18F-FDG PET/CT metrics-based stratification of large B-cell lymphoma receiving CAR-T cell therapy: immunosuppressive tumor microenvironment as a negative prognostic indicator in patients with high tumor burden.

Chimeric antigen receptor T (CAR-T) cell therapy has greatly improved the prognosis of relapsed and refractory patients with large B-cell lymphoma (LBCL). Early identification and intervention of patients who may respond poorly to CAR-T cell therapy will help to improve the efficacy. Ninety patients from a Chinese cohort who received CAR-T cell therapy and underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans at the screening stage (median time to infusion 53.5 days, range 27-176 days), 1 month and 3 months after CAR-T cell infusion were analyzed, with RNA-sequencing conducted on 47 patients at the screening stage. Patients with maximum diameter of the largest lesion (Dmax) < 6 cm (N = 60) at screening stage showed significantly higher 3-month complete response rate (85.0% vs. 33.3%, P < 0.001), progression-free survival (HR 0.17; 95% CI 0.08-0.35, P < 0.001) and overall survival (HR 0.18; 95% CI 0.08-0.40, P < 0.001) than those with Dmax ≥ 6 cm (N = 30). Besides, at the screening stage, Dmax combined with extranodal involvement was more efficient in distinguishing patient outcomes. The best cut-off values for total metabolic tumor volume (tMTV) and total lesion glycolysis (tTLG) at the screening stage were 50cm3 and 500 g, respectively. A prediction model combining maximum standardized uptake value (SUVmax) at 1 month after CAR-T cell therapy (M1) and tTLG clearance rate was established to predict early progression for partial response/stable disease patients evaluated at M1 after CAR-T cell therapy and validated in Lyon cohort. Relevant association of the distance separating the two farthest lesions, standardized by body surface area to the severity of neurotoxicity (AUC = 0.74; P = 0.034; 95% CI, 0.578-0.899) after CAR-T cell therapy was found in patients received axicabtagene ciloleucel. In patients with Dmax ≥ 6 cm, RNA-sequencing analysis conducted at the screening stage showed enrichment of immunosuppressive-related biological processes, as well as increased M2 macrophages, cancer-associated fibroblasts, myeloid-derived suppressor cells, and intermediate exhausted T cells. Collectively, immunosuppressive tumor microenvironment may serve as a negative prognostic indicator in patients with high tumor burden who respond poorly to CAR-T cell therapy.