Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (sC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients

Abstract

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients' group compared to the healthy control group (p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point (p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion (p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion (p = 0.008) and the EASIX scores at day 14 (p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

Keywords: chimeric antigen receptor-T (CAR-T); complement; cytokine release syndrome (CRS); endothelial activation and stress index (EASIX); endothelial dysfunction; growth differentiation factor-15 (GDF-15); immune effector cell-associated neurotoxicity syndrome (ICANS); soluble urokinase plasminogen activator receptor (suPAR).

Figure 1

(A) sC5b9 levels show a significant correlation with sEASIX0 (p = 0.008) and (B) EASIX14 (p = 0.005) scores. sC5b9 = soluble C5b-9 and s-EASIX0 = simplified Endothelial Activation and Stress Index scores were calculated at the day of CAR-T cell infusion; EASIXDAY14 = Endothelial Activation and Stress Index scores were calculated 14 days post-CAR-T cell infusion.

Figure 2

(A) s-EASIX0 score over the median value (1.9, range: 0.74–49.3) was associated with poor OS (p = 0.027); (B) s-EASIX14 score over the median value (3, range: 0.6–74.6) was also associated with poor OS (p = 0.004). Green lines: s-EASIX score below the median; blue lines: s-EASIX score over the median value. S-EASIX0 = simplified Endothelial Activation and Stress Index calculated at the day of the infusion; S-EASIX14 = simplified Endothelial Activation and Stress Index calculated 14 days post-infusion; OS = overall survival.

Figure 3

Methodology used in our study. Samples for sC5b-9, suPAR, and GDF-15 measurements were obtained from CAR-T cell recipients before their admission to the cellular therapy unit, and at the same time point, EASIX, mEASIX, and s-EASIX scores were calculated. EASIX and s-EASIX scores were also calculated on the day of CAR-T cell product infusion and 14 days post-infusion. During the post-infusion period, patients were closely monitored for therapy-related toxicities. The minimum follow-up period was 1 month. LDC = lymphodepleting chemotherapy; EASIX = Endothelial Activation and Stress Index; m-EASIX = modified Endothelial Activation and Stress Index; s-EASIX = simplified Endothelial Activation and Stress Index; sC5b-9 = soluble C5b-9; suPAR = soluble urokinase-type plasminogen activator receptor; GDF-15 = growth differentiation factor-15; CRS = cytokine release syndrome; ICANS = immune effector cell-associated neurotoxicity syndrome.