• Keywords
• Eltranatamab, studie Magnetis MM-3,
• MeSH
• Data Analysis MeSH
• CD3 Complex therapeutic use   drug effects   MeSH
• Progression-Free Survival MeSH
• Clinical Trials as Topic MeSH
• Cohort Studies MeSH
• Humans MeSH
• B-Cell Maturation Antigen therapeutic use   drug effects   MeSH
• Multiple Myeloma * drug therapy   immunology   MeSH
• Recurrence * MeSH
• Check Tag
• Humans MeSH

• MeSH
• Leukemia, Myeloid, Acute * drug therapy   MeSH
• CD28 Antigens MeSH
• CD3 Complex immunology   MeSH
• ADP-ribosyl Cyclase 1 * antagonists & inhibitors   metabolism   MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Humans MeSH
• Membrane Glycoproteins MeSH
• Antibodies, Bispecific therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).

• MeSH
• CD3 Complex antagonists & inhibitors   immunology   MeSH
• Insulin-Secreting Cells drug effects   immunology   MeSH
• C-Peptide analysis   MeSH
• Diabetes Mellitus, Type 1 * diagnosis   immunology   therapy   MeSH
• Child MeSH
• Double-Blind Method MeSH
• Antibodies, Monoclonal, Humanized * adverse effects   pharmacology   therapeutic use   MeSH
• Hypoglycemic Agents administration & dosage   therapeutic use   MeSH
• Insulin administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Adolescent MeSH
• Disease Progression MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

Teklistamab je první bispecifická protilátka proti antigenu zrání B-lymfocytů (BCMA) a proti receptoru CD3 na povrchu T-lymfocytů užívaná v léčbě relabujícího/refrakterního mnohočetného myelomu (RRMM). Nová dlouhodobá data prokazují jeho dlouhodobou účinnost v dosahování hlubokých léčebných odpovědí a jejich udržení v čase, a to i v prodlouženém režimu podávání na 2 týdny

Teklistamab is the fi rst-in-class bispecifi c antibody against B-cell maturation antigen (BCMA) and CD3 receptor on the surface of T-lymphocytes used in the treatment of relapsed/ refractory multiple myeloma (RRMM). New long-term data demonstrate its sustained effi cacy in achieving deep therapeutic responses and maintaining them over time, even with an extended 2-week dosing regimen.

• Keywords
• teklistamab,
• MeSH
• CD3 Complex immunology   MeSH
• Progression-Free Survival MeSH
• Humans MeSH
• B-Cell Maturation Antigen genetics   immunology   MeSH
• Multiple Myeloma * drug therapy   MeSH
• Multicenter Studies as Topic MeSH
• Antibodies, Bispecific * therapeutic use   MeSH
• Neoplasm, Residual MeSH
• Check Tag
• Humans MeSH

V současnosti jsme svědky zapojení imunoterapie využívající anti-CD3 konstrukty (blinatumomab) nebo CAR-T buňky do léčby relabované nebo rezistentní B prekurzorové akutní lymfoblastické leukémie (BCP ALL), ale zatím ne T ALL. Naše laboratoř provádí diagnostiku minimální reziduální nemoci (MRN) pro země EU, Švýcarsko a Izrael. Součástí nového protokolu AIEOP BFM 2017 pro léčbu nově diagnostikovanou BCP ALL bude terapie blinatumomabem pro pacienty s pomalou odpovědí na léčbu. Pro efekt jsou důležité komponenty imunitního systému, zejména T lymfocytů. Rezistence na tento typ cílené léčby může být způsobená různou kombinací dysfunkce T lymfocytů (případně i dalších složek imunitního systému), exprese inhibičních molekul na blastech a změny imunofenotypu blastů, zejména ztráty antigenu CD19 nebo liniového přesmyku (obvykle do monocytární linie, jak jsme nedávno popsali). Ztráta antigenu CD19 představuje výzvu pro detekci MRN, která je důležitá pro stanovení intenzity léčby. Plánujeme detailně popsat mechanismy rezistence na imunoterapii a navrhnout cesty, jak rezistenci obejít.; Immunotherapeutic approaches using anti-CD3 antibody constructs (blinatumomab) or CAR-T cells newly became part of the treatment of the relapsed or resistant B precursor acute lymphoblastic leukemia (ALL) but so far not in T ALL. Our lab serves as a reference center for minimal residual disease (MRD) diagnostics in a blinatumomab trial for the EU, Switzerland and Israel. The next frontline protocol AIEOP BFM 2017 will use blinatumomab for patients with slow response to chemotherapy. Resistance to the blinatumomab therapy is caused by a variable combination of a T cell dysfunction, an expression of inhibitory molecules on blasts and a shift of the immunophenotype of the blasts (a loss of CD19 expression or a lineage switch to the monocytic lineage as we recently described). Loss of CD19 antigen is a challenge for the flow cytometric MRD assessment, which is important for setting the treatment intensity. We plan to describe the detailed mechanisms of immunotherapy resistance and to design ways to circumvent them.

• Keywords
• blinatumomab,
• MeSH
• CD3 Complex MeSH
• Drug Resistance, Neoplasm MeSH
• Molecular Targeted Therapy MeSH
• Immunotherapy MeSH
• Monitoring, Physiologic MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma immunology   therapy   MeSH
• Antineoplastic Agents, Immunological MeSH
• Neoplasm, Residual diagnosis   MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• hematologie a transfuzní lékařství
• alergologie a imunologie
• onkologie
• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

Bispecifické protilátky (bsAb) se od svých předchůdců, monoklonálních protilátek, liší schopností vázat dva různé antigeny: antigen na povrchu nádorové buňky a antigen na povrchu efektorové buňky. V klinickém testování se zatím nejdál dostaly protilátky, které jsou cílené na antigen CD3 efektorových T-lymfocytů. Aktivace endogenních T-lymfocytů vede k nastartování cytotoxické reakce a usmrcení nádorové buňky. Blinatumomab, konstrukt bsAb, je aktuálně schválený v léčbě akutní B-lymfoblastické leukemie. Většina protilátek určených k léčbě non-hodgkinských lymfomů (NHL) teprve vstupuje do II. fáze klinického hodnocení. Blinatumomab se zkouší jako konsolidační terapie u předléčených pacientů po alogenní transplantaci kostní dřeně nebo v 1. linii po klasické chemoimunoterapii. Slibné výsledky zejména v léčbě indolentních NHL dosahují bsAb, které stavebně řadíme mezi imunoglobuliny třídy G (IgG). Limitujícím faktorem všech bsAb v této chvíli zůstává jejich specifická toxicita (syndrom z uvolněných cytokinů a neurologická toxicita). Zásadní pro zvládnutí nežádoucích účinků se zdá být použití kortiko steroidů a časná aplikace monoklonálních protilátek proti interleukinu-6 (IL-6) nebo jeho receptoru.

• MeSH
• Antigens, CD20 drug effects   MeSH
• CD3 Complex antagonists & inhibitors   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Lymphoma, Non-Hodgkin * drug therapy   immunology   MeSH
• Neurotoxicity Syndromes etiology   physiopathology   prevention & control   MeSH
• Antibodies, Bispecific * pharmacology   adverse effects   therapeutic use   MeSH
• Cytokine Release Syndrome chemically induced   physiopathology   prevention & control   MeSH
• Check Tag
• Humans MeSH

PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

• MeSH
• Chemotherapy, Adjuvant MeSH
• CD3 Complex metabolism   MeSH
• Time Factors MeSH
• CD8-Positive T-Lymphocytes * metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local immunology   MeSH
• Microsatellite Instability MeSH
• Survival Rate MeSH
• Mutation MeSH
• Colonic Neoplasms drug therapy   genetics   immunology   pathology   MeSH
• Lymphocyte Count MeSH
• Predictive Value of Tests MeSH
• Disease-Free Survival MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Lymphocytes, Tumor-Infiltrating MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

We retrospectively assessed the utility of a flow cytometry-based test quantifying the percentage of CD3+ T cells with the CD4-/CD8- phenotype for predicting tularemia diagnoses in 64 probable and confirmed tularemia patients treated during 2003-2015 and 342 controls with tularemia-like illnesses treated during 2012-2015 in the Czech Republic. The median percentage of CD3+/CD4-/CD8- T cells in peripheral blood was higher in tularemia patients (19%, 95% CI 17%-22%) than in controls (3%, 95% CI 2%-3%). When we used 8% as the cutoff, this test's sensitivity was 0.953 and specificity 0.895 for distinguishing cases from controls. The CD3+/CD4-/CD8- T cells increased a median of 7 days before tularemia serologic test results became positive. This test supports early presumptive diagnosis of tularemia for clinically suspected cases 7-14 days before diagnosis can be confirmed by serologic testing in regions with low prevalences of tularemia-like illnesses.

• MeSH
• CD3 Complex MeSH
• Early Diagnosis MeSH
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• CD4-CD8 Ratio MeSH
• Flow Cytometry methods   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Serologic Tests methods   MeSH
• Case-Control Studies MeSH
• T-Lymphocytes MeSH
• Tularemia blood   diagnosis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

• MeSH
• CD3 Complex metabolism   MeSH
• Stroke * complications   diagnostic imaging   etiology   MeSH
• Diffusion Magnetic Resonance Imaging MeSH
• Humans MeSH
• Giant Cell Arteritis * complications   diagnostic imaging   etiology   MeSH
• Aged MeSH
• Constriction, Pathologic complications   MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Our work examined the production of intracellular interferon (INF)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 by in vitro stimulated CD3+ cells from 38 chronic myeloid leukemia (CML) patients. At the time of diagnosis the percentages of cells producing INF-γ, TNF-α, and IL-2 were strongly suppressed compared to those in healthy control subjects. Hematological remission achieved through treatment with tyrosine-kinase inhibitors was associated with a highly significant increase in the ratio of cells producing all 4 cytokines. The percentages of CD3+ cells producing cytokines were dependent on age, more so in CML patients than in healthy controls, and they negatively correlated with the number of leukocytes. Patients with an optimal therapy outcome possessed higher percentages of cytokine-producing CD3+ cells at diagnosis than those with nonoptimal outcomes. This difference was statistically significant in the case of INF-γ-producing cells, and it was on the brink of significance in the case of IL-2-producing cells.

• MeSH
• CD3 Complex metabolism   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy   immunology   MeSH
• Cytokines biosynthesis   MeSH
• Adult MeSH
• Interferon-gamma biosynthesis   MeSH
• Interleukin-2 biosynthesis   MeSH
• Interleukin-4 biosynthesis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• T-Lymphocytes immunology   MeSH
• In Vitro Techniques MeSH
• Tumor Necrosis Factor-alpha biosynthesis   MeSH
• Tumor Burden immunology   MeSH
• Age Factors MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH