Frontiers in Immunology (Apr 2022)

T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma

  • Jiachen Wang,
  • Jiachen Wang,
  • Kefeng Shen,
  • Kefeng Shen,
  • Wei Mu,
  • Wei Mu,
  • Weigang Li,
  • Meilan Zhang,
  • Meilan Zhang,
  • Wei Zhang,
  • Wei Zhang,
  • Zhe Li,
  • Zhe Li,
  • Tong Ge,
  • Tong Ge,
  • Zhoujie Zhu,
  • Shangkun Zhang,
  • Caixia Chen,
  • Caixia Chen,
  • Shugang Xing,
  • Shugang Xing,
  • Li Zhu,
  • Li Zhu,
  • Liting Chen,
  • Liting Chen,
  • Na Wang,
  • Na Wang,
  • Liang Huang,
  • Liang Huang,
  • Dengju Li,
  • Dengju Li,
  • Min Xiao,
  • Min Xiao,
  • Jianfeng Zhou,
  • Jianfeng Zhou

DOI
https://doi.org/10.3389/fimmu.2022.873789
Journal volume & issue
Vol. 13

Abstract

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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 [Cmax], initial persistence of the transgene by the CAR transgene level at +3 months [Tlast], 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 CX3CR1I249/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.

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