EHA 2025 | A Phase Ib study of JNJ-90014496, a CD19/CD20 bispecific CAR-T therapy, in patients with R/R LBCL

We know that CD19 CAR T-cell therapies have transformed the landscape in terms of treatment for patients with relapsed/refractory large B-cell lymphoma, but despite that, most of the patients don’t achieve long-term remission. That’s because a lot of these patients can have relapses, and one of the major problems with relapse is antigen loss or antigen escape by the tumor cells. So, the whole idea of this product, JNJ-4496, is that it’s a bispecific CAR-T, so it’s targeting not one antigen but two antigens on the malignant B-cell, so CD19 and CD20, rather than just CD19. And the whole idea is that if you have a dual targeting strategy, you may be able to prevent antigen escape after CD19 CAR T-cell therapy in patients with large B-cell lymphoma. 

So, the structure is that you’ve got a CD19 antibody, FMC63, CD20, which is again, you know, single chain, a variable fragment that targets two regions within the CD20 region. And the co-stimulatory domain is a 4-1BB domain. And this product has been shown to be quite effective in an earlier Chinese study with a CR rate of 86% and 50% with durable CR with a good PFS and OS after four years of follow-up as well. 

So, the Phase Ib global study is really a concurrent study that is looking at a wider population of patients globally rather than just the Chinese population, and we’ve had 51 patients, three dosage groups, so patients that were adults with relapsed/refractory large B-cell lymphoma, CD19 and/or CD20 expression, two or more prior lines of therapy, and one prior line of therapy if they’re older and not transplant eligible. They then can be enrolled onto the study, and these patients are then apheresed, so their T-cells get harvested and get manufactured, and bridging therapy is allowed for these patients at the discretion of the investigators, and then the patients were then dosed according to one of three dosage groups. So, the first one is a weight-based 2 million cells per kilogram dosage group. The second is a fixed 150 million cell group, and the third is a 75 fixed 75 million dosage group. And the 75 million dosage group, the 75 million CAR T-cells, was found to be the most safe and well-tolerated and efficacious. So, that was chosen as the recommended Phase II dose, and then, so we’ve had, you know, really some promising results in terms of efficacy and safety. 

So, in terms of safety, we’ve seen only one case of grade three CRS in the recommended phase two dose group of 75 million CAR T-cells, we didn’t see any grade three or four CRS events; most was a grade one. And with regards to ICANS in the recommended phase two dose group, we’ve had just one grade three ICANS, and that was in a patient that had CNS lymphoma, was found to have CNS lymphoma after study entry, and then another one was a grade one in a patient that had hydrocephalus. But otherwise very well-tolerated, very low infection rate, or grade three or four infection rate as well, so only three cases in the 51 patients, and only one case in the recommended phase two dose group as well. 

And the efficacy is quite promising. So, in the recommended phase two dose group, if the patients only had one prior line of therapy, the CR rat is 80%, the overall response rate is 100%. In those that had two or more prior lines, the CR rate is 75%. So, irrespective of how many lines the patient has had before, patients achieved a really good response with the 75 million CAR T-cell dose. 

So, yeah, let’s hope, you know, this good result will continue on, and obviously more investigations needed, and with a longer follow-up. And so, there will be new cohorts opening up in recruiting patients, for example, high-risk frontline patients that haven’t done as well with frontline therapy. Obviously, we also recruiting patients that have had prior CAR-T’s. So, all the patients that were presented at this conference, they were CAR-T naive, but in the future, we’ll have a CAR-T exposed group as well. And we’ll be enrolling patients to see whether it can salvage these CAR-T failed patients with this bispecific CAR-T product.

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