scholarly journals The Role of T Lymphocytes in Cancer Patients Undergoing Immunotherapy with Autologous Dendritic Cells

2011 ◽  
Vol 5 ◽  
pp. CMO.S6927 ◽  
Author(s):  
Cláudia M. Rodrigues ◽  
Bruna F. Matias ◽  
Eddie F.C. Murta ◽  
Márcia A. Michelin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Cytotoxic T Cells ◽  
Cell Populations ◽  
Tnf Α ◽  
Ifn Γ

Introduction Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. Patients and Methods We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. Results We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Conclusion Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period.

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.

A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5601-TPS5601 ◽  
Author(s):  
Linda R. Duska ◽  
Timothy Norman Showalter ◽  
Gina R. Petroni ◽  
Timothy Bullock
Keyword(s):  
Cervical Cancer ◽  
Immune Response ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Phase Ii ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Hpv Dna ◽  
Randomized Phase Ii

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.

CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4422-4431 ◽  
Author(s):  
Georg Gruenbacher ◽  
Hubert Gander ◽  
Andrea Rahm ◽  
Walter Nussbaumer ◽  
Nikolaus Romani ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Blood ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Γδ T Cell ◽  
Hla Dr ◽  
Tnf Α ◽  
Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

scholarly journals Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells

2000 ◽  
Vol 74 (17) ◽  
pp. 7738-7744 ◽  
Author(s):  
Sangkon Oh ◽  
Maryna C. Eichelberger
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Ifn Γ ◽  
High Doses ◽  
Type Response

ABSTRACT The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.

scholarly journals Expression of Regulatory T Cells in Jejunum, Colon, and Cervical and Mesenteric Lymph Nodes of Dogs Naturally Infected with Leishmania infantum

2014 ◽  
Vol 82 (9) ◽  
pp. 3704-3712 ◽  
Author(s):  
Maria M. Figueiredo ◽  
Beatriz Deoti ◽  
Izabela F. Amorim ◽  
Aldair J. W. Pinto ◽  
Andrea Moraes ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Leishmania Infantum ◽  
Parasite Load ◽  
Mesenteric Lymph Nodes ◽  
Content Type ◽  
Mesenteric Lymph ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTUsing flow cytometry, we evaluated the frequencies of CD4+and CD8+T cells and Foxp3+regulatory T cells (Tregs) in mononuclear cells in the jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected withLeishmania infantumand in uninfected controls. All infected dogs showed chronic lymphadenitis and enteritis. Despite persistent parasite loads, no erosion or ulcers were evident in the epithelial mucosa. The colon harbored more parasites than the jejunum. Frequencies of total CD4+, total Foxp3, and CD4+Foxp3+cells were higher in the jejunum than in the colon. Despite negative enzyme-linked immunosorbent assay (ELISA) serum results for cytokines, levels of interleukin-10 (IL-10), gamma interferon (IFN-γ), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNF-α) were higher in the jejunum than in the colon for infected dogs. However, IL-4 levels were higher in the colon than in the jejunum for infected dogs. There was no observed correlation between clinical signs and histopathological changes or immunological and parasitological findings in the gastrointestinal tract (GIT) of canines with visceral leishmaniasis. However, distinct segments of the GIT presented different immunological and parasitological responses. The jejunum showed a lower parasite load, with increased frequencies and expression of CD4, Foxp3, and CD8 receptors and IL-10, TGF-β, IFN-γ, and TNF-α cytokines. The colon showed a higher parasite load, with increasing expression of IL-4.Leishmania infantuminfection increased expression of CD4, Foxp3, IL-10, TGF-β, IFN-γ, and TNF-α and reduced CD8 and IL-4 expression in both the jejunum and the colon.

Upregulation of Osteoactivin Upon Exposure to Tyrosine Kinase Inhibitors Impairs the T Cell Stimulatory Capacity of Monocyte-Derived Dendritic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1112-1112
Author(s):  
Michael Gutknecht ◽  
Lisa Güttler ◽  
Mark-Alexander Schwarzbich ◽  
Julia Salih ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Transmembrane Glycoprotein ◽  
Stimulatory Capacity ◽  
Ifn Γ ◽  
Tki Treatment ◽  
Cell Stimulatory Capacity

Abstract Abstract 1112 Targeted therapies using tyrosine kinase (TK) inhibitors have significantly improved the treatment of cancer patients. Imatinib (Glivec, Gleevec, STI 571) was the first TK inhibitor (TKI) established for the treatment of cancer and efficiently blocks the activity of c-ABL, a non-receptor TK which is pathologically activated in philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). Nilotinib (Tasigna) and dasatinib (Sprycel) are second-generation TKI that have shown efficacy in the treatment of Ph+ CML resistant or intolerant to imatinib. However, molecularly detectable disease persists in the majority of patients treated with TKI, causing relapse after discontinuation of TKI treatment in many cases. Thus, multiple approaches presently aim to combine TKI treatment with immunotherapy. As TKI, besides targeting their eponymous enzyme, influence multiple other signaling pathways involved in cellular functions, analysis of potential effects of TKI on immune effector cells may be key to develop successful combinatorial strategies. Due to their unique ability to initiate powerful anti-tumor T cell responses, dendritic cells (DC) are employed in many immunotherapeutic strategies aiming to eradicate the malignant cell population. Upon activation they change their expression pattern of cell surface molecules and secreted cytokines/chemokines, a process called DC maturation. Osteoactivin, also known as transmembrane glycoprotein NMB (GPNMB) and dendritic cell-associated transmembrane protein (DC-HIL), is a type I transmembrane glycoprotein that is detected abundantly in DC but not or substantially less in monocytes. Its expression can inhibit T cell activation by binding the type 1 transmembrane proteoglycan syndecan-4 (SD-4) on T cells. Here we extend our findings that the exposure of human peripheral blood monocytes to the immunosuppressive and anti-inflammatory cytokine IL-10 or to therapeutic concentrations of TKI during differentiation into monocyte-derived DC (moDC) leads to significant upregulation of osteoactivin at the transcript and protein level in vitro (Blood 2010 116: abstract 1733). We analyzed the expression of other inhibitory receptors, such as PD-L1, PD-L2, CD80, or CD86 and observed no significant differences of the expression under TKI treatment. Furthermore, we thoroughly examined the expression of osteoactivin in the presence of relevant maturation signals such as TLR ligands, IFN-γ or TNF. LPS, Poly I:C, Pam3Cys or R848 nearly abolished osteoactivin expression compared to untreated control cells. In contrast, IFN-γ or TNF did not significantly reduce osteoactivin expression below the basal level. To evaluate the involvement of osteoactivin in TKI-triggered effects on moDC function we performed mixed lymphocyte reactions with allogenic T cells. Osteoactivin upregulation upon exposure to imatinib, dasatinib and nilotinib resulted in significantly reduced T cell stimulatory capacity of moDC. This was not due to IL-10 upregulation but rather due to direct inhibitory effects of osteoactivin on T cell proliferation which could be overcome by addition of blocking anti-osteoactivin antibody. Our data demonstrate that upregulation of osteoactivin upon exposure of immature moDC to TKI is critically involved in the inhibition of DC function. These findings indicate that inhibition of osteoactivin expression or function may serve as a novel strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

Opposing Effects of PD-1/PD-L1/L2 Engagement and IFN-γ/TNF-α in the Treatment of AML w/ Anti-CD33 Chimeric Antigen Receptor-Modified T Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5891-5891
Author(s):  
Jacob Halum Basham ◽  
Terrence L. Geiger
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Chimeric Antigen Receptor ◽  
Short Term ◽  
Car T Cells ◽  
Tnf Α ◽  
Car T ◽  
Ifn Γ

Abstract Chimeric antigen receptor-modified T lymphocytes (CART cells) have shown benefit as an adjuvant immunotherapy in the treatment of B cell malignancies. This success of re-targeted T cells has not been extended to other hematologic malignancies. We have developed an immunotherapeutic approach to treat acute myeloid leukemia (AML) using CAR T cells re-directed against the myeloid-specific antigen CD33 (CART-33). CART-33 cells are potent and specific in eliminating AML cells in vitro and in vivo. Despite this, CART-33 cells have shown poor in vivo expansion and persistence in NOD-SCID IL2rγ (-/-) (NSG) AML xenograft models. To address the reason for this, we assessed the impact of AML-expressed programmed death ligands 1 & 2 (PD-L1/2) on CART-33 cell activity. PD-L1 inhibits T cell functions upon binding PD-1, which is upregulated with T cell activation. Less is known about PD-L2's effect. Interferon-gamma (IFN-γ), a primary effector cytokine secreted by CD4+ and CD8+ effector T cells, is a known potent inducer of PD-L1 on AML blasts. Using AML cell lines U937, Oci-AML3, CMK, and MV4-11 we show that IFN-γ, TNF-α, and activated CART-33 supernatant can induce up-regulation of PD-L1 and PD-L2 on AML. IFN-γ and TNF-α synergize strongly in up-regulating PD-1 ligands on AML. The kinetics and induction of PD-L2 are distinct from that of PD-L1. Although PD-L1 is well documented to suppress T cell function via ligation of T cell expressed PD-1, induction of PD-L1/L2 had no effect on the cytolytic activity of CART-33 cells against AML in short term (<48 h) cultures. Paradoxically, 24 hr pre-treatment of AML with either IFN-γ or CART-33 supernatant increased AML susceptibility to killing by CART-33 cells despite elevated expression of PD-L1/L2 by AML. Our results highlight the regulatory complexity of AML cytolysis by re-targeted T lymphocytes, and argue that tumor-expressed PD-L1 and PD-L2 impacts the sustainability, but not short-term killing activity, of adoptively transferred CAR T cells in the treatment of AML. Disclosures No relevant conflicts of interest to declare.

Preliminary biomarker and pharmacodynamic data from a phase I study of single-agent bispecific antibody T-cell engager GBR 1302 in subjects with HER2-positive cancers.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 69-69 ◽  
Author(s):  
Martin Wermke ◽  
Juergen Alt ◽  
John S. Kauh ◽  
Jonathan Back ◽  
Yacine Salhi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Bispecific Antibody ◽  
Cell Populations ◽  
Single Subject ◽  
Her2 Positive ◽  
Tnf Α ◽  
Ifn Γ

69 Background: HER2 is overexpressed in many solid tumors and is a validated therapeutic target. GBR 1302 is a HER2xCD3 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to HER2-expressing tumor cells. GBR1302-101 (NCT02829372) is an ongoing, multicenter, open-label, first-in-human study of GBR 1302 in subjects with HER2-positive cancers to evaluate the safety, tolerability, and preliminary efficacy of GBR 1302, and to elucidate the mechanism(s) by which it redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: Adults with progressive HER2-positive solid tumors with no available standard or curative treatment receive intravenous GBR 1302 on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels, starting at 1 ng/kg. The first 4 cohorts consist of a single subject; subsequent cohorts enroll using a 3+3 design. The primary and secondary efficacy and safety endpoints of this trial will be reported at the end of the study. Preliminary pharmacodynamic (PD) data are reported for cellular biomarkers and cytokines as assessed by FACS and ELISA in peripheral blood. Results: Beginning at 30 ng/kg dosing of GBR 1302 (Cohort 4), numbers of peripheral blood CD3, CD4, and CD8 positive T-cell populations decreased within 6 hours of initiating administration, but recovered to levels at or above baseline by 48 hours. A parallel, transient increase was observed in peripheral blood cytokines (IL-2, IL-6, IL-10, IFN-γ, TNF-α). At doses greater than 30 ng/kg, more pronounced cytokine increases were observed, which normalized at 12 hours. At the highest dose level for which data are available (n = 8 subjects; Cohort 5), changes from baseline in cytokine expression at ~340 hours were greater by ~60-fold for IL-6, ~30-fold for IL-2, ~3-fold for IFN-γ, ~5-fold for TNF-α, and ~18-fold for IL-10. Two subjects treated at 100 ng/kg experienced Grade 1 cytokine release syndrome, evidenced by short-lived fever spikes. Dose escalation is ongoing. Conclusions: Preliminary PD data indicate changes in peripheral T-cell populations and inflammatory cytokines following GBR 1302 treatment. Clinical trial information: NCT02829372.

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