P1381: distinct cytokine signatures of idecabtagene vicleucel compared to axicabtagene cileucel and lisocabtagene maraleucel

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Chimeric antigen receptor (CAR) T-cells has improved responses in refractory diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Most CAR-T recipients experience cytokine release syndrome (CRS) related to T-cell activation and expansion of multiple cytokines. Differences in tumor biology between MM and DLBCL and how they contribute to varying rates of CRS are not well understood. Aims: We used multiplex proteomic profiling to evaluate differences in cytokine signatures between three CAR-T cell products. Methods: Between April – December 2022, 27 patients received CAR T-cell therapy and consented to the Yale School of Medicine hematologic disease tissue bank (HIC#1401013259). Three longitudinal cohorts were prospectively enrolled: patients who received (1) axicabtagene cileucel (axi-cel) for DLBCL refractory to 1-2 lines of therapy, (2) lisocabtagene maraleucel (liso-cel) for DLBCL refractory after two lines of therapy, and (3) idecabtagene vicleucel (ide-cel) for MM refractory after 4 lines of therapy. For each patient, the first sample was collected prior to lymphodepleting chemotherapy on day -5 with subsequent samples collected on days 0 (prior to CAR T-cell infusion) and 1, 2, 3, and 7 (after CAR T-cell infusion). Proteomic profiling was performed at Eve Technologies (Calgary, Alberta, Canada). The Human 71-Plex Discovery Assay measuring 71 total cytokines and chemokines was used to interrogate each sample time point. Statistical analysis was performed in GraphPad Prism (GraphPad Software, San Diego, CA) and R (R Core Team). Levels of individual proteins were compared using Wilcoxon tests. P-values <0.05 were statistically significant. Results: Among 12 patients with DLBCL, 7 received axi-cel, 5 received liso-cel, median age was 68 years (range 45-84), 9 (75%) were men, 6 (50%) had clinically bulky disease, and 9 (75%) required bridging chemotherapy. Six patients (50%) had any grade CRS, one patient receiving liso-cel had maximum grade 2 CRS, one patient receiving axi-cel had maximum grade 4 CRS, and 5 (42%) patients received IL-6 inhibition. Three patients (25%) had any grade ICANS, with 2 of those patients receiving axi-cel and having grade ≥ 3 ICANS. By 3 months of follow-up, the objective response rate was 83% (10/12). Among 15 patients with MM, the median age was 62 years (48-71), 8 (53%) were men, 4 (27%) had extramedullary disease, and 11 patients (73%) received systemic bridging therapy. Ten patients (67%) had any grade CRS with no patients having grade ≥ 3 CRS; 10 (67%) had grade 1 ICANS with two patients (13%) having grade ≥ 3 ICANS. Nine patients (60%) received IL-6 inhibition. All patients received growth factor support on day 7 prior to discharge. At 3 months of follow-up, the objective response rate was 67% (10/15). In a longitudinal analysis for all 3 CAR constructs, ide-cel was characterized by significantly higher levels of I-309, 6CKine, Fractaline, IFN-g, IL-10, IL-12p40, IL-13, IL-18, IL-9, M-CSF, MCP-2, MCP-4, MIP-1α, MIP-1β, MIP-1δ at ≥ 2 timepoints, compared to axi-cel and liso-cel (figure). In addition, stem cell factor (SCF) and TPO were significantly elevated in patients with MM at ≥ 5 timepoints both before and after ide-cel infusion. Summary/Conclusion This study provides pre-clinical evidence for a monocytic predominant inflammatory cytokine signature for patients receiving BCMA-CART invoking contribution by disease biology which may warrant alternative toxicity management. Baseline monocytic elevations may explain higher risk of Hemophagocytic lymphohistiocytosis (HLH) or Macrophage Activation Syndrome (MAS) among patients with MM. Further studies with larger cohorts of patients are needed to validate these findings.Keywords: Cellular therapy, Multiple myeloma, Diffuse large B cell lymphoma, CAR-T