ASH 2024 | Association between post-CAR-T terminal complement complex levels and ICANS

So we know that ICANS is an endothelial dysfunction syndrome, right? The CAR-T activation leads to an inflammatory process. And this inflammatory process causes endothelial activation dysfunction, right? And from other syndromes that are associated with endothelial dysfunction, we know that the complement plays a significant role. The complement is activated. And for example, transplant-associated TMA, the complement is a biomarker and also a target of therapy, right? So here we try to explore and describe the complement levels, the terminal complement complex levels of patients that receive anti-CD19 CAR T-cells, of course, [inaudible] CD28 because these are the patients that have a higher risk of ICANS and describe the patients that have ICANS grade 2 or higher or grade 0 or 1. And what we found in both groups, we have shown in a matched pair analysis that the complement was activated and increased levels but the levels are higher in the patient population that had ICANS grade 2 or 4 right but when you look back to the levels before lymphodepletion and before CAR-T infusion they did not differ based on the patient population suggesting that the complement activation might be playing a role in the development of ICANS grade 2 or higher. We also look in the patients that receive prophylactic steroids that’s frequently used with the CD28 CAR-T products and we did not see a difference in the complement activation levels if your patients use prophylactic steroids, suggesting that the use of prophylactic steroids that’s currently the most employed approach to minimize ICANS may not be preventing the complement activation. We also tried to understand which factors could be associated with the complement activation and we saw correlation independent association between the terminal complement complex levels with CAR-T expansion and also with the modified EASIX score that is a surrogate marker of endothelial activation. But interestingly when we look to the multivariable model including the CAR-T expansion levels, soluble terminal complement complex levels and the modified EASIX score, only the CAR-T expansion and the complement remain dependently associated with ICANS grade 2 or higher, suggesting that the complement be a more powerful surrogate marker of the complement activation and the endothelial dysfunction in these patients with ICANS grade 2 or higher. And our data is mainly descriptive and hypothesis-generated, but support further studies to evaluate the role of complement in ICANS pathogenesis and also as a biomarker and therapeutic target.

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