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      Molecular remission using low-dose immunotherapy for relapsed refractory Philadelphia chromosome-positive precursor B-cell acute lymphoblastic leukemia post-allogeneic stem cell transplant

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          Abstract

          Adults with relapsed/refractory acute lymphoblastic leukemia have a poor prognosis. While current immunotherapies are promising, they are toxic, with graft-versus-host disease a major complication of allogeneic therapy. Here, we report a patient with high-risk relapsed/refractory Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (ALL) following chemotherapy induction, matched related donor allogeneic hematopoietic stem cell transplantation (allo-HCT), donor lymphocyte infusion and two tyrosine kinase inhibitors. The patient achieved a complete molecular and cytogenetic remission with minimal adverse events or evidence of GVHD following recombinant human IL-2 (rIL-2), in combination with a tyrosine kinase inhibitor (TKI). There was a ninefold increase in natural killer (NK) cell activity and natural killer T cells (NKT) cells (CD2 +CD26 +). Personalized low dose recombinant human IL-2-mediated NK cell stimulation represents an effective, nontoxic immunotherapy administered in the outpatient setting for relapsed acute lymphoblastic leukemia and warrants further investigation.

          Lay abstract

          Recurrent or refractory adult acute lymphoblastic leukemia (ALL) is often associated with dismal outcomes after standard treatment. Despite great progress in recent immunotherapy approaches, ALL patients encounter a therapeutic challenge due to the toxicity and complications of these new treatments. We report a patient with high-risk relapsed/refractory Philadelphia chromosome-positive B-cell ALL following standard treatment and in whom a personalized immunotherapy treatment resulted in molecular remission with minimal side effects and maintenance of immune tolerance. This nontoxic treatment approach can be used to treat patients with relapsed/refractory ALL and needs to be evaluated in future research.

          Abstract

          Personalized low-dose recombinant human IL-2 (rIL-2)-mediated natural killer (NK) cell stimulation, in combination with a tyrosine kinase inhibitor (TKI), resulted in activation of effector NK cells and an increase in IFN-γ and (T cells + NK cells expressing dipeptidyl peptidase) levels. The CD4 +CD25 + regulatory T cells (Tregs) showed a progressive decrease. This personalized treatment approach which targeted Ph+ acute lymphoblastic leukemia t (9; 22) resulted in molecular remission with minimal side effects.

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          Most cited references 31

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          Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

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            Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia.

            Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. Methods In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).
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              The many roles of FAS receptor signaling in the immune system.

              FAS belongs to the subgroup of the tumor necrosis factor receptor (TNF-R) family that contains an intracellular "death domain" and triggers apoptosis. Its physiological ligand FASL is a member of the TNF cytokine family. Studies with mutant mice and cells from human patients have shown that FAS plays critical roles in the immune system, including the killing of pathogen-infected cells and the death of obsolete and potentially dangerous lymphocytes. Fas thereby functions as a guardian against autoimmunity and tumor development. FAS triggers apoptosis through FADD-mediated recruitment and activation of caspase-8. In certain cells such as hepatocytes, albeit not lymphocytes, FAS-induced apoptosis requires amplification through proteolytic activation of the proapoptotic BCL-2 family member BID. Curiously, several components of the FAS signaling machinery have been implicated in nonapoptotic processes, including cellular activation, differentiation, and proliferation. This review describes current understanding of Fas-induced apoptosis signaling and proposes experimental strategies for future advances.
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                Author and article information

                Journal
                FSOA
                Future Science:Open Access
                Future Sci. OA
                Future Science OA
                Future Science Ltd (London, UK )
                2056-5623
                12 April 2019
                : 0
                : 0
                Affiliations
                1The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL, 33437, USA
                2Stanford University Department of Medicine, Stanford, CA, 94305, USA
                3Florida State University College of Medicine, Tallahassee, FL, 32306-4300, USA
                Author notes
                *Author for correspondence: dmaharaj@ 123456bmscti.org
                10.4155/fsoa-2019-0009
                © 2019 Dipnarine Maharaj

                This work is licensed under a Creative Commons Attribution 4.0 License

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                Self URI (journal page): https://www.future-science.com/loi/fso
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