title: An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells.
abstract: Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Molecular & Immunological Department, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Hanren
authors.initials: H
authors.lastname: Dai
authors.affiliation: Molecular & Immunological Department, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Shi
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Chunmeng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Molecular & Immunological Department, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yelei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Meixia
authors.initials: M
authors.lastname: Chen
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Kaichao
authors.initials: K
authors.lastname: Feng
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular & Immunological Department, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Chuanjie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, 100853, China. lisuxia301@163.com.
authors.forename: Suxia
authors.initials: S
authors.lastname: Li
authors.affiliation: Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.|Molecular & Immunological Department, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.|State key laboratory of kidney disease, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
mesh_terms: D000328:Adult; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D016896:Treatment Outcome
chemical_list: D018941:Antigens, CD19; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D007371:Interferon-gamma; D002097:C-Reactive Protein
keywords: B-cell acute lymphoblastic leukemia; biomarker; chimeric antigen receptor T cells; immunosurveillance; microenvironment