TY - JOUR. T1 - Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies. AU - Stone, Jennifer D.. AU - Kranz, David M.. PY - 2013. Y1 - 2013. N2 - Over the last several years, there has been considerable progress in the treatment of cancer using gene modified adoptive T cell therapies. Two approaches have been used, one involving the introduction of a conventional αβ T cell receptor (TCR) against a pepMHC cancer antigen, and the second involving introduction of a chimeric antigen receptor (CAR) consisting of a single-chain antibody as an Fvfragment linked to transmembrane and signaling domains. In this review, we focus on one aspect of TCR-mediated adoptive T cell therapies, the impact of the affinity of the aß TCR for the pepMHC cancer antigen on both efficacy and specificity. We discuss the advantages of higher-affinity TCRs in mediating potent activity of CD4 T cells. This is balanced with the potential disadvantage of higher-affinity TCRs in mediating ...
Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γc(null) mice under the influence of activated CLL-derived T lymphocytes. By co-transferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4(+) T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic ...
PubMedID: 26100671 | Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer Are Marked by Expression of IL7 Receptor and c-myc. | Cancer Research | 8/15/2015
Adoptive transfer assay for TRAIL and CD69 expression on liver natural killer cells in response to starvation.(A) Isolated TRAIL− natural killer (NK) cells we
यहां हम वीवो बी-1ए सेल माइग्रेशन और स्थानीयकरण में जांच करने के लिए रेट्रोवायरल अतिअभिव्यक्ति और मूत्र बी-1ए कोशिकाओं के दत्तक...
There are many ways to fight cancer using the bodys own immune system. Some methods include the administration of vaccines while others involve stimulatory factors injected near tumors. One promising method is enlisting the help of T cells. To fight cancer effectively, T cells must be able to recognize cancerous antigens and the environment in which these T cells reside must be conducive to their function, survival, and proliferation. This paper discusses a method of providing such an environment called adoptive cell transfer, as well as the elements that effect this protocol and the ways in which the environment can be manipulated to increase the effectiveness of adoptive cell transfer. Many factors contribute to the observation that the effectiveness of adoptive cell transfer increases as immunodepletion increases, namely, the depletion of regulatory T cells. Additionally, the existence of natural killer cells during adoptive cell transfer has been shown to decrease its effectiveness. Also, increased
Adoptive T cell therapy to treat cancer in combination with re-directing specificity through T cell receptor (TCR) gene transfer, represents an effective therapeutic option. However, reduced effector responses due to the immunosuppressive tumour microenvironment and insufficient long-term engraftment of transferred cells represent two potential limitations. Tumours often employ mechanisms to inhibit T cell responses including secretion of TGFβ and depleting the tumour microenvironment of amino acids. The main aim of this PhD project was to develop a strategy to enhance T cell function for tumour therapy. The mammalian target of rapamycin (mTOR) pathway regulates CD8 T cell differentiation such that high mTOR activation leads to enhanced effector whilst low mTOR activation leads to increased T cell memory formation. Two retrovirus constructs have been designed whereby one expresses the positive mTOR regulator Rheb and the other expresses the negative mTOR regulator Pras40. Rheb transduction into ...
Interleukin-7 (IL-7) is an essential cytokine required for the development and maintenance of mature T cell. Its availability is limited under normal conditions, but rises during lymphopenia, leading to increased T cell proliferation. The administration of recombinant IL-7 to normal or lymphopenic mice and humans results in increased T cell numbers and altered T cell phenotype. Hence, IL-7 administration could mediate therapeutic benefits in immunocompromised patients and is currently tested in several clinical trials. However, besides its well-studied effects on T cells little is known about the effect of IL-7 on other immune and non-immune cells and their influence on T cell homeostasis. Therefore, we evaluated the effect of IL-7 therapy on adoptively transferred T cells in IL-7 receptor (IL-7R)-competent and IL-7R-deficient lymphopenic mice. We confirm the benefits of IL-7 therapy on T cell responses but additionally show that many of these effects are dependent on IL-7R expression by host ...
Mechanistically, the authors showed again that peripheral CD4+CD25+Foxp3+ Tregs mediated tolerance, while the results of experiments in T cell receptor transgenic animals showed no evidence for clonal deletion of MBP-reactive effector T cells, despite some level of expression in the thymus of liver MBP-transgenic mice (20). Importantly, expression of MBP in the skin did not protect against EAE, which indicates that expression of this protein in the hepatic environment is critical. In an elegant set of experiments based on adoptive transfer of Tregs and effector T cells labeled with fluorescent dye, the authors showed that Tregs induced by hepatic expression can turn effector T cells into Tregs by inducing expression of the transcription factor Foxp3. Effector T cells lacking TGF-β receptor II were resistant to this infectious tolerance mechanism, indicating dependence on TGF-β signaling. These findings are reminiscent of TGF-β-dependent suppression of CD8+ T cells by CD4+CD25+Foxp3+ Tregs ...
Purpose: : Th17 cells were identified to be highly immunopathogenic in several autoimmune models, including experimental autoimmune uveitis (EAU). More recently, however, the Th17 population was reported by Cuas group to also include a subset of non-pathogenic cells (McGeachy et al., Nature Immunol, 2007). Here we examined this dichotomy by a system of adoptively transferred ocular inflammation. Methods: : Naïve CD4 TCR transgenic cells specific against hen egg lysozyme (HEL) were activated with APC and HEL ("APC/HEL"), or with plate-bound anti-CD3/CD28 antibodies ("PbAb") during polarization with IL-6 and TGF-beta. The cultured cells were tested for production of cytokines, chemokines and chemokine receptors, as well as their capacity to adoptively transfer ocular inflammation in recipient mice expressing HEL in their eyes. Results: : The two culturing procedures yielded populations with similar levels of IL-17 producing cells (~35%) and similar levels of IL-10, but with remarkably different ...
The reported duality of the MALT1 protease to promote cell intrinsic T‐cell effector functions and to suppress activated T cells in a Treg‐dependent manner raises a number of interesting questions. Even though the adoptive transfer demonstrates the potential of Tregs to counteract the autoimmunity, it remains open, if the reduced number of Tregs is indeed sufficient to cause the inflammatory phenotype. In the adoptive transfer experiment, only very few Tregs are sufficient to rescue the autoimmune phenotype raising the possibility that MALT1C472A/C472A Tregs may be less functional. In addition, the increase in IFN‐γ and IL‐4 production in MALT1 protease mutant mice may also indicate that deregulated T‐cell effector functions could also be involved in the early onset of gastritis, which is no longer counteracted due to the loss of peripheral T‐cell tolerance. In this respect, it remains an unresolved question why the autoimmune phenotype is manifested as gastritis. One can speculate ...
Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T cell immunotherapy utilizing chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism and toxicity of this combination approach. Results: In this study we first demonstrated a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8+ T cells following antigen-specific stimulation with PD-L1+ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we demonstrated a significant improvement in growth inhibition of ...
Jin, L.-P., Zhou, Y.-H., Zhu, X.-Y., Wang, M.-Y. and Li, D.-J. (2006), Adoptive Transfer of Paternal Antigen-Hyporesponsive T Cells Facilitates a Th2 Bias in Peripheral Lymphocytes and at Materno-Fetal Interface in Murine Abortion-prone Matings. American Journal of Reproductive Immunology, 56: 258-266. doi: 10.1111/j.1600-0897.2006.00425.x ...
Aims Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-mice are unable Pecam1 to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in …Read More. ...
Cytokine and Chemokine analysis. □ Adoptive T cell therapy. □ Biomarkers. FACS analysis of Tumor Infiltrating Lymphocytes (TIL) in tumor tissues ...
It remains difficult to treat the multiplicity of distinct viral infections that afflict immunocompromised patients. Adoptive transfer of virus-specific T cells (VSTs) can be safe and effective, but such cells have been complex to prepare and limited in antiviral range. We now demonstrate the feasib …
We have initiated a tumor-infiltrating lymphocyte (TIL) therapy program that has now treated over 70 metastatic melanoma patients with an ongoing 45-50% clinica...
Post-Doc position in adoptive T cell immunotherapySummary:Adoptive transfer of gene-modified T cells induces cancer regression in heavily pretreated patients. Treatment involves ex-vivo engineering of autologous lymphocytes, to express a chimeric ant ...
BACKGROUND. Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. METHODS. We analyzed 43 pediatric and young adult subjects participating in a phase I trial of defined composition CD19 CAR T cells (ClinicalTrials.gov, NCT02028455). CAR T cell phenotype, function, and expansion, as well as starting material T cell repertoire, were analyzed in relationship to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia-free survival and B cell aplasia. RESULTS. These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared with products resulting in sustained remissions. However, the initial apheresed ...
New blood cancer breakthroughs - including several involving CAR T cell therapy - were announced by City of Hopes cancer center physicians at the 2017 American Society of Hematology (ASH) annual meeting in Atlanta.
Immunotherapy is an attractive option to extend remission rates in ovarian cancer. The use of adoptive cell transfer (ACT) of ex vivo generated tumor-antigen sp...
Intent on streamlining the production of T-cell therapies, manufacturers are looking into flexible cleanrooms, modular facilities, dynamic reactor environments, and co-culture technologies.
Find out more about Car T-Cell Therapy, its pros and cons and how it will affect the market, also from a Pharmaceutical Consulting point of view.
Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells. In the 1960s, lymphocytes were discovered to be the mediators of allograft rejection in animals. Attempts to use T cells to treat transplanted murine tumors required cultivating and manipulating T cells in culture. Syngeneic lymphocytes were transferred from rodents heavily immunized against the tumor to inhibit growth of small established tumors, becoming the first example of ACT. Description of T cell growth factor interleukin-2 (IL-2) in 1976 ...
We have examined the migration of murine macrophages from the vascular compartment to normal and inflammatory tissues by the adoptive transfer of resident peritoneal macrophages (RPM phi) fluorescently labeled with the hydrophobic dye 1,1-dioctadecyl 3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI). After initial labeling of the plasma membrane of RPM phi, the dye accumulated stably in intracellular vesicles of low density (rho = 1.042-1.045 kg/l) and cells remained viable in culture for 4 weeks. Like the normal monocyte, DiI-RPM phi, but not exudate-derived or fixed cells, migrated to peritoneal exudates, following i.v. adoptive transfer, by a mechanism inhibitable by an antibody to the type 3 complement receptor. In the absence of an inflammatory stimulus there was no migration to the peritoneal cavity, and DiI-RPM phi accumulated within 4 h in the red pulp and marginal zone of the spleen. By day 6 these cells still formed a tight ring of fluorescence in the marginal zone alone, ...
This dose-escalation study investigated the tolerability and efficacy of adoptive transfer of CH 296 (RetroNectin)-induced T-cell therapy in patients with
Adoptive cell therapy can be an effective treatment for some patients with advanced cancer. This report summarizes clinical trial results from the Surgery Branch, NCI, investigating tumor infiltrating lymphocytes (TIL) and gene engineered peripheral blood T cells for the therapy of patients with melanoma and other solid tumors.. Keywords: TIL, melanoma, NY-ESO-1, interleukin-2, lymphodepletion ...
Adoptive transfer of T cells genetically improved to sole anti-TSLPR chimeric antigen receptors can cure B-ALL in xenograft kinds. Philadelphia chromosomeClike (Ph-like) leukemias react badly to regular chemotherapy RICTOR and possess Angiotensin III (human, mouse) high prices of relapse.17 Multiple groupings have got Angiotensin III (human, mouse) now demonstrated that rearrangements accounts for fifty percent of Ph-like ALL genomic alterations and are also highly associated with concomitant and stage mutations.17,18,20,21,32 We keep that the TSLPR features as an ALL oncoprotein provided its cell surface area reflection and association with poor scientific outcomes and thus might be an ideal immunotherapeutic focus on. Furthermore, TSLPR phrase in regular tissue shows up to end up being limited. We demonstrate that a TSLPR CAR may eradicate individual Web site Angiotensin III (human, mouse) completely. For structure of the lengthy CAR constructs, the CH2CH3 websites from IGHG1 ...
Patients are being offered admission to this study to test the side effects of an investigational treatment prepared from special immune cells (T cells) specific for melanoma. A T-cell is a type of lymphocyte. Lymphocytes are a type of white blood cell that protect people from viral infections; help other cells fight bacterial and fungal infections; produce antibodies; fight cancers; and coordinate the activities of other cells in the immune system. These special immune cells will be taken from a sample of the patients tumor tissue that will be surgically removed from their body and grown in the laboratory. They will then given back to the patient in their veins. These cells are called tumor infiltrating lymphocytes (TIL). We wish to study the side effects of TIL when they are given with two chemotherapy drugs to temporarily decrease the patients own immune cells and a drug called Interleukin-2 (IL-2). The two chemotherapy drugs called fludarabine and cytoxan are used to greatly reduce the ...
OT could not be induced in CCR9−/− or β7−/− mice, or when MAdCAM-1 was blocked in wild-type mice, indicating that gut-homing receptors are required for oral tolerization. Consistent with the role of all-trans retinoic acid in inducing gut homing T cells, OT could not be induced in mice depleted of vitamin A. OT was rescued in CCR9−/− mice following adoptive transfer of wild-type T cells, but not CCR9−/− or β7−/− T cells. Gut-homing T cells are therefore necessary and sufficient to induce OT. Wild-type TREG cells and IL-10 were required to restore OT to CCR9−/− mice, indicating that homing and functional differentiation of IL-10-producing TREG cells in the gut is required for OT. Conversely, transfer of CCR9−/− or β7−/− T cells to wild-type mice partially inhibited OT ...
Principal Investigator:ICHIDA Takafumi, Project Period (FY):2002 - 2003, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Gastroenterology
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Lymph node activation is an intrinsic aspect of T cell activation by infectious pathogens and vaccines. We separated the T cell priming event from lymph node activation in space and time by exploiting an experimental model consisting of TCR-transgenic OT-I CD8+ T cells and engineered APCs expressing high levels of the cognate OVA-derived peptide epitope and the costimulatory ligand CD80. Prior work had demonstrated that a 20-h in vitro encounter with these APCs empowered naive OT-I cells to vigorously proliferate in vivo upon transfer to naive syngeneic recipient (15). Furthermore, these T cells were shown to develop into long-lived memory cells, capable of clonal expansion and protective effector function in response to secondary Ag encounter (16). Importantly, progression of the 20 h primed OT-I T cells through primary expansion, contraction, and memory phases required neither in vivo exposure to Ag nor the context of an inflamed, congested lymph node. This model therefore offered a unique ...
Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease Abstract.
In recent years, the search for new cancer treatments has increasingly focused on immunotherapies that harness the bodys own defenses to fight tumors. Adoptive cell therapy (ACT) is a powerful immunotherapeutic strategy that can effectively control some cancers but that also has drawbacks.
The key component of adoptive T cell therapy is generation of functional tumor-specific T cells without immune tolerance to self-antigens. This can be accomplished by genetic modification of patient T cells using genes encoding CARs. Recently, the third-generation of CAR T cells has been developed, which includes an additional co-stimulatory domain, such as CD28 plus 4-1BB or CD28 plus OX40 together with CD3zeta along with the specific target. Results from several clinical trials in different settings including CAR design, culture techniques, lymphodepleting strategies, and target diseases, have provided valuable insights, and CAR T cells are emerging as a powerful therapy in hematologic malignancies [6]. Most clinical successes of CAR T cell therapy are recorded in the setting of B-cell malignancies, by targeting CD19 (Table 1). Several B cell antigens, such as CD20, CD22, CD23, and CD38 are under evaluation as alternative CAR T cell targets in B-cell malignancies. However, targets that are ...
Chemotherapy and IL-2 plus T-cells and the vaccine of dendritic cells received by vein (IV) about 4 hours after T-cells and again on Day 21 (+/- 7 days). Cyclophosphamide 60 mg/kg/d IV over 2 hours Days -7 and -6 (with Mesna) and Fludarabine 25 mg/m^2 IV daily Days -5 to -1 before T cell infusion. On Day 0, up to 1.5 x 10^11 T cells IV infusion over 30-60 minutes. Interleukin-2 12-16 hours after T cell infusion at standard dose of 720,000 IU/kg as intravenous bolus over 15 minute period every 8-16 hours for up to 15 doses on Days 1-5 and 22-26 ...
The data presented show that IFN-I and their signal transducer STAT-1 essentially contribute to the induction of OVA-specific CTL following immunization with OVA peptide and IC31 immune adjuvant. Surprisingly and contrasting many experimental situations with pathogen-specific CTL, OVA-specific CTL did not require IFN-I/STAT-1 as an activation/survival signal. This was shown by the use of conditional IFNAR1 deletion and by adoptive transfer of wt or STAT-1-mutant OT-1 CD8+ T cells into STAT-1-deficient animals. By contrast, adoptive transfer experiments with myeloid DC showed that IFN-I/STAT-1 are required to render these cells fully capable of stimulating CD8+ T cell activation. The IFN-I/STAT-1 effect most likely results from the ability to stimulate DC maturation and activation (35, 36, 37, 38). The reported stimulation of cross-presentation by DC may account for the stronger effect of IFN-I/STAT-1 in vivo when compared with our in vitro experiments, because immunization with the OVA/IC31 ...
Wilms tumor 1 antigen (WT1) is definitely overexpressed in acute myeloid leukemia (AML) a high-risk neoplasm warranting advancement of book immunotherapeutic strategies. (CTLs) demonstrated antigen-specific reactivity against WT1 and against WT1+ leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1?/?.IL2rγc?/? mice were viable for more than three weeks. Migration of human being T cells (huCTLs) to the immunization site was shown following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1+ tumor. Gene array analyses of SmartDC/tWT1 proven upregulation of several genes related to innate immunity. Therefore SmartDC/tWT1 can be produced in a single day time of gene transfer are highly viable culture methods or by gene transfer VER-50589 of transgenic T-cell receptors for adoptive immunotherapy (Ho are usually quiescent which may hamper ...
The Ivan Borrello Lab focuses on the development of a novel approach of adoptive T cell therapy utilizing marrow-infiltrating lymphocytes (MILs) as a more tumor-specific T cell approach. This has led to establishing the first adoptive T cell trials at Johns Hopkins and an exploration of this approach in other diseases, including nonhematologic malignancies. The lab also examines strategies for treating minimal residual disease (MRD) in myeloma with the combination of immune modulation and whole cell-based vaccines.. Research Areas: immunology, vaccines, multiple myeloma, cancer, translational research, immunotherapy, T cells ...
Further verification of a graft-vs-tumor effect came from efforts to treat patients for posttransplant leukemic recurrence by infusing viable donor lymphocytes, resulting in sustained complete remissions in most patients with chronic myelogenous leukemia and in some patients with other hematologic malignancies.11 By the mid-1980s, it was generally accepted that adoptive transfer of allogeneic T cells could be of benefit, but was of limited potency, sometimes associated with significant toxicity in the form of graft-vs-host disease and restricted in its application to the post-allogeneic transplant setting.12 To make adoptive cell therapy more effective and broadly applicable, a large number of challenges presented themselves, including the requirement to be able to clone and expand tumor-reactive T cells, to define conditions that allow for their expansion and survival after reinfusion, to identify appropriate tumor-associated targets, and to develop methods to genetically engineer T cells to ...
In the May 5, 2017, issue of Science Immunology, cancer researchers at the Medical University of South Carolina report that blood platelets blunt the immune response to cancer. Genetic inactivation of platelets improved the ability of T cells to fight melanoma in preclinical tests. Adoptive T cell therapies for cancer could be enhanced when combined with common antiplatelet drugs.
The medical centers listed below currently offer Chimeric Antigen Receptor T-cell (CAR T-cell) therapy that has been approved by the U.S. Food and Drug Administration (FDA). Each center has been carefully trained and certified to offer this new treatment.. These, and other medical centers, may also be testing other types of CAR T-cell therapy that are not yet approved by the FDA, but which may be available to you if you participate in a clinical trial. To learn more about CAR T-cell therapies currently being studied in a clinical trial click here [1].. ...
This page includes the following topics and synonyms: CAR T-Cell Therapy, CAR T Cell Therapy, Chimeric Antigen Receptor T Cell Therapy, Cytokine Release Syndrome, Tisagenlecleucel, Axicabtagene ciloleucel.
Twist Bioscience and Neogene Announce Broad Strategic Partnership for Next Generation Personalized T Cell Therapies - read this article along with other careers information, tips and advice on BioSpace
Passive transfer of DENV2 E85-VRP-immune serum or adoptive transfer of DENV2 E85-VRP-immune B cells can increase the viral RNA levels in the liver upon infectio
Eureka Therapeutics announced FDA allowance of its IND application to commence a phase I clinical trial for ET190L1-ARTEMIS T cells.
Eureka Therapeutics announced FDA allowance of its IND application to commence a phase I clinical trial for ET190L1-ARTEMIS T cells.
High-dose therapy in conjunction with autologous stem cell rescue can achieve a minimal disease state and improve disease-free survival for patients with myeloma and other hematologic malignancies. However, relapses are common due to the lack of an effective antitumor immune response to eliminate residual disease. In principle, the period following high-dose therapy should be conducive to the application of immunotherapy given the low tumor burden and the potential reduction in Treg populations. Unfortunately, following standard autologous transplants, the immune system is typically characterized by immune cell depletion and impaired immune cell function, which may persist for up to 4 to 10 years (32, 33).. In a previous randomized study, we found that a single infusion of ∼8 × 109 costimulated autologous T cells at day +12 after transplant accelerated the numerical and functional recovery of both CD4+ and CD8+ T cells and could provide help for vaccination during the early posttransplant ...
Casein kinase (CK) 1δ/ε is a key component of non-canonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using two murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resemble closely the human CLL. We can demonstrate that CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions - chemotaxis, invasion and communication with stromal cells in primary CLL cells in all major subtypes of CLL ...