Vaccination with Dendritic Cells Loaded with Autologous Leukemic Cells in Combination with Low-Dose Lenalidomide Induced Immune Responses in Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4685-4685
Author(s):  
Lotta Hansson ◽  
Marzia Palma ◽  
Lars Adamson ◽  
Harriet Ryblom ◽  
Barbro Näsman-Glaser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Lymphocyte Count ◽  
Low Dose ◽  
Autologous Tumor ◽  
Proliferation Assay ◽  
Tumor Vaccination ◽  
Gm Csf

Abstract Background and aim. We have previously demonstrated that immunization with ex-vivo generated autologous dendritic cells loaded with apoptotic tumor cells (Apo-DC) induces specific immune responses in CLL patients especially when combined with GM-CSF and low-dose cyclophosphamide (CTX) (Palma et al, CII 2012). In this study we evaluate the safety and immunogenicity of Apo-DC vaccination in combination with low-dose lenalidomide alone, or in combination with GM-CSF and low-dose CTX in CLL patients. In patients with multiple myeloma, lenalidomide boosted the response to a pneumococcal vaccine (Noonan et al, Clin Ca Res 2012); lenalidomide may thus be a useful adjuvant also with tumor vaccines but has not yet been explored in man. In patients with CLL, lenalidomide has immunomodulatory properties including NK and T cell stimulation, as well as enhanced immunoglobulin production. Lenalidomide also induced a clinical "flare" reaction, upregulated adhesion molecules and facilitated synapse formation between CLL and T cells (Ramsay et al, J Clin Invest 2008; Shanafelt et al, Blood 2013)i.e. effects of advantage in tumor vaccination. We here report on the first results using lenalidomide as an adjuvant in tumor vaccination in man. Methods. Ten patients with slowly progressive but asymptomatic CLL were included. The first five patients were immunized intradermally five times during fourteen weeks with a mean of 16x106 Apo-DCs. Low-dose lenalidomide was given daily as an adjuvant at a dose of 2.5 mg from start of vaccination, for four weeks, and then escalated to 5 mg daily until week 24 (cohort I). The next five patients were treated in the same way but also received 300 mg/m2 CTX at day -3 and GM-CSF sc day 1-4 (cohort II). Clinical and immune effects of the vaccination were evaluated at regular time intervals for 1 year. A vaccine-induced immune response was defined as a ≥ 2-fold increase compared to pre-immunization values in either 3H-thymidine incorporation (proliferation) assay or ELISpot assay as described (Palma et al, CII 2012). Changes in the numbers of lymphocyte subpopulations including regulatory T cells (Tregs) as well as in T-cells expressing activation (CD69, CD137) and regulatory markers (CD103) were also evaluated. Results. To date, the 8 first included patients have completed treatment as planned and passed study week 52. The remaining 2 patients are between study week 24 and 52. No adverse events (AE) > grade 2 have been observed with the exception of one patient who had grade 3 hemolysis (AIHA) at study week 6 (cohort I) and one patient who had grade 4 thrombocytopenia at study week 5 (cohort II). AIHA was treated with steroids and lenalidomide was temporarily withdrawn for 4 weeks. The grade 4 thrombocytopenia required a 10 weeks withdraw of lenalidomide, upon which the thrombocytopenia resolved to grade 1. A decrease in the lymphocyte count fulfilling the criteria for partial response (clinical PR) was seen in 5 patients during lenalidomide treatment (one in cohort I and four in cohort II), but the lymphocyte count increased again to pre-vaccination levels at withdrawal of lenalidomide at week 24. Vaccine-induced immune responses were noted in 4/5 patients in cohort I and in 2/5 patients in cohort II. An inverse correlation between Tregs numbers and proliferation assay values was observed (r = -0.46, p=0.0015) i.e. high proliferative response was associated with low Tregs count. Changes in T cells expressing activation markers (CD69 and CD137) as well as the regulatory marker CD103 were also observed. Summary/conclusions. This is the first study on lenalidomide as an immunomodulatory agent in tumor vaccination. The results indicate that immunization of CLL patients with autologous tumor-loaded DCs combined with low-dose lenalidomide induced specific immune responses in CLL patients. Lenalidomide as a low-dose immune adjuvance had acceptable tolerability. This therapeutic approach should be explored further to define an optimal combination of vaccination schedule, lenalidomide dose and combination with other immunomodulatory agents interfering with the tumor-microenvironment with the aim to induce a potent immune response with a clinical impact. Disclosures Off Label Use: Lenalidomide is used as an adjuvant in this CLL vaccination study. Österborg:Celgene: DMC memeber of Celgene-initiated phase 3 trials Other.

scholarly journals Immune Response of Indian Preterm Infants to Pentavalent Vaccine Varies With Component Antigens and Gestational Age

2021 ◽  
Vol 12 ◽  
Author(s):  
Archana Kulkarni-Munje ◽  
Nandini Malshe ◽  
Sonali Palkar ◽  
Aniket Amlekar ◽  
Sanjay Lalwani ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Hepatitis B ◽  
Immune Responses ◽  
Antibody Response ◽  
Preterm Infants ◽  
Gestational Age ◽  
Childhood Vaccination ◽  
Pentavalent Vaccine

Childhood vaccination plays critical role in protecting infants from several dreaded diseases. Of the global 15 million preterm (PT) infants with compromised immune system born annually, India contributes to >3.5 million. Generation of adequate vaccine-induced immune response needs to be ensured of their protection. Immune response of Indian PT (n = 113) and full-term (FT, n = 80) infants to pentavalent vaccine administered as per the national recommendation was studied. Antibody titers against component antigens of pentavalent vaccine, immune cells profiling (T and B cells, monocytes and dendritic cells) and plasma cytokines were determined pre- and post-vaccination. Additionally, cell-mediated recall immune responses to pentavalent antigens were evaluated after short time antigenic exposure to infant PBMCs. Irrespective of gestational age (GA), all the infants developed adequate antibody response against tetanus, diphtheria, and protective but lower antibody levels for Haemophilus influenzae type-b and hepatitis B in preterm infants. Lower (~74%) protective antibody response to pertussis was independent of gestational age. PT-infants exhibited lower frequencies of CD4 T cells/dendritic cells/monocytes, increased plasma IL-10 levels and lower proliferation of central and effector memory T cells than in term-infants. Proliferative central memory response of FT-infants without anti-pertussis antibodies suggests protection from subsequent infection. Responder/non-responder PT-infants lacked immunological memory and could be infected with Bordetella. For hepatitis B, the recall response was gestational age-dependent and antibody status-independent. Humoral/cellular immune responses of PT-infants were dependent on the type of the immunogen. Preterm infants born before 32 weeks of gestation may need an extra dose of pentavalent vaccine for long lived robust immune response.

Development of CD40L-modified tumor small extracellular vesicles for effective induction of antitumor immune response

Nanomedicine ◽  
2020 ◽  
Vol 15 (17) ◽  
pp. 1641-1652
Author(s):  
Wen Liu ◽  
Yuki Takahashi ◽  
Masaki Morishita ◽  
Makiya Nishikawa ◽  
Yoshinobu Takakura
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Extracellular Vesicles ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Cd40 Ligand ◽  
Further Development

Aim: Tumor-derived small extracellular vesicles (TEVs) are considered for use in inducing tumor antigen-specific immune responses as they contain tumor antigens. The delivery of tumor antigens to the antigen presentation cells (especially dendritic cells [DCs]), and the activation of DCs are the main challenges of TEV therapy. Materials & methods: TEVs were modified with CD40 ligand (CD40L), which can target CD40 expressed on the surface of DCs and can activate them via CD40L-CD40 interactions. Results: It was found that CD40L-TEVs were efficiently taken up by DCs and also activated them. Moreover, tumor antigens were efficiently presented to the T cells by DCs treated with CD40L-TEVs. Conclusion: This study proved that CD40L-modification of TEVs will be helpful for further development of TEV-based tumor vaccination.

scholarly journals Tumors and the danger model.

2002 ◽  
Vol 49 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Dariusz W Kowalczyk
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Tumor Antigens ◽  
Critical Role ◽  
Immune Surveillance ◽  
Tumor Escape ◽  
Principal Mechanism

This article reviews the evidence for the danger model in the context of immune response to tumors and the insufficiency of the immune system to eliminate tumor growth. Despite their potential immunogenicity tumors do not induce significant immune responses which could destroy malignant cells. According to the danger model, the immune surveillance system fails to detect tumor antigens because transformed cells do not send any danger signals which could activate dendritic cells and initiate an immune response. Instead, tumor cells or antigen presenting cells turn off the responding T cells and induce tolerance. The studies reviewed herein based on model tumor antigens, recombinant viral vectors and detection of tumor specific T cells by MHC/peptide tetramers underscore the critical role of tumor antigen presentation and the context in which it occurs. They indicate that antigen presentation only by activated but not by cancer or resting dendritic cells is necessary for the induction of immune responses to tumor antigens. It becomes apparent that the inability of dendritic cells to become activated provides a biological niche for tumor escape from immune destruction and seems to be a principal mechanism for the failure of tumor immune surveillance.

Eleven-Year Follow-up of Idiotype Vaccine and DA-EPOCH-Rituximab in Untreated Mantle Cell Lymphoma: Correlation of Survival with Idiotype Immune Response

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2707-2707 ◽  
Author(s):  
Cliona Grant ◽  
Sattva S. Neelapu ◽  
Larry W Kwak ◽  
Kieron Dunleavy ◽  
Therese White ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Humoral Response ◽  
Autologous Tumor ◽  
Antitumor Effects ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Mantle Cell

Abstract Abstract 2707 Background: We hypothesized that immunotherapy with autologous tumor-derived idiotype (Id)-vaccine may improve the outcome of mantle cell lymphoma (MCL). Some murine lymphoma models have shown that Id-vaccine can induce an anti-tumor humoral response but others indicate that eradication of tumor requires a CD4+ and/or a CD8+ T-cell response. Antitumor T-cells may produce one or many cytokines. The Th1/Tc1 cytokines (IFNγ, IL-2, TNFα, GM-CSF) are commonly believed to mediate antitumor effects. However, a recent paper (Codarri et al. Nat Immunol 2011) proposes that production of GM-CSF by helper T-cells relies on activation of RORγt and that GM-CSF secretion is required for induction of autoimmune inflammation irrespective of helper T-cell polarization. We reported the results of Id-vaccine following DA-EPOCH-R in 26 untreated MCL patients (Neelapu et al Nat Med 2005) and found no association between PFS (19%) or OS (89%) and immune responses at the median of 46 months potential follow-up. We now present an 11-year follow-up and association between OS and antitumor immune responses. Study Design: DA-EPOCH-R was administered q3 weeks × 6, followed by 5 cycles of Id-vaccine beginning at least 12 weeks later to untreated MCL patients. Id protein was produced using hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH), and administered together with GM-CSF × 5 over 6 months. Pre- and post-vaccine samples were tested in parallel to assess humoral and cellular immune responses. Anti-Id and anti-KLH antibody responses were determined by ELISA. KLH-specific cellular responses were determined by intracellular cytokine assay and cellular responses against autologous tumor cells were determined by cytokine induction and IFNγ ELISPOT assays. For cytokine induction assay, PBMCs were cultured with and without autologous tumor cells. After 6 days TNFα, IFNγ and GM-CSF were assessed in culture supernatants by ELISA. Normalized post-vaccine responses were calculated for each patient. Results: Characteristics of all 26 patients: median age 57 (r 22–73), PS 1 (0–2), male sex 73%, blastoid variant 15%, and MIPI (low-65%; intermediate-16%; high-19%). Responses to DA-EPOCH-R: CR-92%, PR-8%. Immune analyses were performed in 24 patients; vaccine could not be made in one patient and one patient progressed and did not have immune analyses. The associations between OS and MIPI scores and normalized immune responses (KLH and anti-Id antibody responses, frequency of KLH-specific CD4+ T-cell responses in PBMC (intracellular IL-2 and TNFα), antitumor cytokine responses and IFNγ ELISPOT) were determined. With 122 mos median potential follow-up (r 111–132), the median PFS is 24 mos and OS is 104 mos. MIPI was significantly associated with OS (Fig 1; p=0.01); median OS: low (not reached), intermediate (84 mos) and high (44 mos). There was no association between OS and KLH humoral response or KLH-specific CD4+ T cells. There was also no association between OS and Id-specific humoral response, IFNγ ELISPOT, or antitumor TNFα, or IFNγ cytokine responses. However, there was a significant association between antitumor GM-CSF production and OS (Fig 2). The median OS at the median GM-CSF normalized value (<4.3 versus >4.3) was 79 mos versus not reached, respectively (p=0.015 (unadjusted) and p=0.045 (bonferroni adjusted)). MIPI and GM-CSF were jointly assessed in a Cox model and showed a trend toward improved OS for higher GM-CSF (p=0.10) after adjusting for MIPI (p=0.20). Conclusions: With 10-year median potential follow-up, GM-CSF cytokine response mediated by antitumor T-cells was significantly associated with OS. Recent studies support the hypothesis that antitumor T-cells that produce significant amounts of GM-CSF are uniquely polarized and that non-GM-CSF producing T-cells do not induce antitumor effects even if they produce TNFα or IFNγ. This may explain why we did not observe an association between OS and TNFα or IFNγ cytokine responses or an anti-Id-antibody response. These results provide the first evidence that Id-vaccines may improve the survival of MCL following induction with immuno-chemotherapy and need to be confirmed in future trials. Disclosures: Neelapu: Biovest International, Inc.: Research Funding. Kwak:Biovest International, Antigenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biovest International: Other remuneration; Antigenics, Xeme Biopharma: Equity Ownership.

Dendritic cells regulate T-cell deattachment through the integrin-interacting protein CYTIP

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1003-1009 ◽  
Author(s):  
Susanne Hofer ◽  
Karina Pfeil ◽  
Harald Niederegger ◽  
Susanne Ebner ◽  
Van Anh Nguyen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Interactions ◽  
Detailed Knowledge ◽  
Active Process ◽  
Interacting Protein ◽  
T Cell Priming

AbstractWhen T cells are primed by dendritic cells (DCs) to initiate antigen-specific immune responses screening for matching antigen receptor-MHC/peptide pairs takes place in DC-T-cell conjugates. For an immune response DC-T-cell conjugates formed during priming events need to dissolve. Although detailed knowledge on molecules involved in the conjugate formation is available, dissolving of them has not been considered to be an active process. Here, we identify CYTIP (cytohesin-interacting protein) to mediate DC-T-cell deattachment. CYTIP, which is induced during maturation of DCs, shortly accumulates to the contact zones with T cells within the first hour of coculture. Specific silencing of CYTIP results in stronger adhesion of DCs to T cells and to fibronectin. When a need for deattachment is created in a T-cell priming assay by only partially loading DCs with antigen, CYTIP silencing causes reduced priming capacity. Thus, CYTIP allows DCs to actively control DC-T-cell interactions.

Anti-Myeloma Effects Induced by Myeloma Idiotype Pulsed Dendritic Cells In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5131-5131
Author(s):  
Mei Zhang ◽  
Xiaoran Yin ◽  
Yunya Luo ◽  
Xiu Lin ◽  
Pengcheng He ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Peripheral Blood ◽  
Gm Csf ◽  
Tnf Α

Abstract As the most potent antigen-presenting cells, Dendritic cells (DCs), capable of inducing immune responses from naive T cells, are operative tools for tumor immunotherapy. Derived DCs are extremely effective in capturing and presentation of antigens to T cells and play a key role in the induction of cytotoxic T lymphocytes (CTLs). In vitro culture system containing the combination of GM-CSF, IL-4 and TNF-α cytokine can affect CD14 + progenitor cells from mononuclear cells (MNCs) of peripheral blood (PB) developing into functional DCs, which have enough quantities for application in vitro researches and clinical practices. Multiple myeloma cells(MM)are able to secrete a great quantity of immunoglobulin (Ig) expressing idiotypic antigen called idiotype (Id) in its mutational hotspot. This kind of idiotypic structure regions also expressing on the surface of MM cells are high specific autologous tumor associated antigen (TAA). The combination use of DCs and tumor specific antigen can improve the immunogenicity of MM cells and stimulate specific anti-tumor immunological response effectively, so by using this new kind of DC tumor vaccine, following high dose chemical therapy, the tiny residual pathological changes might be cleared totally in the future. To investigate the specific antitumor immune response induced by Id-pulsed dendritic cells(DCs) in vitro. DCs were generated from peripheral blood monocytes of the multiple myeloma(MM) patients using GM-CSF, IL-4, and TNF-α. pulsed with idiotype protein at the immature stage, DCs could activate T cells to become tumor specific cytotoxic T lymphocytes (CTLs). The morphologic characteristics of those cells were observed with light and electron microscopes. The phenotypic figures were analyzed with FACS analysis. Methy-thiazoly-Tetrazolium (MTT) assay was employed to evaluate the effect of proliferation of autologous T cells and the inhibition rate of CTL on MM cells. DCs precursors in peripheral blood could be induced to typical mature DCs in medium containing GM-CSF, IL-4 and TNF-α. Mature DCs with Id could operatively increase proliferation of the autologous T cells and active naive T cells to become tumor specialized CTLs. Any doses of CTLs had significant inhibition or killing ability on autologous MM cells. These results suggest in suitable cytokine environment, the precursors in peripheral blood of MM patients could be induced to functional DCs, and vaccination with Id-pulsed DCs could induce active antitumor immune response. Multiple cycles of immunization using DC as APC in vitro can be beneficial in generating antigen- specific T cells from normal PBMC, and Id an auto-specific tumor antigen, can be got with ammonium sulfate four-step precipitated method, By digestion of pepsin and affinity chromatography so as to stimulate MM specific immunological responce, and Id-pulsed mature DCs from MM patients can stimulate not only the proliferation of autologous T cells, but also the specific CTL immune response against autologous MM cells. In addition, in vitro immunization may provide an alternative approach to in vivo immunization of MM. We believe that DCs vaccine can bring the breakthrough of therapy to MM in the near future.

scholarly journals Dendritic Cells in the Gut: Interaction with Intestinal Helminths

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Fela Mendlovic ◽  
Ana Flisser
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Surface Markers ◽  
Intestinal Helminths ◽  
Danger Signals ◽  
Th2 Responses ◽  
Inflammatory Processes

The mucosal environment in mammals is highly tolerogenic; however, after exposure to pathogens or danger signals, it is able to shift towards an inflammatory response. Dendritic cells (DCs) orchestrate immune responses and are highly responsible, through the secretion of cytokines and expression of surface markers, for the outcome of such immune response. In particular, the DC subsets found in the intestine have specialized functions and interact with different immune as well as nonimmune cells. Intestinal helminths primarily induce Th2 responses where DCs have an important yet not completely understood role. In addition, this cross-talk results in the induction of regulatory T cells (T regs) as a result of the homeostatic mucosal environment. This review highlights the importance of studying the particular relation “helminth-DC-milieu” in view of the significance that each of these factors plays. Elucidating the mechanisms that trigger Th2 responses may provide the understanding of how we might modulate inflammatory processes.

scholarly journals Atypical activation of dendritic cells by Plasmodium falciparum

2017 ◽  
Vol 114 (49) ◽  
pp. E10568-E10577 ◽  
Author(s):  
Anton Götz ◽  
Mei San Tang ◽  
Maureen C. Ty ◽  
Charles Arama ◽  
Aissata Ongoiba ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Plasmodium Falciparum ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Transcriptional Program ◽  
Activation Pathways ◽  
Unusual Phenotype

Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by Plasmodium falciparum, the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with P. falciparum-infected erythrocytes activated antigen-specific naïve CD4+ T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to P. falciparum exhibited a transcriptional program distinct from a classical LPS response, pointing to unique P. falciparum-induced activation pathways that may explain the uncharacteristic immune response to malaria.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

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