Neutralization of IFNγ improves the safety profile of CAR T-cells while maintaining unaffected efficacy against B-cell malignancies

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Март 1, 2023

Abstract Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary approach to induce long-lasting remission in patients with B-cell malignancies not responding conventional therapies. Nevertheless, possible severe side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, whose management is still challenging, as well lack of pathophysiological experimental models investigate novel interventions, limit the widespread use this therapy. In light these considerations, we developed comprehensive humanized mouse model role IFNγ neutralization, provided by clinically approved monoclonal antibody, emapalumab, controlling toxicity related CAR T cells. We demonstrated that emapalumab reduces pro-inflammatory environment animal model, allowing CRS control preventing brain damage, characterized multifocal hemorrhages. Furthermore, proved inhibition does affect ability CAR.CD19 cells eradicate CD19+ lymphoma cells, both vitro vivo .

Язык: Английский

---

Diffusion Idiopathic Skeletal Hyperostosis (DISH), a Link between Gut Microbiota and Spinal Degenerative Diseases<strong> </strong>

Опубликована: Окт. 20, 2023

The interplay between Diffuse Idiopathic Skeletal Hyperostosis (DISH) and the gut microbiota represents a compelling area of research, offering insights into relationship spinal degenerative diseases gut's microbial inhabitants. This comprehensive review seeks to unravel complex connection, shedding light on its implications for human health potential therapeutic avenues. A crucial section dives world (GM), exploring impact health, featuring defining characteristics, highlighting role in metabolism, immunomodulation, host interaction, how composition changes over time. subsequent portion delves microbiome pathological bone development, including link Intervertebral Disc Degeneration (IDD) inflammation, emphasizing inflammation GM dysbiosis play pivotal roles. Further dissecting interconnections, various axes influence, gut-spine axis, gut-bone gut-joint gut-disc axis (specific DISH), gut-ligament gut-muscle are discussed. Of particular interest is DISH-derived pain, addressing critical aspect condition's manifestation. discusses modulation as treatment DISH, providing hope advancements. Additionally, it highlights positive lifestyle interventions, such dietary modifications, sleep optimization, exercise regimens, mitigating potentially improving DISH outcomes. Lastly, intriguing prospect fecal transplant management examined, opening new avenues research interventions. In conclusion, this underscores intricate microbiota, fresh perspective diseases. It emphasizes innovative treatments, presents an exciting future exploration.

Язык: Английский

---

Investigation of Interferon Gamma Activity Using Bioinformatics Methods.

DOAJ (DOAJ: Directory of Open Access Journals), Год журнала: 2021, Номер 76(5), С. 1245 - 1253

Опубликована: Ноя. 1, 2021

Breast cancer grows from the breast tissue and is a severe health problem worldwide. Genetics believed to be primary cause of all cases via gene mutation. Bioinformatics methodology has been used determine sequences structures bioactive substances. This study aimed analyze function structure Interferon Gamma (IFNγ) in healthy controls patients with using bioinformatics methods. Blood samples were collected 75 25 subjects as control samples. The results showed transition mutation (30%) transversion (70%) cancer. Moreover, missense mutations (84%) silent (16%) detected by BLAST. In addition, amino acid IFNγ protein consisting alpha-helical, β-sheet, coil secondary was determined this BioEdit. physicochemical properties reflect function, stability, molecular weight, isoelectric point, instability index ProtParam. affected percentage alpha-helix, β-turns, compared groups reference NCBI PSIpred program. Additionally, PHYRE2 server RasMol program tertiary patients. Furthermore, STRING revealed poly interacted other proteins perform its functions normally. From recorded data current study, it concluded that considered marker for

Язык: Английский

---

NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation

Stem Cell Reports, Год журнала: 2022, Номер 17(3), С. 443 - 445

Опубликована: Март 1, 2022

We read with great interest the manuscript by Lobo de Figueiredo-Pontes and colleagues (Lobo et al., 2021Lobo L. Adamcova M.K. Grusanovic S. Kuzmina M. Aparecida Lopes I. Fernandes Oliveira Costa A. Zhang H. Strnad Lee Moudra al.Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma.Stem Cell Reports. 2021; 16: 1999-2013Abstract Full Text PDF PubMed Scopus (2) Google Scholar) on potential clinical usefulness NK IFNγ to favor engraftment in allogeneic (HSCT). Indeed, role regulating hematopoiesis during acute or chronic inflammation through modulation transcription factor expression perturbation cytokine signaling is well characterized (Merli 2021Merli P. Quintarelli C. Strocchio Locatelli F. The interferon-gamma its pathway pediatric hematological disorders.Pediatr. Blood Cancer. 68: e28900Crossref (5) Scholar). Thus, we agree that marrow microenvironment may be a useful strategy HSCT setting. recently confirmed setting has an important pathogenic immune-mediated graft failure (GF) 2019Merli Caruana De Vito R. Weber G. Bufalo F.D. Buatois V. Montanari Cefalo M.G. Pitisci al.Role interferon-γ after transplantation.Haematologica. 2019; 104: 2314-2323Crossref (32) Scholar), also showing this emapalumab (a grade, IFNγ-inhibiting monoclonal antibody developed for treatment resistant/relapsed primary HLH; 2020Locatelli Jordan M.B. Allen Cesaro Rizzari Rao Degar B. Garrington T.P. Sevilla J. Putti M.C. al.Emapalumab Children Primary Hemophagocytic Lymphohistiocytosis.N. Engl. Med. 2020; 382: 1811-1822Crossref (155) might improve selected patients (e.g., those affected HLH). However, do not concur authors, who propose "NK depletion actually HSC donor non-neoplastic diseases patients." In fact, addition anti-tumor activity, cells exert control over pathogens (Zuo Zhao, 2021Zuo W. Zhao X. Natural play virus infection control: Antiviral mechanism, subset expansion application.Clin. Immunol. 227: 108727Crossref (13) These properties have been exploited clinic, especially haploidentical field, optimizing ex vivo T obtain "designed" grafts retain immune effector cells, γδ memory cells), while avoiding potentially harmful alloreactive populations αβ naive cells). improvements increased use donors because improved results (superimposable replete/HLA-matched transplants according some reports; 2017Locatelli Merli Pagliara D. Li Pira Falco Pende Rondelli Lucarelli Brescia L.P. Masetti al.Outcome children leukemia given HLA-haploidentical T-cell B-cell depletion.Blood. 2017; 130: 677-685Crossref (195) Moreover, are able kill both lymphocytes antigen-presenting recipients, thus contributing prevention rejection graft-versus-host disease (GvHD) (Ruggeri 2002Ruggeri Capanni Urbani E. Perruccio K. Shlomchik W.D. Tosti Posati Rogaia Frassoni Aversa al.Effectiveness alloreactivity mismatched transplants.Science. 2002; 295: 2097-2100Crossref (2598) To further corroborate our statement, retrospectively analyzed 2 cohorts transplanted depletion: TCRαβ/CD19-depletion (thus containing, among others, CD34+, NK, TCRγδ cells) was used Rome (Locatelli Scholar; 2022Merli Galaverna Andreani Leone Amodio Pinto R.M. Bertaina al.TCRαβ/CD19 depleted from relative treat different nonmalignant disorders.Blood Adv. 2022; 6: 281-292Crossref (6) CD3/CD19-depletion containing CD34+ Tübingen (Lang 2014Lang Teltschik H.M. Feuchtinger T. Müller Pfeiffer Schumm Ebinger Schwarze C.P. Gruhn Schrauder al.Transplantation CD3/CD19 allografts family paediatric leukaemia.Br. Haematol. 2014; 165: 688-698Crossref (78) experiences resemble models colleagues. One-hundred fifty were TCRαβ/CD19-depletion, 80 malignant [56 cases lymphoblastic (ALL) 24 myelogenous (AML)] 70 non-malignant condition (primary immunodeficiencies, red blood disorders, inherited bone syndromes, aplastic anemia, metabolic diseases) at median age 7.2 years (range 0.3–20.9). Median content 17.3 × 106/kg 6.0–48.8) 40.0 3.8–156.1), respectively. Cumulative incidence GF 100 days 14.7% (95% CI 9.9–21.5) whole cohort 30.4% 21.0–42.7) disorders. It did differ content, received less than 40 cumulative 14.2% 7.9–24.9), compared 15.4% 8.8–26.2) receiving more (p = 0.87). Also group patients, [lower 36.6% 22.2–56.4) versus 29.0% 16.2–48.4) higher p 0.49]. time neutrophil platelet recovery 13 9–33) 11 7–51). number infused influence engraftment, patient subset. detail, group, 14 16 11–25) below above 0.54), Concerning recovery, 8–51) 10 7–34) 0.8), 157 HSCTs performed; those, 132 performed solid tumors 25 diseases. Patient ranged 0.3 26.5 (median 8.1). 14.87 1.8 – 55.98). Data available 126 transplantations 73.9 9.1–379.0) 77.77 9.63–275.56) cohort. Neutrophil occurred 7–40) 2–188), respectively, group. Number value affect recovery. Neutrophils recovered 8–29) platelets 12 6–27) 9–40, 0.65) 9 4–188, 0.45) cells. Likewise, independent (neutrophils, days, range 9–11 platelets, 7–17) 9–11, 0.57 6–28, 0.61) At 15.5% 6.2–28.7) 28% 6.9–54.6) patients. There no significant difference (NK low 12.7%, 95% 1.6–35.7; high, 14.7%, 2.5–37.0, 0.9) low, 20%, 0.2–66.9; 30.8%, 4.3–64.4, 0.68). discrepancies between experiments conducted due variables included model tested presence myeloid-derived suppressor Additionally, reflect where mega-doses infused, making negative effect clinically significant. it mentioned interpretation confounded TCRαβ ± can produce IFNγ. Removal increase risk infections immediately transplant (i.e., period type complication). setting, depriving mature impair graft-versus-leukemia effect; indeed, would require 6 8 weeks KIR+ surprisingly, outcome using recent methods demonstrated superior post-HSCT outcomes as positive selection (Lum 2021Lum S.H. Sobh Carruthers Nademi Z. Watson McNaughton Selvarajah Deyà-Martínez Abinun Flood survival function immunodeficiency.Bone Marrow Transplant. 56: 1200-1204Crossref (4) summary, despite interesting showed coauthors, think that, data, proposal cell-depletion questionable; nonetheless, targeted specific cytokines detrimental such IFNγ, preferable high rejection. This work partly supported grant Associazione Italiana Linfoistiocitosi Emofagocitica (P.M.). Improved interferon-gammaLobo al.Stem ReportsJuly 8, 2021In BriefThe (NK) completely understood. al. demonstrate (HSC) via cytokine-mediated mechanisms, show NKs preparations neutralizing activity improves outcome. Full-Text Open AccessResponse does seem transplantationLobo ReportsMarch 08, 2022In BriefIn publication Stem Reports 2021), assessed fate concluded possibly secretion (and particular IFNγ), negatively frequency function. their letter issue Reports, report carrying out attempt translate observations clinics 2022). Access

Язык: Английский

---

Reactive Hemophagocytic Lymphohistiocytosis Secondary to Ovarian Adenocarcinoma: A Rare Case Report

Journal of Inflammation Research, Год журнала: 2022, Номер Volume 15, С. 5121 - 5128

Опубликована: Сен. 1, 2022

Hemophagocytic lymphohistiocytosis (HLH), a syndrome of immune hyperactivation and abnormal regulation that causes life-threatening inflammation, is mainly characterized by fever, hepatosplenomegaly, cytopenia, other symptoms. Reactive HLH (rHLH) typically secondary to deregulation caused underlying rheumatologic, infectious, or malignant conditions. Malignancy-associated (M-HLH) continues be critical health problem worldwide. Most malignancies associated with are hematologic tumors, M-HLH in non-hematologic tumors very rarely occurs.A 34-year-old Chinese woman had history persistent acute dizziness, bicytopenia. She was found have developed bilateral ovarian cancer. Additional tests showed splenomegaly, hemophagocytes the bone marrow, low natural killer activity, hyperferritinemia, which met diagnostic criteria put forth Histiocyte Society HLH-2004. The patient treated correcting anemia, increased platelets, glucocorticoid therapy but no response. progressively deteriorated died 55 days later.Hemophagocytic related solid tumor extremely rare. To best authors' knowledge, present case first report rHLH adenocarcinoma. It significant for better understanding disease mechanisms should attract attention hematologists clinicians as condition progresses cost treating it increases.

Язык: Английский

---