubt, for the CLL patient population. With respect to this bispecific therapeutics, it’s really about potent activation and cytotoxic activity through CD4 positivity and CD8 positive cells, so really trying to incorporate that into this population of patients with CLL. The clinical trial that was presented was carried out by Kater [Arnon P. Kater, MD, PhD, of Cancer Center Amsterdam, Netherlands] and colleagues, was a Phase 1B2 trial to assess dose-limiting toxicities and early evidence of clinical efficacy of epcoritamab in the relapsed/refractory CLL patient population. Eligible patients, or the patients they reviewed, had to be receiving at least 2 or more lines of treatment for CLL, so it could have been BTK [Bruton tyrosine kinase]BCL2 [B-cell lymphoma 2], etc In the end, they had 2 types of dosing regimens. One was at 24 milligrams and the other was at 48 milligrams. And what the data suggests is that these levels up to 48 milligrams had good clinical activity in patients with high-risk characteristics and were well tolerated. Now, notable things they observed in this clinical trial; cytokine release syndrome occurred in almost all observed patients. Again, this was a small subset of patients in this clinical trial. They noted fatigue, reactions at the injection site and nausea. But all that CRS that happened was mostly in the first cycle, and there really weren’t any CRS events that were rated above a grade 2, so generally well managed. But also, as Dr. Perissinotti said, these therapeutics, CAR T, bispecific therapeutics, our non-covalent BTK inhibitors, and even our newest PI3K [phosphoinositide 3-kinase] inhibitors, all of these things are in the works, but we’re starting to evaluate them in terms of, could we use them next? From what we’ve seen at ASH, none of these therapies are yet able to replace the standard first-line therapy we’ve mentioned, or even in this second-line setting, from the data of efficiency that we have highlighted here today.
Transcript edited for clarity.