T 细胞缺陷：弥漫大 B 细胞淋巴瘤中 CD19/CD22 鸡尾酒 CAR-T 细胞免疫治疗原发性耐药因素的新见解

Despite impressive progress, a significant portion of patients still experience primary or secondary resistance to chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The mechanism of primary resistance involves T-cell extrinsic and intrinsic dysfunction. In the present study, a total of 135 patients of DLBCL treated with murine CD19/CD22 cocktail CAR T-therapy were assessed retrospectively.

Based on four criteria (maximal expansion of the transgene/CAR-positive T-cell levels post-infusion [C max ], initial persistence of the transgene by the CAR transgene level at +3 months [T last ], CD19+ B-cell levels [B-cell recovery], and the initial response to CAR T-cell therapy), 48 patients were included in the research and divided into two groups (a T-normal group [n=22] and a T-defect [n=26] group).

According to univariate and multivariate regression analyses, higher lactate dehydrogenase (LDH) levels before leukapheresis (hazard ratio (HR) = 1. 922; p = 0. 045) and lower cytokine release syndrome (CRS) grade after CAR T-cell infusion (HR = 0. 150; p = 0. 026) were independent risk factors of T-cell dysfunction.

Moreover, using whole-exon sequencing, we found that germline variants in 47 genes were significantly enriched in the T-defect group compared to the T-normal group (96% vs. 41%; p<0. 0001), these genes consisted of CAR structure genes (n=3), T-cell signal 1 to signal 3 genes (n=13), T cell immune regulation- and checkpoint-related genes (n=9), cytokine- and chemokine-related genes (n=13), and T-cell metabolism-related genes (n=9).

Heterozygous germline UNC13D mutations had the highest intergroup differences (26. 9% vs. 0%; p =0. 008). Compound heterozygous CX3CR1 I249/M280 variants, referred to as pathogenic and risk factors according to the ClinVar database, were enriched in the T-defect group (3 of 26). In summary, the clinical characteristics and T-cell immunodeficiency genetic features may help explain the underlying mechanism of treatment primary resistance and provide novel insights into CAR T-cell immunotherapy.