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      CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

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          Abstract

          Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 10 6 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)

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          Most cited references 35

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          Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

          Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.
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            Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.

            Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
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              Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

              To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                14 October 2017
                20 November 2017
                January 2018
                20 May 2018
                : 24
                : 1
                : 20-28
                Affiliations
                Pediatric Oncology Branch, (T.J.Fr., N.S., R.J.O. *, P.W., S.P-M., C.D., B.Y., H.S, T.J.Fo., J.F.S, L.Z., S.N., H.Q., S.R., P.W., S.P-M., H.O., D.W.L. **) Cancer and Inflammation Program (Y.F., D.S.D.) and Laboratory of Pathology, (M.S.S., C.Y.), Center for Cancer Research, National Cancer Institute; Department of Transfusion Medicine, NIH Clinical Center (D.S., M.S.)- all at the National Institutes of Health, Bethesda, Maryland. Lentigen Corporation, Gaithersburg, MD (B.D. *), Stanford University, Stanford, CA (R.G.M. and C.L.M.)
                Author notes
                Address reprint requests to: Terry J. Fry, MD, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20816, fryt@ 123456mail.nih.gov , ph: 301-402-0215, fax: 301-451-7052
                [*]

                Current Affiliation, Lentigen Technology Inc., A Miltenyi Biotec Company, Gaithersburg, MD, USA

                [**]

                Current Affiliation, Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA

                Article
                NIHMS913214
                10.1038/nm.4441
                5774642
                29155426

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