ASH 2025 | Impact of putative cell of origin on CD19+ CAR-T outcomes in patients with DLBCL

So the impact of putative cell of origin, germinal center B or activated B-cell or non-germinal center B is well known in terms of conferring an impact on outcomes for patients with large B-cell lymphoma. It has also been looked at with autologous transplantation where the results did not actually read out in a retrospective manner. This specific impact of putative cell of origin, GCB versus non-GCB, has not been looked at in a CAR T-cell setting. So with this in mind, we designed this study at a single center at MD Anderson Cancer Center in over 400 patients with a uniform study design and we included CD19-targeted CAR T-cell therapy in adult patients over 18 who met the inclusion criteria. And then we stratified further by line of therapy, so second line versus third line, obviously following the FDA label and commercial availability. In second line, we have two CAR constructs; in third line, we have three CAR constructs, so we wanted to look at the impact of cell origin or CAR outcomes stratified by lines of therapy, second line versus third line and beyond. In terms of key results, in a cohort of 400 plus patients at MD Anderson, we saw that CAR in second line conferred a significant survival advantage as compared to third line. And that is sort of a known fact. Now, cell of origin impact-wise, CAR T-cell in patients who had GCB cell of origin subtype did fairly well in terms of PFS as compared to non-GCB subtype. Similarly, in the third-line setting, GCB subtype actually did pretty well as compared to non-GCB subtype. So I think the key takeaway from this single-center study, and this is that we have to do better for non-GCB subtype in terms of CAR-T constructs, particularly in third line and beyond setting. The study is single center, certainly has limitations, but it has over 400 patients and comes from a very homogenous cohort of CD19 CAR constructs, large B-cell histology. And results really demonstrate that even CAR T-cells don’t fare as well in terms of PFS with non-GCB as compared to GCB. And really, the results are clearly reading out considerably differently in second line versus third line as determined by cell of origin’s impact. So it really allows us to do a cell of origin-adapted approach towards selecting the right CAR construct for the right patient with the right cell of origin subtype and histology. This does pave the way for further research, prospective studies, to tease out CAR outcomes, both PFS and overall survival stratified by line of therapy, stratified by cell of origin, and pave the way for a more risk-adapted and cell of origin-adapted approach.

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