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Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

ABSTRACT: Few studies have described chimeric antigen receptor-modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

SUBMITTER: Chen LY

PROVIDER: S-EPMC7399187 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

Chen Li-Yun LY Kang Li-Qing LQ Zhou Hai-Xia HX Gao Han-Qing HQ Zhu Xue-Fei XF Xu Nan N Yu Lei L Wu De-Pei DP Xue Sheng-Li SL Sun Ai-Ning AN

Translational oncology 20200731 11

Few studies have described chimeric antigen receptor-modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrol ...[more]

PMID: 32745961

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Project description:BackgroundCentral nervous system (CNS) mucormycosis is insidious and difficult to diagnose. It progresses rapidly and causes high mortality. Rare cases have been reported during ibrutinib use, which have poor prognosis. Through this case, we share the experience of successful diagnosis and treatment. We also emphasize the importance of focusing on high-risk groups, early diagnosis and prompt management.Case descriptionIn this case, a 52-year-old patient was diagnosed with chronic lymphocytic leukemia (CLL) for more than 5 years. He was in remission after rituximab plus fludarabine and cyclophosphamide (RFC) regimen, and relapsed in the fourth year. During the ibrutinib monotherapy, the patient presented with sudden headache. Cranial imaging examination revealed a definite right occipitoparietal lobe mass with extensive edema. A rapid diagnosis of mucormycosis infection was made using metagenomic next-generation sequencing (mNGS). The patient at that time didn't have neutropenia, but he had hypogammaglobulinemia. The infection was treated with amphotericin B cholesteryl sulfate complex, posaconazole, and interventional surgery, and the treatment was successful. At the same time, we considered the control of disease progression in this relapsed patient with, as well as to the drug interaction with posaconazole. We chose the next generation Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib as the treatment, whose safety has been identified. As of the submission date, the patient has been followed up for nearly 1 year, and his disease is stable.ConclusionsWhen new clinical problems arise in recurrent CLL patients, it is important to identify multiple factors, especially the insidious fungal infections. In particular, the immunocompromised patients should be concerned. CNS mucormycosis is extremely deadly, the early diagnosis will improve the prognosis. In clinical practice, the gold standard diagnosis of mucormycosis is difficult to obtain through pathology. In this case, mNGS was applied to quickly diagnose mucormycosis, enabling earlier treatment and ameliorating the prognosis. Thus, it will help us to early detect this group of people who may be potentially infected. Current guidelines do not recommend the prophylactic use of antifungal agents in treated CLL patients. However, in patients with prior severe infection or hypogammaglobulinemia, intravenous immunoglobulin is recommended to reduce the associated infection rate.

Dataset Information

Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

Publications

Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia.

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