Dataset Information

MIP3α as an early prognostic predictor for patients with B-cell malignancies receiving CD19/CD22-redirected CAR-T cell cocktail therapy.

ABSTRACT:

Purpose

Identifying the temporal pattern of recurrence and prognostic biomarkers would further help improve the efficacy of chimeric antigen receptor (CAR) -T therapy.

Methods

We examined the prognoses of 119 patients after sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-target CAR (CAR19/22) T cells in an open-label, single-center clinical trial (ChiCTR-OPN-16008526). And we, from a 70-biomarker panel, identified candidate cytokines that might predict the treatment failure, including primary non-response (NR) and early relapse (ER).

Results

In our study, 3 (11.5%) patients with B-cell acute lymphoblastic leukemia (B-ALL) and 9 (12.2%) cases of B-cell non-Hodgkin lymphoma (NHL) failed to respond to sequential CAR19/22 T-cell infusion (NR). A total of 11 (42.3%) B-ALL patients and 30 (52.7%) B-NHL patients had relapses during follow-up. Most recurrence events (67.5%) occurred within six months of sequential CAR T-cell infusion (ER). We found that macrophage inflammatory protein (MIP)-3α was a highly sensitive and specific prognostic predictor for patients with NR/ER and those attaining over-6-month remission. Patients who had higher MIP3α levels after sequential CAR19/22 T-cell infusion had significantly favorable progression-free survival (PFS) than their counterparts with relatively lower MIP3α expression. Our experiments demonstrated that MIP3α could enhance the therapeutic effect of CAR-T cells by promoting T-cell infiltration into and enriching memory-phenotype T cells in the tumor environment.

Conclusion

This study showed that relapse occurred mainly within six months after sequential CAR19/22 T-cell infusion. Moreover, MIP3α could act as a valuable post-infusion biomarker for identifying patients with NR/ER.

SUBMITTER: Jin J

PROVIDER: S-EPMC10264474 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

MIP3α as an early prognostic predictor for patients with B-cell malignancies receiving CD19/CD22-redirected CAR-T cell cocktail therapy.

Jin Jin J Liu Tianjiao T Cheng Jiali J Meng Jiao J Wang Na N Huang Liang L Zhou Xiaoxi X Chen Liting L Luo Hui H Zhou Jianfeng J

Cancer immunology, immunotherapy : CII 20230304 7

<h4>Purpose</h4>Identifying the temporal pattern of recurrence and prognostic biomarkers would further help improve the efficacy of chimeric antigen receptor (CAR) -T therapy.<h4>Methods</h4>We examined the prognoses of 119 patients after sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-target CAR (CAR19/22) T cells in an open-label, single-center clinical trial (ChiCTR-OPN-16008526). And we, from a 70-biomarker panel, identified candidate cytokines that might predict the t ...[more]

PMID: 36869895

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Project description: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.

Dataset Information

MIP3α as an early prognostic predictor for patients with B-cell malignancies receiving CD19/CD22-redirected CAR-T cell cocktail therapy.

Purpose

Methods

Results

Conclusion

Publications

MIP3α as an early prognostic predictor for patients with B-cell malignancies receiving CD19/CD22-redirected CAR-T cell cocktail therapy.

Similar Datasets

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