scholarly journals Janus Kinase Inhibitors and Cell Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Amer Assal ◽  
Markus Y. Mapara
Keyword(s):  
Cell Therapy ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Chronic Gvhd ◽  
Critical Role ◽  
Janus Kinase ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Inflammatory Conditions ◽  
Immunological Mechanisms

Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.

scholarly journals The Role of Monitoring the Bcr-Abl Transcript Levels in the Management of Patients with Chronic Myeloid Leukemia

2013 ◽  
Vol 59 (2) ◽  
pp. 71-74
Author(s):  
Aliz-Beáta Tunyogi ◽  
I Benedek ◽  
Judit Beáta Köpeczi ◽  
Erzsébet Benedek ◽  
Enikő Kakucs ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Transcript Levels

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

scholarly journals Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3350-3359 ◽  
Author(s):  
Chuang Sun ◽  
Gianpietro Dotti ◽  
Barbara Savoldo
Keyword(s):  
Tumor Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Donor Lymphocyte Infusion ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells

Abstract Hematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.

scholarly journals Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

2018 ◽  
Vol 159 (20) ◽  
pp. 786-797 ◽  
Author(s):  
Bálint Egyed ◽  
Gábor Kovács ◽  
Nóra Kutszegi ◽  
Andrea Rzepiel ◽  
Judit Csányiné Sági ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Residual Disease ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
T Cell Therapy

Abstract: Owing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy. The number of genes with identified alterations in leukemic lymphoblasts is over thirty and their pathobiologic role is only partly clear. There are known patient groups where the use of specific drugs is based on gene expression profiling (e.g., tyrosine kinase inhibitors in Philadelphia-like B-cell ALL). The continuous assessment of minimal residual disease became a routine due to the determination of a leukemia-associated immunophenotype by flow cytometry or a sensitive molecular marker by molecular genetics at diagnosis. Epitopes of cluster differentiation antigens on blast surface (primarily CD19, CD20 and CD22 on malignant B cells) can be attacked by monoclonal antibodies. Moreover, antitumor immunity can be strengthened utilizing either cell surface markers (bispecific T cell engagers, chimeric antigen receptor T cell therapy) or tumor-specific immune cells (immune checkpoint inhibitors). This review gives an insight into current knowledge in these innovative therapeutic directions. Orv Hetil. 2018; 159(20): 786–797.

scholarly journals Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent

2021 ◽  
Vol 12 ◽  
Author(s):  
Khaled Alharshawi ◽  
Holger Fey ◽  
Alyx Vogle ◽  
Tori Klenk ◽  
Miran Kim ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Liver Injury ◽  
Immune Cell ◽  
Tissue Injury ◽  
Alcohol Exposure ◽  
The United States ◽  
Alcoholic Liver Injury ◽  
Hematopoietic Stem ◽  
Female Mice ◽  
Inflammatory Conditions

Monocytes develop in the bone marrow from the hematopoietic stem cells and represent heterogeneous phagocyte cells in the circulation. In homeostatic and inflammatory conditions, after recruitment into tissues, monocytes differentiate into macrophages and dendritic cells. Alcohol use causes about 3.3 million worldwide deaths per year, which is about 5.9% of all deaths. In the United States and Europe, alcohol use disorders represent the fifth leading cause of death. Females are more susceptible to alcoholic liver injury in both humans and mice. Strikingly, we still do not know how much of this difference in tissue injury is due to the differential effect of alcohol and its toxic metabolites on a) parenchymal or resident cells and/or b) immune response to alcohol. Therefore, we used a model of chronic alcohol exposure in mice to investigate the dynamics of monocytes, an innate immune cell type showed to be critical in alcoholic liver injury, by using immunophenotypic characterization. Our data reveal a sex-dimorphism of alcohol response of hepatic monocytes in female mice that is interferon receptor alpha dependent. This dimorphism could shed light on potential cellular mechanism(s) to explain the susceptibility of females to alcoholic immunopathogenesis and suggests an additional targetable pathway for alcoholic liver injury in females.

scholarly journals Repurposing of Biologic and Targeted Synthetic Anti-Rheumatic Drugs in COVID-19 and Hyper-Inflammation: A Comprehensive Review of Available and Emerging Evidence at the Peak of the Pandemic

2020 ◽  
Vol 11 ◽  
Author(s):  
Giulio Cavalli ◽  
Nicola Farina ◽  
Corrado Campochiaro ◽  
Giacomo De Luca ◽  
Emanuel Della-Torre ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Janus Kinase Inhibitors ◽  
Inflammatory Conditions ◽  
Published Evidence ◽  
Main Driver ◽  
Stimulating Factor ◽  
Necrosis Factor

Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.

The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1840-1850 ◽  
Author(s):  
Kam Tong Leung ◽  
Kathy Yuen Yee Chan ◽  
Pak Cheung Ng ◽  
Tze Kin Lau ◽  
Wui Man Chiu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Critical Role ◽  
Janus Kinase ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Short Term Exposure ◽  
Cd34 Cells ◽  
Cord Blood Cd34

Abstract The stromal cell–derived factor-1 (SDF-1)/chemokine C-X-C receptor 4 (CXCR4) axis plays a critical role in homing and engraftment of hematopoietic stem/progenitor cells (HSCs) during bone marrow transplantation. To investigate the transcriptional regulation provided by this axis, we performed the first differential transcriptome profiling of human cord blood CD34+ cells in response to short-term exposure to SDF-1 and identified a panel of genes with putative homing functions. We demonstrated that CD9, a member of the tetraspanin family of proteins, was expressed in CD34+CD38−/lo and CD34+CD38+ cells. CD9 levels were enhanced by SDF-1, which simultaneously down-regulated CXCR4 membrane expression. Using specific inhibitors and activators, we demonstrated that CD9 expression was modulated via CXCR4, G-protein, protein kinase C, phospholipase C, extracellular signal-regulated kinase, and Janus kinase 2 signals. Pretreatment of CD34+ cells with the anti-CD9 monoclonal antibody ALB6 significantly inhibited SDF-1–mediated transendothelial migration and calcium mobilization, whereas adhesion to fibronectin and endothelial cells was enhanced. Pretreatment of CD34+ cells with ALB6 significantly impaired their homing to bone marrow and spleen of sublethally irradiated NOD/SCID (nonobese diabetic/severe combined immune-deficient) mice. Sorted CD34+CD9− cells displayed lower bone marrow homing capacity compared with that of total CD34+ cells. CD9 expression on homed CD34+ cells was significantly up-regulated in vivo. Our results indicate that CD9 might possess specific functions in HSC homing.

Adoptive Immune Cell Therapy for the Control of Fungal Infections in Hematopoietic Stem Cell Transplant Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4358-4358
Author(s):  
Lung-Ji Chang ◽  
Yin Liang ◽  
Lily Lien ◽  
Chun- Rong Tong ◽  
Lu-Jia Dong ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Fungal Infections ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells ◽  
Transplant Patients ◽  
Fungal Antigens ◽  
Anti Fungal

Abstract Similar to virus infections, fungal infections are commonly seen in immunosuppressed transplant patients and can be life-threatening. Invasive Aspergillosis and Candidiasis are principal fungal infections among hematopoietic stem cell transplant (HSCT) patients, but Aspergillosis and other molds are the leading cause of deaths by fungal infections in immunocompromised allogeneic HSCT patients. The most effective treatment for fungal infections is preemptive and empirical anti-fungal therapies using agents such as fluconazole and amphotericin B deoxycholate (AmB-D). However, the success rate of antifungal therapy is generally low (in the 30–40% range) and associated with high toxicity. Both diagnosis and treatment for fungal infections are expensive and often ineffective. While improved formulations of AmB-D, second-generation triazoles, and echinocandins may be tolerable, newer generations of anti-fungal agents are very expensive. In animal studies, it has been shown that Aspergillosis can be successfully treated using Aspergillus-specific cytotoxic T cells (CTLs). Therefore, it is conceivable that CTLs specific to fungal antigens are effective in controlling fungal infections in allogeneic HSCT patients. To explore anti-fungal immune cell therapy, we used two different approaches to generate fungus-specific immune cells: Trichoderma and Rhizopus fungal lysates as antigen source to pulse dendritic cells (DCs), and pooled antigenic peptides to pulse DCs. The antigen-primed DCs were then co-cultured with lymphocytes to generate antigen-specific immune effector cells. The ex vivo generated anti-fungal immune cells displayed antigen-specific effector functions as illustrated by intracellular IFN-γ and CD107a staining. Interestingly, the fungus-specific immune effector cells are mostly CD4 T cells for all three species of fungal antigens. In a pilot clinical study, patients were selected when diagnosed with invasive aspergillosis based on galactomannan and beta-glucan assays, radiographs, CT scans, and/or blood cultures, or after an extended unsuccessful anti-fungal treatment with non-tolerable organ toxicity. Early indications suggest that the infusion of anti-fungal immune cells is safe, with therapeutic efficacy based on objective clinical evidence and importantly, is cost-effective. Nevertheless, more effective diagnosis and surveillance tools are needed to document the effectiveness of our anti-fungal immune cell treatment.

Allogeneic hematopoietic cell transplantation after reduced intense conditioning as adoptive cell therapy in resistant metastatic colorectal carcinoma. The European experience

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3596-3596
Author(s):  
M. Aglietta ◽  
L. Barkholt ◽  
D. Caravelli ◽  
C. Minotto ◽  
A. Capaldi ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Tumor Response ◽  
Adoptive Cell Therapy ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Allogeneic Cell Therapy

3596 Background: Allogeneic reduced intense conditioning regimens decreased morbidity and mortality related to hematopoietic stem cell transplantation (HCT), retaining a powerful graft versus tumor effect (GVT). On this basis, it became possible to explore the existence of alloreactivity in solid tumors. A GVT effect was described in metastatic colorectal cancer (CRC). Methods: We report the data on 35 patients with CRC treated with non-myeloablative allogeneic HCT in Europe. Median time from the diagnosis of metastatic disease to transplant was 16 (4–47) months; 25 patients (67%) received at least 2 lines of therapy before transplant. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (14%) and partial response (PR) in 2 (6%). Patients were treated according to different nonmyeloablative regimens. All but one patient received allogeneic peripheral hematopoietic cells [median CD 34+ cells/kg was 6.7 × 106 (2,5–55), median CD3 + cells/kg was 4.9 × 108 (0,11–33)] from HLA identical familiar donors. GVHD prophylaxis consisted of cyclosporine A (CyA) + Mycophenolate Mofetil in 24 (68%), of CyA + methotrexate in 6 (25%) and other CyA regimens in the others (18%). Results: Myelosuppression was mild and all patients engrafted with a median donor chimerism of 90% (45–99) on CD 3 cells on day +60. Transplant-related toxicities were limited. Grades II-IV acute GVHD occurred in 18 patients (51%) and chronic GVHD in 6 patients (25%). Transplant-related mortality was the cause of death in 4 patients (11%). As best tumor response we observed: 1 complete response (3%), 8 PRs (20%) and 9 SDs (29). Overall median survival from the date of transplant was 198 days (6–1020); median overall survival for the responding patients was 353 days (113–1020). Conclusions: Allogeneic HCT after RIC is safe and feasible in metastatic CRC. The results obtained compared favorably with those observed in patients with hematologic malignancies or metastatic CRC beyond second line in terms of transplant-related complications and tumor response respectively. Thus a study of allogeneic cell therapy in a less advanced patient cohort is warranted. No significant financial relationships to disclose.

scholarly journals Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies

Blood ◽  
2020 ◽  
Vol 135 (15) ◽  
pp. 1287-1298 ◽  
Author(s):  
Kirk R. Schultz ◽  
Amina Kariminia ◽  
Bernard Ng ◽  
Sayeh Abdossamadi ◽  
Madeline Lauener ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Acute Gvhd ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Chronic Gvhd ◽  
Area Under The Curve ◽  
Activated T Cells ◽  
Hematopoietic Stem ◽  
Effect Ratio

Abstract Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

scholarly journals Clonal hematopoiesis and its emerging effects on cellular therapies

Leukemia ◽  
2021 ◽  
Author(s):  
Malte von Bonin ◽  
Helena Klara Jambor ◽  
Raphael Teipel ◽  
Friedrich Stölzel ◽  
Christian Thiede ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Hematologic Malignancies ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Cell Therapies ◽  
Immune Effector ◽  
Effector Cells ◽  
Clonal Hematopoiesis ◽  
Inflammatory Conditions ◽  
Inflammatory Phenotype

AbstractThe accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.

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