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1.
Ursula Elsässer-Beile Ulrich Wetterauer Wolfgang Schultze-Seemann Harald Gallati Jürgen Schulte Mönting Sabine von Kleist 《Cancer immunology, immunotherapy : CII》1996,42(2):93-98
The immunological properties of tumor-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal
cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated
from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all
non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads.
These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1α (IL-1α), IL-1β, IL-2, interferon γ
(IFNγ), and tumor necrosis factor α (TNFα) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures
a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of
each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1α, IL-1β, IFNγ and TNFα were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing
capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.
Received: 8 August 1995 / Accepted: 23 January 1996 相似文献
2.
N. Tsavaris C. Baxevanis P. Kosmidis M. Papamichael 《Cancer immunology, immunotherapy : CII》1996,43(2):94-102
In the present study we evaluated the response rate and the immunorestorative properties of interferon α2b (IFnα2b) administered
to patients with advanced renal cell carcinoma (RCC), melanoma (MEL) or colorectal cancer (CC). We studied the immune status
and correlated it with clinical responses. Thirty-five patients with advanced RCC, and 14 with MEL were treated with recombinant
INFα2b. The dose was increased progressively from 5×106 IU/day in the first week (three times every week) to 10×106 IU/day in the second week and thereafter to 15×106 IU/day subcutaneously. In patients with CC INFα2b was given at 5×106 IU/day every other day (three times every week); these patients also received (together with INF) leucovorin 200 mg m–2 day–1 in a 1-h i. v. infusion every week, and mid-infusion 400 mg/m2 5-FU was administered as an intravenous bolus every week. The response rate was as follows: for RCC, 6 patients achieved
partial response (PR), 10 stable disease (SD), and 21 progressed (PD); for MEL, 5 patients achieved PR and 9 PD; for CC, 6
achieved PR, 5 SD, and 9 PD. In all patients blood was withdrawn prior to INFα2b treatment and then monthly. T lymphocytes,
after isolation from peripheral blood, were tested for proliferation in the autologous mixed-lymphocyte reaction and allogeneic
mixed-lymphocyte reaction, interleukin-2 (IL-2) production, expression of IL-2 receptors during the allogeneic-mixed-lymphocyte
reaction, and the production of IL-1 by peripheral blood monocytes. Striking increases were demonstrated in all parameters
2 months after treatment with INFα2b. In comparison to normal controls, all patients with the malignant neoplasms presented
decreased (>45%) mean values of the immunological parameters under investigation (P 0.0001). Responders (patients with RCC, MEL, and PR) presented lower mean values of all the parameters studied than did non-responders
(P 0.0001). Patients with CC presented the lowest mean values of the parameters than did the other patients (RCC, MEL) (P 0.0001). After therapy with INFα2b, patients with RCC experiencing PR showed a mean increase of more than 30% (P 0.0001). Patients with SD showed a mean increase of about 20% (P 0.0001), and those with PD showed a 6% increase in the immunological parameters under investigation. Patients with MEL experiencing
PR showed a mean increase of more than 30% and patients with PD a decrease of more than 10% (P 0.0001). All patients, regardless of the clinical response, achieved an increase of more than 60% (P 0.0001). Administration of IFNα2b resulted in a marked potentiation of a deficient cellular immune response in vitro in those
patients with RCC and MEL who responded to the treatment. On the other hand, non-responders demonstrated a decrease in the
examined parameters and, in some, deterioration of the already depressed immunological functions was observed. This observation
can have prognostic significance regarding clinical response of INF. In contrast, our findings show that the immune stimulation
associated with INFα treatment in all our CC patients did not predict an improved clinical outcome. There are several theoretical
explanations for this discrepancy.
Received: 30 November 1996 / Accepted: 25 June 1996 相似文献
3.
Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide 总被引:3,自引:0,他引:3
Höltl L Ramoner R Zelle-Rieser C Gander H Putz T Papesh C Nussbaumer W Falkensammer C Bartsch G Thurnher M 《Cancer immunology, immunotherapy : CII》2005,54(7):663-670
In this phase I/II study, we evaluated the feasibility, safety and efficacy of allogeneic dendritic cells (DCs) with or without cyclophosphamide in the treatment of patients with metastatic renal cell carcinoma (RCC). Immunomagnetic beads were used to isolate CD14+ monocytes from healthy donor leukapheresis products, and CD83+ antigen-pulsed monocyte-derived DCs (moDCs) loaded with tumor lysate and keyhole limpet hemocyanin (KLH) were generated. Twelve patients were treated with allogeneic moDCs alone, while ten patients also received cyclophosphamide on days 4 and 3 prior to vaccination. Of the 22 patients enrolled, 20 received full treatment consisting of at least three vaccinations at monthly intervals. Two mixed responses with substantial tumor regression were observed. In 3 patients, disease stabilization occurred, in 13 patients disease progressed and 4 patients were lost to follow-up. Overall, immune responses against KLH and tumor lysate were weak or absent; however, the strongest increases in antigen-independent and KLH-specific responses were observed in the 2 patients with mixed responses. In addition, 1 of them showed a substantial increase in oncofetal antigen (OFA)-specific IFN- production. Importantly, the 2 mixed responders and 1 patient with stable disease belonged to the cyclophosphamide group. Median overall survival in the cyclophosphamide group was 23.2 and 20.3 months in the group that received allogeneic moDCs alone. Allogeneic immunotherapy with moDCs is feasible and well tolerated. However, the immunogenicity of allogeneic moDCs is clearly less pronounced than that of autologous moDC immunotherapy. Cyclophosphamide may have the capacity to augment DC-induced antitumor immunity. 相似文献
4.
N. J. Meropol Grace M. Barresi Todd A. Fehniger James Hitt Margaret Franklin Michael A. Caligiuri 《Cancer immunology, immunotherapy : CII》1998,46(6):318-326
Natural killer (NK) cells may be expanded in vivo with a prolonged course of daily subcutaneous interleukin-2 (IL-2). However,
cellular activation requires higher concentrations of IL-2 than are achieved with low-dose therapy. The objective of the current
trial was to determine the toxicity and immunological effects of periodic subcutaneous intermediate-dose IL-2 pulses in patients
receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL-2 at 1.25×106 International Units (1.25 MIU) m–2 day–1. After 4–6 weeks, patients received escalating 3-day intermediate-dose IL-2 pulses administered as single daily subcutaneous
injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m–2 day–1, with transient hypotension, fatigue, and nausea/vomiting dose-limiting. Subcutaneous IL-2 resulted in in vivo expansion
of CD56+ NK cells (796±210%) and CD56bright natural killer (NK) cells (3247±1382%). Expanded NK cells coexpressed CD16, and showed lymphokine-activated killer activity
and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrations above
100 pM. Cellular activation was suggested by rapid margination of NK cells following pulsing, coincident with peak IL-2 levels,
with return to baseline by 24 h. In addition, interferon γ production in response to lipopolysaccharide was augmented. Subcutaneous
daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outpatient regimen that results in in vivo expansion
and potential activation of NK cells, with possible application in the treatment of malignancy and immunodeficiency.
Received: 31 December 1997 / Accepted: 20 April 1998 相似文献
5.
R. Ridolfi Emanuela Flamini Angela Riccobon F. De Paola Roberta Maltoni A. Gardini Laura Ridolfi Laura Medri Giovanni Poletti Dino Amadori 《Cancer immunology, immunotherapy : CII》1998,46(4):185-193
Adoptive tumour infiltrating lymphocytes (TIL) in combination with a modulated dosage of interleukin-2 (IL-2) can be used
with acceptable toxicity in the treatment of immunogenic tumours. Following an experience of reinfusion in advanced melanoma,
colorectal and renal cancer patients, treatment was given to disease-free patients after metastasectomy. The high risk of
relapse and favourable ratio between reinfused TIL and possible microscopic residual disease determined this choice of adjuvant
treatment. A group of 12 patients with advanced disease (7 melanoma, 4 colorectal carcinoma, 1 kidney carcinoma) were treated
with TIL (median 5.8×1010 cells) and IL-2 (West’s schedule) modulated towards a lower dosage (from 12 to 6 MIU/day) in order to maintain an acceptable
level of toxicity. As treatment was well tolerated, it was offered to another 22 patients in an adjuvant setting after metastasectomy
(11 melanoma, 10 colorectal carcinoma, 1 renal cancer), the median dose of TIL reinfused being 4.95×1010 cells. No objective response was observed in advanced patients: all patients progressed after a median of 1.5 months (0–8
months) and median survival was 8 months (3–22+ months). Thirteen patients from the second group are still disease-free after
a median of 23+ months (9+–47+ months). The remaining 9 patients relapsed after a median of 5 months (3–18 months). Toxicity
was moderate as clinical and hepatic/renal function parameters were used to assess the need for dose reductions. Consequently,
there was great diversity in IL-2 dosages administered. In particular, there seemed to be a difference in IL-2 doses administered
between disease-free cases and those who progressed (17.5 MIU/day versus 7 MIU/day in melanoma patients; 11.2 MIU/day versus
7.1 MIU/day in colorectal cancer patients). By contrast, no differences were observed between number of TIL reinfused and
clinical response. Phenotypical characteristics of reinfused TIL were similar to those reported in the literature: 97% were
CD3 and 92% were CD8. Aspecific cytolytic activity was evaluated on 12 cases whereas, in 2 melanoma cases, autologous tumour
tissue was available for the specific cytotoxicity test. Perforin levels in TIL measured at the end of culture were generally
high or very high. Cytokine levels were measured on the supernatant at the end of culture, with an estreme variability in
results. Finally, ζ chain and p56lck were histologically assessed on the resected tissue from which TIL were cultivated. There were virtually none of the former
and a complete absence of the latter, which concurs with data reported in the literature. The same immunocytochemical analysis
was carried out on TIL at the end of culture. This time an almost complete restoration of both functions was seen, especially
in melanoma patients, who are still free from disease. The study is on-going and it has been decided to focus on disease-free
patients after metastasectomy in order to increase the number and possibility of clinical and histological correlations. 相似文献
6.
Raymond P. Abratt Alan R. Pontin Helen S. Ball 《Cancer immunology, immunotherapy : CII》1993,37(2):140-141
Twelve patients with metastatic renal cell carcinoma were entered into a phase-2 study of an 8-week course of interferon (INF) therapy. INF was given subcutaneously at a dose of 3 mu, three times per week. The patients were WHO performance status 0–2. A complete response was obtained in two patients (17% response rate), which has been maintained at 23 and 45 months. One of these patients presented with cranial and lung metastases and received cranial irradiation and decradron concurrent with INF. The toxicity of INF has been low. The optimal duration of INF therapy warrants further evaluation. 相似文献
7.
Gregers G. Hermann Poul F. Geertsen Hans von der Maase Jesper Zeuthen 《Cancer immunology, immunotherapy : CII》1991,34(2):111-114
Summary The purpose of this study was to determine immunological parameters in the peripheral blood that correlate with the clinical effect of interleukin-2 (IL-2) in patients with metastatic renal cell cancer. A group of 26 patients with metastatic renal cell cancer underwent IL-2 treatment using a 36-day schedule with continuous intravenous IL-2 infusion (3 × 106 units m–2 day–1) administered from days 1 to 5 and days 12 to 16. The white blood cell count and the absolute and relative number of neutrophils, lymphocytes, eosinophils and monocytes were recorded six times in peripheral blood during the treatment. Also the blood counts of T cell and NK cell subsets and cells expressing the T cell activation markers IL-2R and VLA-1 were measured. The lymphokine-activated killer (LAK) cell cytotoxicity was measured either with or without additional in vitro stimulation by IL-2. Multivariate statistical analysis showed that the clinical responses were related to the administered dose of IL-2, to a low number of blood cells expressing IL-2 receptors and to a reduction in the blood monocyte count (P <0.05). 相似文献
8.
9.
Donskov F Bennedsgaard KM Hokland M Marcussen N Fisker R Madsen HH Fode K von der Maase H 《Cancer immunology, immunotherapy : CII》2004,53(8):729-739
With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon (IFN-) alone (n=23) or in combination with histamine dihydrochloride (n=26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low expression, whereas blood lymphocytes showed almost normal levels of expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, -chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN- in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients. 相似文献
10.
Richard A. J. Janssen Jan Buter Elske Straatsma Agnes A. Heijn Dirk Th. Sleijfer Elisabeth G. E. de Vries Nanno H. Mulder T. Hauw The Lou de Leij 《Cancer immunology, immunotherapy : CII》1993,36(3):198-204
The effect of subcutaneous recombinant interleukin-2 (rIL-2) therapy on the activation status of peripheral blood lymphocytes (PBL) of 17 renal cell carcinoma patients was investigated in a longitudinal study. The expression of the activation markers HLA-Dr and CD25 on cytotoxic T cells, helper T cells, and natural killer (NK) cells, was analysed using two-colour flow cytometry of whole-blood samples. In addition, the ability of isolated PBL to proliferate in vitro in response to various stimuli was investigated. The absolute amounts of NK cells and HLA-DR-expressing NK cells increased continuously during the whole course of therapy. The absolute amounts of T cells and HLA-Dr-expressing T cells, however, showed an early increase only during the first 1 or 2 weeks of therapy, after which the absolute amounts of HLA-Dr-expressing T cells decreased. In particular, the absolute amount of HLA-Dr-expressing CD8bright+ T cells was significantly lowered in the second half of therapy. PBL collected on day 7 of therapy (post-cycle-1 PBL) showed, as compared to those collected prior to therapy (pretherapy PBL), a decreased proliferative response in vitro after stimulation with phytohaemagglutinin, concanavalin A, soluble CD3 mAb (WT32) or rIL-2. This decreased in vitro response of post-cycle-1 PBL was also reflected in a decrease in the percentage of CD8bright+ T cells expressing HLA-Dr in cultures with rIL-2 or CD3 mAb, in contrast to cultures of pretherapy PBL, which showed an increase of this percentage. We conclude that T cells are the predominantly stimulated subpopulation during the first 2 weeks of subcutaneous rIL-2 therapy. The significant decrease in the absolute amounts of HLA-Dr-expressing T cells in the peripheral blood during the second half of therapy may partly be explained by a decreased responsiveness to rIL-2, but a selective redistribution of HLA-Dr-expressing cells may also be involved. 相似文献
11.
Griffiths RW Elkord E Gilham DE Ramani V Clarke N Stern PL Hawkins RE 《Cancer immunology, immunotherapy : CII》2007,56(11):1743-1753
Background Regulatory T cells are important in maintaining immune homeostasis, mediating peripheral tolerance and preventing autoimmunity.
Increased frequencies of CD4+CD25high T regulatory (TReg) cells have been documented in the peripheral blood of patients with several types of cancer consistent with a role in tumour
escape from immunological control. We have investigated the presence of TReg cells systemically and in situ in previously untreated patients with renal cell carcinoma (RCC).
Results We have shown that there is a significant increased frequency of CD4+CD25high T cells in RCC patients (n = 49) compared to normal donors (n = 38), respectively, 2.47% versus 1.50%; P < 0.0001. We confirmed these data using the FOXP3 marker of TReg cells in a subset of these patients and normal donors. The population of TReg cells identified showed the expected phenotype with CD4+CD25high population in both RCC patients and normal donors contained higher proportions of CD45RO and GITR than CD4+CD25−/low populations and exhibiting suppressive activity in an anti-CD3 and anti-CD28 induced proliferation assay. CD4+FOXP3+ T cells were detected in the tumour microenvironment by immunofluorescence and the numbers enumerated in lymphocytes recovered
following enzymatic disaggregations of biopsies; their frequency was higher in the tumour than the peripheral blood of the
same patients. The early follow up data show an association between higher peripheral blood regulatory T-cell count and adverse
overall survival.
Conclusion These data confirm the increase of TReg cells in RCC patients and provide impetus to further investigate modulation of TReg activity in RCC patients as part of therapy.
Richard W. Griffiths and Eyad Elkord have equally contributed to the study. 相似文献
12.
David D. Stenehjem Michael Toole Joseph Merriman Kinjal Parikh Stephanie Daignault Sarah Scarlett Peg Esper Katherine Skinner Aaron Udager Srinivas Kiran Tantravahi David Gill Alli M. Straubhar Archana M. Agarwal Kenneth F. Grossmann Wolfram E. Samlowski Bruce Redman Neeraj Agarwal Ajjai Alva 《Cancer immunology, immunotherapy : CII》2016,65(8):941-949
13.
H. Belfrage Mikael Dohlsten Gunnar Hedlund Terje Kalland 《Cancer immunology, immunotherapy : CII》1997,44(2):77-82
Injection of the superantigen staphylococcal enterotoxin A (SEA) activates both CD4+ and CD8+ T cells expressing certain families of T cell receptor (TCR) variable-region β (Vβ) chain. T cells respond with profound cytokine production and induction of cytotoxicity. Repeated injections, however, cause
deletion and anergy of both CD4+ and CD8+ T cells, resulting in reduced frequency of SEA-responsive cells TCR-Vβ11+ as well as reduced cytokine levels in serum upon challenge with SEA. Exogenous interleukin-2 (IL-2) in vivo rescued SEA-responsive
CD4+ and CD8+ cells from SEA-induced deletion and/or increase expansion of SEA-primed cells as well as preventing down-regulation of endogenous
IL-2 production in vivo. Combined treatment with SEA and IL-2 also superinduced production of important cytokines for the
cytotoxic function of T cells, tumour necrosis factor α, interferon γ and IL-6, on a cellular level. These studies show that
continuous stimulation with IL-2 in vivo could be useful for superantigen-based immunotherapy by induction of excessive T
cell activation and by prevention of the development of T cell deletion and anergy.
Received: 29 August 1996 / Accepted: 16 January 1997 相似文献
14.
Bex A Mallo H Kerst M Haanen J Horenblas S de Gast GC 《Cancer immunology, immunotherapy : CII》2005,54(7):713-719
Twenty-two patients with metastatic renal cell carcinoma and removal of the primary tumor were treated with subcutaneous pegylated interferon alfa-2b (PEG-Intron) to evaluate toxicity and efficacy. Start dose was 3.0 g/kg/week, escalated to 6.0 g/kg/week. After 2 months, therapy was extended in case of response or stable disease (SD) until progressive disease (PD) or relapse for a maximum of 2 years. National Cancer Institute common toxicity criteria (NCI-CTC) were monitored every 2–4 weeks. After 2 months, nine patients did not continue (8 PD, 1 SD with grade 4 CTC) and 13 extended treatment [three partial response (PR), 10 SD], of these, 11 progressed. One patient with PR developed a durable complete response later. Overall response rate was 13.6% (3/22). Median overall survival is 13 months (range 3–35 months). Dosage was escalated to 6 g/kg/week in three patients . NCI-CTC grade 2 and 3 required dose attenuation in 12 patients during escalation, and reduction in 10 during the trial. Three patients discontinued because of grade 4 CTC (two fatigue, one hyperglycemia). Fatigue was the major dose-limiting toxicity. These results suggest an efficacy and toxicity of PEG-Intron comparable to standard interferon alfa-2b in patients with mRCC and removal of the primary tumor.Author disclosure declaration: None of the authors has a relationship with pharmaceutical companies, biomedical device manufacturers or other corporations whose products or services are related to the subject matter of the submission, nor do the authors have financial interests such as investments, licensing, or other commercial interest in any drugs, goods, or services in connection with the matter under consideration. 相似文献
15.
Diaz D Chara L Chevarria J Carballido J Esteban E Navas V Monserrat J Prieto A de la Hera A Alvarez-Mon M 《Cancer immunology, immunotherapy : CII》2009,58(2):235-245
The peripheral blood lymphocytes of eight patients with metastatic renal cell carcinoma, and of eight healthy volunteers were
analyzed by four-color flow cytometry to characterize the immunophenotypic alterations manifested, determine the prevalence
of lymphocyte apoptosis, and detect evidence of the systemic effect of inhaled IL-2. The T, B and NK lymphocytes of untreated
patients were found to have undergone profound changes characterized by an increase in susceptibility to both spontaneous
and mitogen-induced ex vivo apoptosis, a modified distribution of the main lymphocyte populations in the peripheral blood,
and alterations in activation status. An increase in the proportion of regulatory T cells was also seen in these patients.
Treatment with inhaled IL-2, however, normalized the rate of apoptosis in all the lymphocyte subpopulations studied, as well
as their distribution and activation status. These findings demonstrate that inhaled IL-2 has systemic immunomodulatory effects. 相似文献
16.
17.
Induction of accessory cell function of human alveolar macrophages by inhalation of human natural interleukin-2 总被引:1,自引:0,他引:1
Gernot Zissel Walter E. Aulitzky J. Lorenz Christoph Huber J. Müller-Quernheim 《Cancer immunology, immunotherapy : CII》1996,42(2):122-126
Accessory function allows antigen-presenting cells to produce sufficient secondary signals for optimum T cell proliferation
and interleukin-2 (IL-2) production. Alveolar macrophages are inferior accessory cells compared to monocytes (PBM). We report
here that the accessory index (AI) of alveolar macrophages and PBM of patients with lung metastases of solid tumors treated
with inhalations of human natural IL-2 (hnIL-2) increased following its administration (P<0.005). The accessory index was significantly elevated from baseline values after 2 weeks of inhalation of 300 000 IU hnIL-2/day
(8.2±10.2 compared to 1.1±1; P<0.001). The inhalation of 150 000 IU also induced increases in the index (AI = 2.3±1.9), however, without reaching statistical
significance. In addition at 300 000 IU IL-2/day a significant increase in the accessory index was observed for PBM (4±2.5;
P<0.05). The indices of PBM and alveolar macrophages prior to inhalation showed a significant negative correlation with the
age of the patients (r
s = – 0.5; r
s = – 0.8, respectively; P<0.03 for all comparisons). Our data demonstrate that the inhalational application of hnIL-2 enhances the accessory function
of alveolar macrophages and, to lesser extent, the accessory index of PBM, indicating the occurrence of pharmacological immunostimulation.
Received: 16 August 1995 / Accepted: 4 January 1996 相似文献
18.
Ding Peng Anbang He Shiming He Guangzhe Ge Shuo Wang Weimin Ci Xuesong Li Dan Xia Liqun Zhou 《International journal of biological sciences》2022,18(3):995
Exploring the regulatory mechanism of PD-L1 in renal cancer is one of the key strategies to improve the response of renal cancer patients to checkpoint blockade therapy. In this study, the synergistic effect of ascorbic acid (vitamin C) supplementation and the impact of TET2 depletion on anti-PD-L1 therapy were determined in xenograft model experiments. Lymphocyte infiltration and chemokine expression were determined using flow cytometry and qRT-PCR. To determine the downstream targets of TET2, we performed hMeDip-seq and RNA-seq analyses. The molecular mechanism was further confirmed by hMeDip-qPCR, MeDip-qPCR, bisulfite sequencing, Western blotting, qRT-PCR and xenograft model experiments in vitro and in vivo. The present study demonstrated that ascorbic acid enhanced the efficacy of immunotherapy and that the loss of TET2 function enabled renal cancer cells to evade antitumor immunity. Ascorbic acid treatment significantly increased the intratumoral infiltration of T cells and the expression of cytokines and chemokines, while the loss of TET2 impaired the infiltration of T cells and the expression of cytokines and chemokines. TET2 was recruited to IRF1 by IFN-γ-STAT1 signaling, thereby maintaining IRF1 demethylation and ultimately inducing PD-L1 expression. These results suggest a new strategy of stimulating TET activity to improve immunotherapy for renal cell carcinoma. 相似文献
19.
Filiberto Belli Flavio Arienti J. Sulé-Suso C. Clemente Luigi Mascheroni Alessandro Cattelan Cristina Santantonio Gian Francesco Gallino Cecilia Melani Stefania Rao Mario P. Colombo Michele Maio Natale Cascinelli G. Parmiani 《Cancer immunology, immunotherapy : CII》1997,44(4):197-203
From January 1994 to July 1996 we immunized metastatic melanoma patients with HLA-A2-compatible, interleukin-2 (IL-2)-secreting,
immunogenic melanoma lines in an attempt to induce a systemic reaction that might also affect distant melanoma lesions. Twelve
patients (6 male and 6 female) aged from 28 to 72 years, affected with visceral and/or subcutaneous (s.c.) melanoma metastases,
were treated. Two different HLA-A2+ melanoma lines were transduced with the human IL-2 gene (14932/IL-2 and 1B6/IL-2) and used as vaccine. Two groups of 4 patients
each were injected s.c. with 5×107 and 15×107 irradiated 14932/IL-2 melanoma cells respectively, whereas a third group received 5×107 cells of the second line (1B6/IL-2). All patients received the vaccine on days 1, 13, 26; if no progression was evident,
further immunizations were administered at monthly intervals. All patients were assessable for clinical response after at
least three injections of the vaccine. In 4 cases a stabilization of disease lasting from 2 to 6 months was observed; in 2
of them a mixed type of response to treatment was noted with simultaneous evidence of regressing and non-responding lesions
in the same patients. No signs of clinical response were found in the remaining patients. Nine patients died of disease between
3 and 24 months after the onset of therapy, whereas 3 were alive 3 months after the end of therapy. The local and systemic
side-effects of treatment were mild. These results indicate that vaccination with cells bearing the appropriate antigens and
releasing IL-2 locally can produce weak clinical responses, but also indicate that better results may be achieved through
modifications of the vaccine, the schedule of immunization and/or a more appropriate selection of patients.
Received: 20 December 1996 / Accepted: 27 February 1997 相似文献
20.
W. M. C. Mulder M. J. Stukart E. de Windt J. Wagstaff R. J. Scheper E. Bloemena 《Cancer immunology, immunotherapy : CII》1996,42(6):351-356
Mucins (MUC) are highly glycosylated molecules widely expressed on epithelia of different origins, including colonic mucosa.
Altered glycosylation processes in tumour cells result in the exposure of normally cryptic peptide epitopes, which may then
be recognized as tumour-specific antigens. Recently, MUC1-specific antibodies were detected in the serum of a broad range
of cancer patients, and from different tumours tumour-specific cytotoxic T lymphocytes (CTL) were isolated that recognized
MUC1. Absence of HLA restriction in the recognition has been ascribed to the highly repetitive sequence of the polypeptide
core, allowing simultaneous recognition of multiple identical epitopes and cross-linking and aggregation of T cell receptor
on mucin-specific T cells. We investigated the expression of MUC1 epitopes in 56 cell suspensions from Dukes’ B to D colorectal
carcinomas using antibodies that recognize distinct peptide sequences on the glycosylated or deglycosylated MUC1 protein backbone.
No relation was observed between MUC1 expression, or the extent of its glycosylation, and Dukes’ stage, tumour location and
tumour differentiation, but a positive correlation was detected between the percentages of tumour cells expressing mucin-1
and the numbers of CD3+ infiltrating cells. These tumour-infiltrating lymphocytes contained, however, only a few MUC1-specific T lymphocytes, as
CTL showing preferential killing of MUC1-expressing target cells were only obtained from one tumour. Since, in addition, the
majority of colorectal carcinomas were found to express the fully glycosylated MUC1 glycoprotein, its potential role as a
target antigen for T-lymphocyte-mediated immunotherapy in this tumour type is probably limited.
Received: 2 April 1996 / Accepted: 28 May 1996 相似文献