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1.
Fury MG Lipton A Smith KM Winston CB Pfister DG 《Cancer immunology, immunotherapy : CII》2008,57(2):155-163
Introduction MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor
(FcγRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the
tumor cytotoxicity of bispecific antibodies.
Methods In group 1, patients received MDX-447 intravenously (IV) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5,
7, 10, 15, 20, 30, and 40 mg/m2. In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days −3 to +2, 5–9, 12–16, etc.).
Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m2.
Results Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients
received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups,
with seven patients experiencing ≥grade 3 events. MDX-447 half-life (T1/2) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and
peak levels of circulating tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447
alone was 30 mg/m2. When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns,
with the last patient being treated at the 7 mg/m2 dose level. There were no objective complete or partial responses in either group.
Conclusion MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m2 weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation. 相似文献
2.
Pullarkat V Deo Y Link J Spears L Marty V Curnow R Groshen S Gee C Weber JS 《Cancer immunology, immunotherapy : CII》1999,48(1):9-21
A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating
factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of
the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics
of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect
of MDX-H210 with G-CSF. MDX-H210 is a F(ab)′ × F(ab)′ humanized bispecific murine antibody that binds to both HER2/neu and
the FcγR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three
more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients
had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The β-elimination half-life
varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor α was observed after administration of
bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric
analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third
infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.
Received: 23 July 1998 / Accepted: 6 November 1998 相似文献
3.
Cristoph Renner Frank Hartmann M. Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,45(3-4):184-186
A group of 15 patients with refractory Hodgkin′s disease were treated in a phase I/II trial with the natural-killer (NK)-cell-activating
bispecific monoclonal antibody HRS-3/A9, which is directed against the Fcγ receptor III (CD16 antigen) and the Hodgkin’s associated
CD30 antigen. The antibody was given four times every 3 – 4 days, starting with 1 mg/m2. The treatment was well tolerated and the maximum tolerated dose was not reached at 64 mg/m2. Side-effects were rare and consisted of fever, pain in involved lymph nodes and a maculopapulous rash. Nine patients developed
human anti-(mouse immunoglobulin) antibodies. One complete and one partial remission (lasting 5 and 3 months, respectively),
three minor responses (1 to 11+ months), and one mixed response were achieved. There was no clear-cut dose side-effect or
dose/response correlation. NK cell activity increased in most of the patients treated with 4 mg/m2 or higher doses but lasted no longer than 6 weeks after therapy. Our results encourage further clinical trials with this novel
immunotherapeutic approach and emphasize the necessity to reduce the immunogenicity of the antibody to allow retreatment of
responding patients.
Accepted: 14 October 1997 相似文献
4.
Wallace PK Romet-Lemonne JL Chokri M Kasper LH Fanger MW Fadul CE 《Cancer immunology, immunotherapy : CII》2000,49(9):493-503
Objective: The aim was to determine the ability of macrophage-activated killer cells (MAK cells) obtained from peripheral blood of normal
volunteers to kill glioblastoma multiforme (GBM) cell lines. Another goal was to investigate whether a bispecific antibody
(bsAb) MDX-447, recognizing the high-affinity Fc receptor for IgG (FcγRI) and epidermal growth factor receptor (EGFR), would
enhance MAK cell tumoricidal activity. Methods: Monocytes, from leukapheresis product, were isolated by countercurrent elutriation and differentiated into MAK cells by culture
with granulocyte/macrophage-colony-stimulating factor, vitamin D3 and interferon γ. Cells were checked for sterility, endotoxin and phenotypic markers. MAK cell functional activity was measured
by a flow-cytometric phagocytosis assay. Target cells, a carcinoma cell line and two glioma cell lines expressing EGFR, were
stained with PKH-26. MAK cells were labeled with fluorescein-conjugated anti-CD14. Combined effectors, targets and bsAb were
incubated and the percentage of MAK cells with phagocytosed targets was determined by flow cytometry. Conclusion: We demonstrate that a large number of highly purified monocytes, isolated from peripheral blood, can be differentiated into
MAK cells for use as an adjuvant for cancer treatment. After culture these cells are sterile, endotoxin-free and comprise
more than 95% MAK cells. Increased amounts of CD14, CD64 and HLA-DR, which are characteristics of macrophage activation, were
expressed. MAK cells were extremely phagocytic in comparison to monocytes, even in the absence of bsAb. Moreover, bsAb enhanced
the tumoricidal activity of elutriated MAK cells targeted against GBM cell lines. Therefore, intracavity MAK cells armed with
MDX-447 could be an effective adoptive immunotherapy for EGFR-positive GBM.
Received: 5 April 2000 / Accepted: 12 July 2000 相似文献
5.
Renner C Hartmann F Jung W Deisting C Juwana M Pfreundschuh M 《Cancer immunology, immunotherapy : CII》2000,49(3):173-180
Fifteen patients with refractory Hodgkin's disease were treated in a dose-escalation trial with the bispecific monoclonal
antibody (bi-mAb) HRS-3/A9, which is directed against the Fcγ receptor III (CD16 antigen) and the Hodgkin's-associated CD30
antigen. Treatment consisted of four cycles of four bi-mAb infusions given over 1 h every 3–4 days at different dose levels
ranging from 1 mg/m2 to 64 mg/m2. Measurable serum levels (above 0.1 μg/ml) of circulating bi-mAb could be detected in patients treated with doses above 4 mg/m2, reaching peak levels of 9.5 μg/ml immediately after the end of antibody infusion on the highest dose level. Bi-mAb elimination
corresponded to second-order kinetics with a terminal half-life time (t
1/2,β) of 28–32 h. Bi-mAb treatment induced the occurrence of human anti-(mouse Ig) antibodies (HAMA) in 6 out of 13 patients initially
testing negative. All 6 patients not only developed anti-isotypic anti-(mouse Ig) but also anti-idiotypic and anti-anti-idiotypic
antibodies. While no consistent changes of peripheral blood cell counts, or of any lymphocyte subpopulation including natural
killer (NK) cells, has been observed, 4 out of 6 evaluable patients treated with doses of at least 4 mg/m2 showed an increase of NK cell activity within 2 weeks after treatment, which lasted for a maximum of 12 weeks. Circulating
amounts of soluble CD30 antigen could be detected in the serum of 6 patients. However, like the results and time courses of
all the other immunological parameters evaluated, this was not predictive for treatment outcome.
Received: 16 September 1999 / Accepted: 6 January 2000 相似文献
6.
R. Landmann M. Wesp C. Ludwig R. Obrist C. Knüsli J. P. Obrecht 《Cancer immunology, immunotherapy : CII》1990,31(5):292-296
Summary The expression of the monocyte membrane glycoprotein CD14 was measured and related to the serum interferon (IFN) concentration in thirteen patients with disseminated cancer during treatment with human recombinant interferon (rIFN). The drug was administered by continuous subcutaneous infusion using an escalating dose schedule, starting at 50 µg/day or 100 µg/day and increasing weekly up to 600 µg/day, if tolerated. Treatment was continued at a mean maximal tolerated dose of 200 µg/day for a median duration of 43 days. Serum IFN concentration and monocyte CD14 antigen expression (immunofluorescence with the monoclonal antibody LeuM3 and fluorescence-activated cell sorting analysis) were determined weekly. The serum IFN concentration was positively correlated with the rIFN dose (P <0.05). Therapy induced a dose-dependant enhancement of CD14 antigen expression. The increase in mean CD14 fluorescence intensity was on average 60% after 3 weeks of treatment at a mean dose of 220 µg rIFN/day and was reversed after withdrawal of therapy. Patients with a rapidly rising serum IFN concentration (starting dose 100 µg/day) showed a smaller increment in CD14 fluorescence intensity than those with slowly rising serum IFN levels (starting dose 50 µg/day). Since rIFN is known to down-regulate CD14 antigen expression in vitro, monocytes from patients off therapy and from healthy volunteers were cultured with this cytokine. A similar decrease of CD14 fluorescence was observed in both groups. In patients several factors, such as IFN concentration, duration of drug effect and type of serum, were evaluated and could not explain the discrepant in vivo and in vitro findings. In conclusion, the monocyte marker CD14 was found to be differentially regulated by rIFN in vivo and in vitro. In vivo, secondary mediators, induced by rIFN and acting on a constantly renewed cell population, may contribute to the enhanced CD14 expression. 相似文献
7.
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
8.
van Vuuren AJ van Roon JA Walraven V Stuij I Harmsen MC McLaughlin PM van de Winkel JG Thepen T 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(10):5833-5838
Macrophages are known to play a key role during inflammation in rheumatoid arthritis (RA). Inflammatory macrophages have increased expression of CD64, the high-affinity receptor for IgG. Targeting this receptor through a CD64-directed immunotoxin, composed of an Ab against CD64 and Ricin A, results in effective killing of inflammatory macrophages. In this study, we show elevated levels of CD64 on synovial macrophages in both synovial lining and synovial fluid in RA patients. The CD64-directed immunotoxin efficiently eliminates activated synovial macrophages in vitro, while leaving quiescent, low CD64-expressing macrophages unaffected. To examine whether killing of CD64 macrophages results in therapeutic effects in vivo, we established an adjuvant arthritis (AA) model in newly generated human CD64 (hCD64) transgenic rats. We demonstrate that hCD64 regulation in this transgenic rat model is similar as in humans. After AA induction, treatment with CD64-directed immunotoxin results in significant inhibition of disease activity. There is a direct correlation between immunotoxin treatment and decreased macrophage numbers, followed by diminished inflammation and bone erosion in paws of these hCD64 transgenic rats. These data support synovial macrophages to play a crucial role in joint inflammation in AA in rats and in human RA. Selective elimination of inflammatory macrophages through a CD64-directed immunotoxin may provide a novel approach for treatment of RA. 相似文献
9.
Increased bone resorption mediated by osteoclasts causes various diseases such as osteoporosis and bone erosion in rheumatoid
arthritis (RA). Osteoclasts are derived from the monocyte/macrophage lineage, but the precise origin remains unclear. In the
present study, we show that the purified CD16- human peripheral blood monocyte subset, but not the CD16+ monocyte subset, differentiates into osteoclast by stimulation with receptor activator of NF-κB ligand (RANKL) in combination
with macrophage colony-stimulating factor (M-CSF). Integrin-β3 mRNA and the integrin-αvβ3 heterodimer were only expressed
on CD16- monocytes, when they were stimulated with RANKL + M-CSF. Downregulation of β3-subunit expression by small interfering RNA
targeting β3 abrogated osteoclastogenesis from the CD16- monocyte subset. In contrast, the CD16+ monocyte subset expressed larger amounts of tumor necrosis factor alpha and IL-6 than the CD16- subset, which was further enhanced by RANKL stimulation. Examination of RA synovial tissue showed accumulation of both CD16+ and CD16- macrophages. Our results suggest that peripheral blood monocytes consist of two functionally heterogeneous subsets with distinct
responses to RANKL. Osteoclasts seem to originate from CD16- monocytes, and integrin β3 is necessary for osteoclastogenesis. Blockade of accumulation and activation of CD16- monocytes could therefore be a beneficial approach as an anti-bone resorptive therapy, especially for RA. 相似文献
10.
Hélène Haegel Christine Thioudellet Rémy Hallet Michel Geist Thierry Menguy Fabrice Le Pogam Jean-Baptiste Marchand Myew-Ling Toh Vanessa Duong Alexandre Calcei Nathalie Settelen Xavier Preville Marie Hennequi Benoit Grellier Philippe Ancian Jukka Rissanen Pascal Clayette Christine Guillen Ronald Rooke Jean-Yves Bonnefoy 《MABS-AUSTIN》2013,5(5):736-747
Cancer progression has been associated with the presence of tumor-associated M2-macrophages (M2-TAMs) able to inhibit anti-tumor immune responses. It is also often associated with metastasis-induced bone destruction mediated by osteoclasts. Both cell types are controlled by the CD115 (CSF-1R)/colony-stimulating factor-1 (CSF-1, M-CSF) pathway, making CD115 a promising target for cancer therapy. Anti-human CD115 monoclonal antibodies (mAbs) that inhibit the receptor function have been generated in a number of laboratories. These mAbs compete with CSF-1 binding to CD115, dramatically affecting monocyte survival and preventing osteoclast and macrophage differentiation, but they also block CD115/CSF-1 internalization and degradation, which could lead to potent rebound CSF-1 effects in patients after mAb treatment has ended. We thus generated and selected a non-ligand competitive anti-CD115 mAb that exerts only partial inhibitory effects on CD115 signaling without blocking the internalization or the degradation of the CD115/CSF-1 complex. This mAb, H27K15, affects monocyte survival only minimally, but downregulates osteoclast differentiation and activity. Importantly, it inhibits monocyte differentiation to CD163+CD64+ M2-polarized suppressor macrophages, skewing their differentiation toward CD14-CD1a+ dendritic cells (DCs). In line with this observation, H27K15 also drastically inhibits monocyte chemotactic protein-1 secretion and reduces interleukin-6 production; these two molecules are known to be involved in M2-macrophage recruitment. Thus, the non-depleting mAb H27K15 is a promising anti-tumor candidate, able to inhibit osteoclast differentiation, likely decreasing metastasis-induced osteolysis, and able to prevent M2 polarization of TAMs while inducing DCs, hence contributing to the creation of more efficient anti-tumor immune responses. 相似文献
11.
BACKGROUND: Cells from AML patients can differentiate into the phenotype of DC when cultured with GM-CSF and IL-4. Such cytokine-treated AML-derived DC (AML-DC) can stimulate autologous T cells. In this study we examined whether an anti-CTLA-4 MAb (MDX-010) could enhance the generation of autologous anti-AML T cells. METHODS: MAb MDX-010 was added to AML PBMC cultures in the presence of GM-CSF and IL-4, a previously reported AML-DC culture method of generating anti-AML T cells. T-cell activation and proliferation were examined thereafter. RESULTS: Addition of MDX-010 to GM-CSF/IL-4-conditioned AML-DC cultures induced a mean seven-fold increase in the numbers of autologous T cells compared with cultures without MDX-010 (P < 0.007). T cells stimulated by AML-DC with CTLA-4 blockade were significantly more cytotoxic towards autologous AML cells than those without MDX-010 (42 +/- 23% vs. 26 +/- 15%, E:T ratio of 20). T cells stimulated by AML-DC with CTLA-4 blockade had significantly greater proportions of T cells producing IFN-gamma in response to autologous AML cells than those cultured with AML-DC alone (10.7 +/- 4.7% vs. 4.5 +/- 2.4% for CD4+ IFN-gamma+ CD69+ and 9.8 +/- 4.1% vs. 4 +/- 2.1% for CD8+ IFN-gamma+ CD69+ with or without MDX-010; n = 7; P < 0.007, P < 0.003, respectively). DISCUSSION: CTLA-4 blockade enhances the activity and numbers of AML-reactive T cells that can be stimulated by autologous AML-DC and may enhance the efficacy of adoptive immunotherapy of AML. 相似文献
12.
Background aimsMesenchymal stromal cells (MSC) possess immunomodulatory activity both in vitro and in vivo. However, little information is available regarding their function during the initiation of immunologic responses through their interactions with monocytes. While many studies have shown that MSC impair the differentiation of monocytes into dendritic cells and macrophages, there are few articles showing the interaction between MSC and monocytes and none of them has addressed the question of monocyte subset modulationMethodsTo understand better the mechanism behind the benefit of MSC infusion for graft-versus-host treatment through monocyte involvement, we performed mixed leucocyte reactions (MLR) in the presence and absence of MSC. After 3 and 7 days, cultures were analyzed by flow cytometry using different approachesResultsMSC induced changes in monocyte phenotype in an MLR. This alteration was accompanied by an increase in monocyte counting and CD14 expression. MSC induced monocyte alterations even without contact, although the parameters above were more pronounced with cell–cell contact. Moreover, the presence of MSC impaired major histocompatibility complex (MHC) I and II, CD11c and CCR5 expression and induced CD14 and CD64 expression on monocytes. These alterations were accompanied by a decrease in interleukin (IL)-1β and IL-6 production by these monocytes, but no change was observed taking into account the phagocytosis capacity of these monocytesConclusionsOur results suggest that MSC impair the differentiation of CD14++ CD16? CD64+ classical monocytes into CD14++ CD16+ CD64++ activated monocytes, having an even earlier role than the differentiation of monocytes into dendritic cells and macrophages. 相似文献
13.
《MABS-AUSTIN》2013,5(2):256-266
The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m2 SM03. Mean clearance was similar at doses ≤ 360 mg/m2 and decreased significantly at dose 480 mg/m2, supporting saturation of B-cell binding at 360 mg/m2. Across all dose levels and histologies, one patient achieved partial response at 480 mg/m2 dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60–480 mg/m2 and had potential efficacy in Chinese patients with follicular lymphoma. 相似文献
14.
The expression of monocyte cell-surface receptors represents one index of immune dysfunction, which is common with aging.
Although mouse models of aging are prevalent, monocyte subset assessment is rare. Our purpose was to compare cell receptor
expression on classic (CD115+/Gr-1high) and non-classic (CD115+/Gr-1low) monocytes from 80- or 20-week-old CD-1 mice. Three-colour flow cytometry was used to determine the concentration of monocyte
subsets and their respective cell-surface expression of TLR2, TLR4, CD80, CD86, MHC II and CD54. These receptors were selected
because they have been previously associated with altered monocyte function. Data were analysed with independent t-tests; significance was set at P < 0.05. Old mice had a greater concentration of both classic (258%, P = 0.003) and non-classic (70%, P = 0.026) monocytes. The classic : non-classic monocyte ratio doubled in old as compared with that in young mice (P = 0.006), indicating a pro-inflammatory shift. TLR4 (↓27%, P = 0.001) and CD80 (↓37%, P = 0.004) were decreased on classic monocytes from old as compared with those from young mice. TLR2 (↑24%, P = 0.002) and MHCII (↓21%, P = 0.026) were altered on non-classic monocytes from old as compared with those from young mice. The increased classic : non-classic
monocyte ratio combined with changes in the cell-surface receptor expression on both monocyte subsets is indicative of immune
dysfunction, which may increase age-associated disease risk. 相似文献
15.
Gerald J. Vosika Charles Barr Dennis Gilbertson 《Cancer immunology, immunotherapy : CII》1984,18(2):107-112
Summary Endotoxin and the lipid-A portion of the molecule have a variety of biological effects, including the induction of necrosis and regression of malignancy. To date extensive clinical trials of endotoxin as a potential therapeutic agent have been shunned due to the toxicity of the material.Several lipid-A analogues have been described which have reduced toxicity and retain antitumor activity. We have investigated in a phase-I trial the clinical toxicity and immunological effects of monophosphoryl lipid A prepared from Salmonella typhimurium and Salmonella minnesota.Patients entered on the study received IV monophosphoryl lipid A twice weekly for a total of 4 weeks. At least three patients were entered sequentially at each of the dose levels of 10, 25, 50, 100, and 250 g/m2 body surface area. One patient was treated at the dose level of 500 g/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 g/m2. Two instances of bronchospasm occurred in one patient who received 250 g/m2. One patient received 500 g/m2 and became hypotensive.Sequential clinical data showed no evidence of renal or hepatic toxicity. A transient decrease in the WBC and platelets occurred during the first 24 h after therapy. Immune function testing measured T cells, monocyte cytostasis, monocyte suppressor cell activity, and NK activity. These data suggested a shift in monocyte populations with activated cells moving into the tissue.Direct objective antitumor activity or necrosis was not observed in this group of patients. We conclude that monophosphoryl lipid A can be given to patients in a dose of up to 100 g/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated. 相似文献
16.
Su Li Dongsheng Zhang Jian Sun Zhinming Li Liting Deng Benyan Zou Jing Zhan Wenqi Jiang 《MABS-AUSTIN》2012,4(2):256-266
The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m2 SM03. Mean clearance was similar at doses ≤360 mg/m2 and decreased significantly at dose 480 mg/m2, supporting saturation of B-cell binding at 360 mg/m2. Across all dose levels and histologies, one patient achieved partial response at 480 mg/m2 dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60–480 mg/m2 and had potential efficacy in Chinese patients with follicular lymphoma. 相似文献
17.
Mundy-Bosse BL Young GS Bauer T Binkley E Bloomston M Bill MA Bekaii-Saab T Carson WE Lesinski GB 《Cancer immunology, immunotherapy : CII》2011,60(9):1269-1279
Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages
of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated
with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between
plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma
IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/lowCD14+ MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33+HLADR−CD15+ MDSC (P = 0.008) and IL-10 with CD33+HLADR−CD15− MDSC (P = 0.002). The percentage of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFN-α-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFN-α responsiveness in both PBMC and the CD4+ subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased
percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness
in patients with GI malignancies. 相似文献
18.
Monocyte activation by an oral immunomodulator (bestatin) in lymphoma patients following autologous bone marrow transplantation 总被引:2,自引:0,他引:2
Kazuhiko Ino Philip J. Bierman Michelle L. Varney Dean G. Heimann Charles A. Kuszynski Sheryl A. Walker J. E. Talmadge 《Cancer immunology, immunotherapy : CII》1996,43(4):206-212
Bestatin (ubenimex), an inhibitor of aminopeptidase, is an oral immunomodulator that binds to CD13 (aminopeptidase N) on
macrophages/monocytes. To examine its immunomodulatory effect after high-dose therapy and autologous bone marrow transplantation
(BMT), a dose-finding phase Ib trial was conducted with 30 Hodgkin’s disease and non-Hodgkin’s lymphoma patients who received
no drug (control), 10 and 30 mg (low dose), or 90 and 180 mg (high dose) of bestatin daily for 60 days following autologous
BMT. Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on 2 consecutive days.
The serum neopterin levels, an indicator of monocyte/macrophage activation, increased in the high-dose group compared to the
control group (not significantly) and the low-dose group (significantly). Similarly, the colony-stimulating activity in the
sera was significantly increased in the high-dose group compared to the control and low-dose groups. We also examined the
expression of cell-surface markers on monocytes in these patients by fluorescent cytometry analysis. There was no significant
difference either in the frequency or absolute number of monocytes (CD14+) among the three groups at any time. However, a significant increase in the frequency of CD16(FcgRIII)-positive monocytes
(a marker of activation) was observed in the high-dose group compared to controls from day 14 to day 60 after the start of
bestatin administration. Further, the frequency of HLA-DR+ monocytes (another marker of activation) was significantly increased in the high-dose group. These results indicate that
bestatin at higher doses (90 and 180 mg daily), but not lower doses, activates macrophages/monocytes, as demonstrated by phenotypic
marker (HLA-DR and CD16) up-regulation, and this provides augmentation of neopterin and colony-stimulating activity in the
serum of patients following autologous BMT.
Received: 24 June 1996 / Accepted 13 September 1996 相似文献
19.
Shimon Slavin Aliza Ackerstein Reuven Or Michael Y. Shapira Benjamin Gesundheit Nadir Askenasy Shoshana Morecki 《Cancer immunology, immunotherapy : CII》2010,59(10):1511-1519
The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK)
with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies
and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes;
amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host
disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine
25 mg/m2 or a single dose of cyclophosphamide 1,000 mg/m2, 2 subcutaneous injections of alpha interferon (IFN) 3 × 106 and COX2 inhibitors, followed by administration of IMAK (65 ± 5 CD3+CD56−; 17 ± 5 CD3−CD56+) in conjunction with low dose subcutaneous rIL-2 (6 × 106 IU/m2/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we
present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological
malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on
an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited
grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of
21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude
that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term
disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors,
preferably at a stage of minimal residual disease with the goal in mind to eradicate all malignant cells at an early stage
of the disease. 相似文献
20.
Summary The influence of immunotherapy with high dose (50×106 units/m2) recombinant leukocyte A interferon on blood monocyte functions was studied in eight patients with bronchogenic carcinoma. Monocyte chemotactic responsiveness (MCR) was initially depressed (9.8±1.6 cells/field) compared to healthy controls (17.6±5.1 cells/field), P<0.01. Recombinant interferon was administered three times weekly, and after 7 days a significant improvement in chemotaxis was observed (16.6±3.0 cells/field), P<0.05. The MCR remained normal until cessation of interferon therapy (>1 month). Phagocytic and candidacidal activities were normal in the patients and were not influenced by treatment with interferon. In conclusion, high dose recombinant interferon given to cancer patients caused a normalization of defective blood monocyte chemotaxis, which persisted for >1 month. 相似文献