Venous thromboembolism associated with CD19-directed CAR T-cell therapy in large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Hashmi H
PROVIDER: S-EPMC7479945 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Venous thromboembolism associated with CD19-directed CAR T-cell therapy in large B-cell lymphoma.
Hashmi Hamza H Mirza Abu-Sayeef AS Darwin Alicia A Logothetis Constantine C Garcia Franco F Kommalapati Anuhya A Mhaskar Rahul S RS Bachmeier Christina C Chavez Julio C JC Shah Bijal B Pinilla-Ibarz Javier J Khimani Farhad F Lazaryan Aleksandr A Liu Hien H Davila Marco L ML Locke Frederick L FL Nishihori Taiga T Jain Michael D MD
Blood advances 20200901 17
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Project description:CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.
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Project description:IntroductionCAR T cell therapy provided transformative outcomes for patients with B-cell lymphoma; however, a large fraction of patients remains at risk for relapse, underlying the need to uncover mechanisms of resistance and predictive biomarkers. Herein, we leveraged the ZUMA-7 phase III randomized trial of relapsed/refractory large B-cell lymphoma (LBCL) patients treated with axicabtagene ciloleucel (axi-cel; CD19-targeting CAR T cells) to discover tumor gene expression signatures (GES) associated with outcome.MethodsWith tumor transcriptomics from 134 axi-cel patients, we employed multivariate penalized Cox models analyzing event-free survival (EFS), progression-free survival (PFS), and duration of response (DOR).Results and discussionWe identified two novel GES, a six-gene/transcript signature (6-GES; CD19, CD45RA, CCL22, KLRK1, SOX11, SIGLEC5) correlated with improved outcome after axi-cel (HR: 0.27, 95% CI: 0.16-0.44 for EFS), representing lymphomas with abundant target antigen (CD19) expression, adhesion molecules, and relatively low immune infiltration mostly composed of cytotoxic lymphocytes (T and NK cells) and DCs, and secondly, a 17-gene/transcript signature (17-GES; CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN,GLUD1, ESR1, ARID1A, and SLC16A1) correlated with disease progression after axi-cel (HR: 6.12, 95% CI: 3.57-10.50 for EFS), consistent with high immune inflammation and escape mechanisms, such as the upregulation of genes involved in repair of damaged DNA or chromatin remodeling, inhibition of apoptosis, and a metabolically restrictive environment. These signatures did not correlate with outcome in the standard-of-care arm of ZUMA-7 (chemotherapy, followed by transplant) or frontline therapy, supporting their predictive rather than prognostic value. The findings were technically reproduced in a subset of ZUMA-7 samples profiled by RNA-seq (axi-cel, n=124; SOC, n=125). The 6-GES was reduced, whereas the 17-GES was elevated at progression post axi-cel, consistent with the notion that these signatures represent features relevant for response and resistance to CAR T-cell therapy.ConclusionOur transcriptomic analysis identified gene expression signatures potentially predictive of outcome with CD19-directed CAR T-cell therapy, and these findings are informative for risk stratification and development of next-generation products.
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