Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
Abstract. Foxp3 is a nuclear transcription factor that is both a tumor suppressor factor and regulator of T-regulatory cell (Treg) function, and is a potential therapeutic target in both autoimmunity and cancer. In order to distinguish molecular pathways responsible for these separate Foxp3 functions, deletion mutants of Foxp3 proteins were transduced and analyzed for cytotoxic activity in human cancer cell lines Skov3, MDA-MB-231, MCF-7 and Jurkat. Human Foxp3 cDNA mutants were amplified and ligated to produce plasmids for direct cell transfection. Constructs were produced and confirmed by DNA sequencing. Lipofectamine 2000 was used for plasmid transfection. Foxp3 cells were then examined. The results of our experiments reveal retention of tumor suppressor function in the absence of NFAT binding and transcriptional activation required for Treg function. Our results have significant implications for the design of autoimmune and cancer therapies that target Foxp3 and Treg cells. IntroductionFoxp3 is an X-linked nuclear transcription factor essential to the development and program of T-regulatory cells (Tregs) that protect against the development of autoimmunity (1,2). The tumor suppressor activity of Foxp3 was identified when it was serendipitously observed that female mice heterozygous for the mutation in the X-linked scurfin gene (homolog to human Foxp3) have high rates of mammary cancer as well as other types of cancers (3). Additional studies confirmed a relationship between mutations of Foxp3 and breast cancer in humans, and identified Foxp3-mediated repression of HER-2/ ErbB2 and SKP2 oncogenes as a potential mechanism for the tumor suppressor effect (3,4). Although Tregs suppress the development of autoimmunity, they are thought to be permissive for the development of cancer (5,6). Thus, Foxp3 has dual but opposing roles with respect to autoimmunity and cancer. Tregs and Foxp3 have become significant therapeutic targets in autoimmunity and cancer. Defining Foxp3 pathways responsible for its divergent functions should be helpful in the design of therapies that specifically target Foxp3. Development of the Treg function requires transcriptional activation and binding of Foxp3 to the transcription factor, NFAT (7). In this study, Foxp3 was found to exhibit tumor suppressor activity independent of transcriptional activation and binding NFAT. Materials and methodsCell lines. Human cancer cell lines Skov3 (ovarian), MDA-MB-231 (breast), MCF-7 (breast) and Jurkat (T cells) were obtained from the American Type Tissue Collection (Rockville, MD, USA).Antibodies. The antibodies used included mouse monoclonal IgG1 to human Foxp3 (sc-56680) and mouse anti-goat IgG-HRP (sc-2354) (Santa Cruz Biotechnology, Santa Cruz, CA, USA).Plasmid constructs. Human Foxp3 cDNA was amplified by PCR from plasmid 13250 (Addgene, Cambridge, MA, USA) and ligated into pIRES2-ZsGreen1 (Clontech, Mountain View, CA, USA) to produce the plasmid pIRES2-ZsGreen1-Foxp3, pIRES2-ZsGreen1-Foxp3C (C-terminal deletion of residues 328-431) and pIRES2-Zs...
Background Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a promising therapeutic option for relapsed/refractory non-Hodgkin lymphoma. However, access to CAR T cell therapy remains limited as CAR T cells are routinely administered in the hospital setting. Hence, there's a growing interest in standardizing outpatient administration of CAR T cells to increase patient access and minimize costs. Here, we describe our institution's experience with outpatient administration of CAR T cells. Methods In this retrospective study, we reviewed who received CAR T cell therapy in the outpatient setting at Karmanos Cancer Center between June 2019 and June 2021.Charts were reviewed for age, disease pathology, prior lines of therapy, need for hospitalization within 30 days, development of CRS and/or neurotoxicity, need for ICU admission, need for steroids and/or tocilizumab, length of admission, and disease state at last follow up. All patients received fludarabine and cyclophosphamide as lymphodepletion (LD) therapy day -5 to -3. CAR T cells were infused on day 0. Patients subsequently followed up in clinic daily for 2 weeks and were started on allopurinol, ciprofloxacin, fluconazole, acyclovir and levetiracetam. First response was assessed by FDG PET scan 4 weeks after CAR T cell . Results A total of 12 patients received CAR T cells during the study period. All patients had a diagnosis of DLBCL and received Tisagenlecleucel. Median age at CAR T cell therapy was 69.5 years (40-78 years). Median number of prior lines of therapy was (2-3) while 2 patients had received prior stem cell transplantation. Table 1 describes patient characteristics and lines of therapy. Two patients received bridging therapy prior to LD. Overall response rate was 58.3% (complete response-3, partial response-4). Median duration of follow up was 6.7 (0.6-13.8 months). Four patients required subsequent therapy after CAR T cell for disease progression while 9 patients were alive at the time of data cut off. Figure 1 summarizes disease response and follow . Table 2 summarizes complications during follow up. Nine (75%) patients developed anemia (grade 3-4 n=4, 33.3%), 8 (66.7%) developed thrombocytopenia (grade 3-4 n= 3, 37.5%), and 8 (66.7%) developed neutropenia (grade 3-4 n=8, 66.7%). Median time to platelet recovery to >,000 and neutrophil recovery to >500 was 66 days (44-81 days) and 11.5 days (6-65 days), respectively. Three (25%) patients required platelet and red blood cell transfusion support. Six (50%) patients developed cytokine release syndrome (CRS) with median grade 2 (range 1-3, grade 3-4 n=1). Five (5/6) patients required hospitalization, five (5/6) required tocilizumab, and one (1/6) required steroids. One (8.3%) patient developed neurotoxicity of grade 1 severity improved without systemic therapy. Six patients required hospitalization within 30 days of CAR T cell infusion. Median day of admission from CAR T cell infusion was 4 days (range 2-12 days (range 2-12 days, admission within 3 days n=2, admission under observation n=1). Patient characteristics at admission are summarized in table 3. Of these, 5 patients were diagnosed with CRS,1 patient with colitis and none with blood stream infection. Two patients required ICU admission. Median length of hospital admission was 5.5 days (2-9 days). All patients were alive at discharge while 1 patient required subsequent admission within 30 . Conclusion Outpatient administration of Tisagenlecleucel is feasible with low risk of hospital admission within 3 days of infusion. Adoption of outpatient CAR T cell therapy may increase patient access for treatment of DLBCL and diseases such as multiple myeloma while reducing administration costs for this novel therapy. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.
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