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At least 73 records · Page 4Linked to original sources

Adjuvant autologous tumour cell-lysate vaccine versus no adjuvant treatment in patients with M0 renal cell carcinoma after radical nephrectomy: 3-year interim analysis of a German multicentre phase-III trial.

Even M0 RCC is associated with tumour progression in approximately 30% of all patients after radical nephrectomy. Nevertheless, no effective adjuvant treatment after radical nephrectomy has been established. In a multicentre phase-III trial we investigated the impact of an adjuvant autologous tumour cell-lysate vaccination on the progression-free survival of patients with M0 RCC after radical nephrectomy. Between January 1997 and August 1998 a total of 558 patients with a renal tumour were enrolled at 55 different centres (study group) in Germany. Prior to radical nephrectomy all patients were centrally randomized (Quintiles Germany) to either receive an adjuvant autologous tumour cell-lysate vaccine (6 applications at 4-week intervals after radical nephrectomy) or to receive no adjuvant treatment (control group) after radical nephrectomy. All patients were evaluated following standardized diagnostic investigations at 6-month intervals. Following the inclusion criteria (RCC stages pT2-3bpN0-3M0, TNM-classification, UICC 1993), 365 patients were evaluable for the 3-year progression-free survival analysis. There were 240 patients with stage pT2pN0M0 (104 in the vaccine group and 136 patients in the control group) and 89 patients with stage pT3pN0M0 (46 in the vaccine group and 43 patients in the control group). The remaining 36 patients had positive lymph nodes. The trial was performed according to ICH-GCP guidelines. The 3-year progression-free survival rate for all tumour stages was 84.7% in the vaccine group and 80.9% in the control group. Patients with RCC stage pT3pN0-3M0 in the vaccine group demonstrated an advantage (74.4% in the vaccine group vs 65.9% in the control group). For RCC stage pT2pN0-3M0 the 3-year progression-free survival rate in the vaccine group was 89.7% compared to 85.7% in the control group. Follow-up of all patients enrolled in this trial is ongoing. This is the first randomized trial indicating a benefit from an adjuvant vaccination in patients with M0 RCC after radical nephrectomy. The advantage in terms of progression-free survival was more pronounced in patients with T3-tumours. However, it must be emphasized that the results of the final study report (2003) must be awaited before definite recommendations can be made.

Adjuvants, Immunologic↗

Studies on adjuvants for human prophylactics. II. Influence of the route of injection on the activity of adjuvants to tetanus toxoid in guinea pigs.

The effects of the route of the injection and adjuvants on the immune response of guinea pigs were investigated at various stages of immune response to tetanus toxoid. Delayed-type hypersensitivity (DH) was observed as the first immune response to the toxoid before initiation of antitoxin production. The DH reaction was weak when plain toxoid was administered subcutaneously. Water-in-oil in water (w/o/w) enhanced greatly the reactivity of the immunized animals; pertussis vaccine, endotoxin and aluminium showed adjuvanticities in this order. The foot pad (fp) injection of plain toxoid promoted remarkably the induction of DH. The reactivity was enhanced considerably by w/o/w and to a less extent by aluminium. However, pertussis vaccine showed an adverse effect on DH by the fp route. Active cutaneous anaphylaxis (ACA) induced by the subcutaneous route was enhanced by w/o/w, endotoxin, pertussis vaccine and, to a less extent, by aluminium. The fp route compared with the sc route enhanced ACA by plain toxoid; w/o/w and aluminium but not endotoxin and the vaccine showed adjuvanticities. The influences of adjuvants and the route of injection on Arthus reactions were inconsistent. The effect of adjuvants on antitoxin production was quite different from that on DH when antitoxin was produced abundantly. Aluminium showed consistently a potent adjuvanticity, but activities of w/o/w, endotoxin and pertussis vaccine were inconsistent 4-6 weeks after the primary stimulus by the subcutaneous route. The adjuvant effect became less significant in the secondary response. The fp route was more favorable for antitoxin production than the subcutaneous route with most adjuvants except pertussis vaccine added to tetanus toxoid. Antitoxin production by plain toxoid was very poor when administered intraperitoneally; aluminium and w/o/w but not endotoxin showed a remarkable adjuvanticity for the antitoxin production.

Adjuvants, Immunologic↗

Studies about the adjuvant activity of saponin fractions in foot and mouth disease vaccine. III. Comparison of the irritant, adjuvant and hemolytic activities of six commercial saponins and their hemolytic fractions obtained by chromatography on sephadex G 100.

12 experimental vaccines were prepared to compare the irritant and adjuvant activity in cattle of 6 commercial saponin preparations and their hemolytic fractions. It is still not known if a single substance is responsible for the irritant, adjuvant and hemolytic activities of the saponin preparations. The quantities of saponin added were standardised on the base of a constant hemolytic activity rather than on a weight of powder per dose of vaccine base. A FMD vaccine was used to reveal the adjuvant activity. It was concluded that the irritation is related to the hemolytic activity and not to the weight of powder. Irritation is slightly reduced when a toxic effect appears. The adjuvant activity was higher for untreated saponin preparations with high hemolytic activity used at low dose and for one of the chromatographic saponin fractions. The adjuvant activity is reduced when toxic effect appear. Toxicity of less hemolytic saponins used at high dose is removed by chromatography. Highly hemolytic saponins used at low dose become toxic after chromatographic treatment.

Adjuvants, Immunologic↗

Adjuvant arthritis: influence of the adjuvant volume and composition on the established arthritis.

Adjuvant arthritis remains an interesting model for the evaluation of therapeutic agents and for the study of inflammatory mechanisms. The severity and time course of the primary nonspecific inflammation and of the induced polyarthritis are influenced by the composition and volume of the injected adjuvant. The injection of complete adjuvant produces always an oedema which is much greater than the sum of the oedemas induced by mineral oil or mycobacteria alone. In Lewis rats, highly susceptible to adjuvant arthritis, the intensity of the induced lesions increases with the injected oil volume and for equal volumes is maximal with 500 micrograms of Mycobacterium butyricum. In the injected paw the specific immune character of the inflammation is more important when a small volume of adjuvant is used and is maximal for 500 micrograms of mycobacteria in 0.1 ml of mineral oil.

Animals↗

Granulocyte-macrophage colony-stimulating factor as adjuvant therapy for factor as adjuvant therapy for interferon alpha treatment of chronic hepatitis C.

The safety and efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy for interferon alpha (IFN-alpha) treatment has been evaluated in 20 non-cirrhotic patients with chronic hepatitis C virus (HCV) infection. Adjuvant therapy with GM-CSF plus IFN-alpha was associated with less myelosuppression than with IFN-alpha alone (P < .01), although the rate of local adverse reactions increased. GM-CSF adjuvant therapy led to a 50% biochemical response (transaminase values within the normal range at therapy end) and to reductions in HCV RNA concentrations (median HCV RNA reduction of 99%, range 8-100%), which were similarly observed in single IFN-alpha recipients (median HCV RNA reduction of 91%, range 38-100%). However, HCV RNA became undetectable in three biochemical responders to the GM-CSF adjuvant therapy, but in only one biochemical non-responder to IFN-alpha alone. The use of GM-CSF as adjuvant therapy is safe and, although it has not improved the biochemical response, it might potentiate the virologic response to IFN-alpha treatment alone.

Adult↗

Adjuvant activity of incomplete Freund's adjuvant.

The water-in-oil emulsion adjuvants developed by Jules Freund and coworkers have been, and continue to be, used in research and veterinary vaccines. Incomplete Freund's Adjuvant (IFA) has also been widely tested in humans where it was shown to augment antibody responses greater than other adjuvants, such as alum, and to be well tolerated. Toxicity associated with the use of IFA has been controlled by the use of high grade oils and purified surfactants and clinical testing is ongoing to day. One potential limitation of IFA is that it does not augment the types of cellular immune responses that thought to be critical to the control of many viral infections and tumors. However, IFA can be mixed with or used in conjunction with other adjuvant-active compounds, such as saponins and cytokines. These mixed formulations or vaccine protocols have proved successful in animal testing and may soon be tested in clinical trials. Thus, the toxicity and potential limited adjuvant activity of IFA can be controlled or corrected making IFA a useful product in the vaccine industry.

Journal Article↗

Adjuvant effects of dimethyl dioctadecyl ammonium bromide, complete Freund's adjuvant and aluminium hydroxide on neutralizing antibody, antibody-isotype and delayed-type hypersensitivity responses to Semliki Forest virus in mice.

Outbred mice were inoculated subcutaneously with inactivated Semliki Forest virus (SFV) in saline and combinations of the virus with complete Freund's adjuvant (CFA) aluminium hydroxide (Al) and dimethyl dioctadecyl ammonium bromide (DDA). The immune response was evaluated for delayed-type hypersensitivity, for total ELISA antibodies and antibody-isotypes and for neutralizing antibodies. DDA was the most efficient adjuvant in inducing DTH, CFA the second and Al induced a DTH response that was only slightly higher (statistically not significant) than that induced by the inactivated virus without adjuvants. All adjuvants enhanced the production of ELISA antibodies to similar levels. However, the levels of neutralizing antibodies induced were low in mice which were inoculated with the inactivated SFV alone or mixtures of the virus with Al. DDA induced high levels of neutralizing antibodies and CFA induced intermediate levels. The pattern of antibody-isotypes induced by DDA and CFA was different from the pattern induced by the inactivated virus or by the virus mixed with Al: DDA and CFA induced low amounts of IgG1 antibodies and relatively higher amounts of IgG2a and IgG2b antibodies while the inactivated virus and the mixture of the virus with Al induced higher proportions of IgG1 antibodies. In sera from convalescent mice the majority of antibody activity resided in the IgG2a and IgG2b immunoglobulin subclasses, while IgG1 antibodies were undetectable.

Adjuvants, Immunologic↗

Postmastectomy radiotherapy and concomitant adjuvant chemotherapy versus adjuvant chemotherapy alone in premenopausal breast cancer patients with positive axillary nodes.

AIMS: To evaluate the efficacy of postmastectomy radiotherapy (RT) combined with adjuvant chemotherapy compared to adjuvant chemotherapy alone as regards overall survival (OS), overall disease-free survival (ODFS), local disease-free survival (LDFS) and distant disease-free survival (DDFS). METHODS: We reviewed retrospectively two non-randomized groups of premenopausal high-risk breast cancer patients treated from 1985 to 1990 in the following Institutions: Department of Radiation Oncology of Brescia University, "Istituto del Radio O. Alberti" (IRA), and Department of Oncology of Brescia Hospital "Beretta Foundation" (BF). A total of 163 patients was found to satisfy the criteria of the current analysis: 81 patients received adjuvant chemotherapy alone [6 cycles CMF(1-8)] at BF and 82 patients received postoperative radiotherapy and chemotherapy [8 cycles CMF(1-21)] at IRA. A modified CMF schedule was chosen at IRA to avoid the feared increase in toxicity due to the association with RT. Primary surgical treatment was modified radical mastectomy with axillary node dissection in both cases. RESULTS: A statistically significant improvement in OS was found in systemic adjuvant therapy patients compared to those also given RT (77.6% vs 59%; P = 0.0025). No statistically significant improvement in ODFS was found in the CMF(1-8) arm compared to the RT and CMF(1-21) stm: 51.6% vs 43.6%; P = 0.46. A statistically significant improvement in LDFS at 5 years was found in irradiated patients (89.3% vs 76.2%; P <0.05). The DDFS was also improved, although without evidence of statistical significance, in the CMF(1-8) group: at 5 years 65% vs 44% (P = 0.059). CONCLUSIONS: The study confirmed that RT reduces the risk of local recurrence but without a statistically significant reduction in mortality. The lack of a survival benefit may somehow reflect the dose reduction in CMF(1-21). The evidence that CMF(1-8) offers undoubtable advantages over the CMF(1-21) regimen in OS and, perhaps, in distant control suggests that the dose intensity of CMF in this setting may also be important. In fact, although many CMF(1-8) patients received a dose intensity lower than 100%, 95% of them received a dose intensity higher than the maximum one of the CMF(1-21) patients. Although our results should be interpreted with caution, they seem to provide further rationale for testing the association of postoperative radiotherapy and the CMF(1-8) regimen in stage II breast cancer with positive nodes and treated with demolitive surgery, as already done in the conservative management of breast cancer, also in view of the new support therapies now available (i.e. hematologic growth factors).

Adult↗

Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials.

PURPOSE: Lymph node (LN) -negative breast cancer tumors > or = 5 cm occur infrequently, and their optimal management is not well defined. In this study, we assess patterns of locoregional failure (LRF) in LN-negative patients who underwent mastectomy, either with or without adjuvant chemotherapy or hormonal therapy and without postmastectomy radiation therapy (PMRT). PATIENTS AND METHODS: Of 8,878 breast cancer patients enrolled onto National Surgical Adjuvant Breast and Bowel Project B-13, B-14, B-19, B-20, and B-23 node-negative trials, 313 had tumors that were 5 cm or larger (median, 5.5 cm; range, 5.0 to 15.5 cm) at pathology and were treated by mastectomy. Median follow-up time was 15.1 years. Therapy included adjuvant chemotherapy in 34.2% of patients; tamoxifen in 21.1%; chemotherapy plus tamoxifen in 19.2%; and no systemic therapy in 25.5%. RESULTS: Twenty-eight patients experienced LRF. The overall 10-year cumulative incidences of isolated LRF, LRF with and without distant failure (DF), and DF alone as first event were 7.1%, 10.0%, and 23.6%, respectively. Cumulative incidences for isolated LRF as first event for patients with tumors of 5 cm or more than 5 cm were 7.0% and 7.2%, respectively (P = .9). For patients who underwent no systemic treatment, chemotherapy alone, tamoxifen alone, or chemotherapy plus tamoxifen, the incidences were 12.6%, 5.6%, 4.6%, and 5.3%, respectively (P = .2). The majority of failures occurred on the chest wall (24 of 28 patients). Multivariate analysis did not identify significant prognostic factors for LRF. CONCLUSION: In patients with LN-negative tumors > or = 5 cm who are treated by mastectomy with or without adjuvant systemic therapy and no PMRT, LRF as first event remains low. PMRT should not be routinely used for these patients.

Adult↗

RhinoVax is an efficient adjuvant in oral immunisation of young chickens and cholera toxin B is an effective oral primer in subcutaneous immunisation with Freund's incomplete adjuvant.

Forty-five approximately 50% in-bred 14-day-old White Leghorn female chickens (Gallus domesticus) originating from 11 hens were distributed into 5 treatment groups containing one sister in each treatment group. Phase I involved oral administration of an antigen, Bovine Serum Albumin (BSA), in combination with various adjuvant preparations, either Cholera Toxin B-subunit (CTB) and/or RhinoVax (RV). A positive control group received BSA emulsified in Freund's Incomplete Adjuvant (FIA) by subcutaneous injection. All chickens responded with immunospecific IgA, IgM and IgG antibodies in their circulation. Classical parenteral immunisation with FIA was generally the most potent mode of antigen administration. The highest immunospecific IgG concentrations recorded in the orally-immunised chickens were in the group immunised with 20% RV as the adjuvant. The concentration in this group was approximately 5 times lower than that recorded in the FIA group. For practical egg yolk polyclonal antibody production purposes, the oral regime using 20% RV as adjuvant seems an attractive alternative to the more invasive technique of injecting the antigen in FIA emulsions. In Phase 2 all chickens were subjected to traditional subcutaneous immunisation with a new antigen, human IgG emulsified in FIA. The two groups of chickens that had received CTB orally during Phase I responded with significantly higher immunospecific antibody concentrations than did the other chickens, indicating that oral administration of CTB prior to traditional parenteral immunisation may have a priming effect on the humoral immune system. The immunospecific antibody response varied between the 11 families of chickens. There was no correlation between familial responsiveness to oral and subcutaneous immunisations. Families that were high responders to oral immunisation were not high responders to parenteral immunisation and vice versa.

Adjuvants, Immunologic↗

Comparison of antibody response by use of synthetic adjuvant system and Freund complete adjuvant in rabbits.

Two commercially available synthetic adjuvant systems, trehalose dimycolate (TDM) and TDM + monophosphoryl lipid A (MPL), were compared with Freund complete adjuvant (FCA) for the ability to stimulate antibody production in New Zealand White rabbits (Oryctolagus cuniculus). In addition, each animal was evaluated for adverse reactions. The antigen, rat liver microsomal epoxide hydrolase, was administered SC emulsified with FCA, TDM, or TDM + MPL. Serum antibody titers were stimulated with all 3 adjuvant-antigen combinations. The highest titer was produced by use of FCA; TDM + MPL produced an intermediate response, and TDM produced the lowest titer. All of the rabbits immunized with FCA developed sterile subcutaneous abscesses. Rabbits immunized with TDM or TDM + MPL developed no abscesses, and only slight reactions at the injection site. The synthetic adjuvant system TDM + MPL is recommended for use in rabbits, considering its adequate stimulation of antibody production with minimal adverse reactions.

Adjuvants, Immunologic↗

The comparative selectivity of adjuvants for humoral and cell-mediated immunity. II. Effect on delayed-type hypersensitivity in the mouse and guinea pig, and cell-mediated immunity to tumour antigens in the mouse of Freund's incomplete and complete adjuvants, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin.

Corynebacterium parvum was the only adjuvant of those tested which consistently potentiated delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) in the mouse, although this required the antigen-adjuvant mixture to be injected subcutaneously in the footpad rather than the flank. For induction of DTH to ovalbumin (OVA) in the guinea pig, C. parvum and MDP could be substituted for the mycobacteria in FCA. C. parvum was effective in aqueous solution provided that the OVA was absorbed onto alhydrogel. Saponin also potentiated DTH when injected with OVA in aqueous solution. C. parvum was the sole adjuvant of those tested to promote protective cell-mediated immunity (CMI) to M4 fibrosarcoma cells. It is concluded that C. parvum is a promising candidate adjuvant for promoting CMI induction without recourse to a water-in-oil emulsion.

Acetylmuramyl-Alanyl-Isoglutamine↗

Experimental allergic encephalomyelitis induced by basic protein with synthetic adjuvant in comparison with Freund's complete adjuvant. Role of antibodies in correlation with the clinicopathological features.

Experimental allergic encephalomyelitis (EAE) was induced in guinea pigs with bovine myelin basic protein (BP) with adjuvant of either synthetic muramyl dipeptide (Mdp) or Mycobacterium tuberculosis (Tbc). The following results were obtained: (1) The body temperature of the animals was studied serially after sensitization and its elevation was shown to be an early sign of EAE. (2) Several animals developed the clinical and histological signs of hyperacute EAE. (3) An optimal combined dosage of BP and adjuvant was found for induction of clinical EAE and for the the production of complement fixing (CF) antibodies. (4) Little passive hemagglutinating (PH) antibody was produced by single immunization. These results displayed no essential difference in EAE induced by either adjuvant. (5) Detectable PH antibodies developed later in addition to CF antibodies in a few animals immunized with Tbc adjuvant. These animals were skin-tested to BP, and had recovered from body weight loss or limb weakness. The results suggest that humoral antibodies play a role in modifying the disease process, even if they are not essential in production of EAE.

Acetylmuramyl-Alanyl-Isoglutamine↗

Effects of immunological adjuvants on the mouse complement system. I. The inability of the polyanion heparin to act as an adjuvant is paralleled by inefficient alternative complement pathway inhibition.

Interference with hemolytic complement activity by polyanionic substances was studied in relation to the ability of these compounds to act as an adjuvant for a dead listeria vaccine. Heparin appeared a poor inhibitor of the mouse alternative pathway not only in contrast to its effects on the mouse classical and the human classical and alternative pathways, but also when compared to two polyanions with known adjuvant activity: dextran sulfate and suramin. For the three polyanions mentioned a correlation between adjuvant activity and mouse alternative pathway inhibition was observed. These findings suggest a possible causal relationship between interference with alternative complement pathway activation and adjuvant activity.

Adjuvants, Immunologic↗

Adjuvant activity of iscoms; effect of ratio and co-incorporation of antigen and adjuvant.

We have studied the importance of co-incorporation of antigen and adjuvant in iscoms and the effects of different ratios of adjuvant and antigen in the iscom particles. Immune responses to influenza virus antigens (flu-Ag) in iscoms were compared to those induced by flu-Ag mixed with iscom-matrix, i.e. antigen and adjuvant delivered in separate packages. Higher doses of Quil A were required with iscom-matrix to induce strong immune responses compared to iscoms containing the same amount of antigen. The immunogenic properties of iscoms were affected by the ratio between antigen and adjuvant in the particles. Both iscoms and flu-Ag mixed with iscom-matrix induced antigen-specific antibodies with similar IgG subclass distribution and activated spleen cells producing high levels of IL-2 and IFN-gamma in vitro.

Adjuvants, Immunologic↗

Prevaccination with diluted Freund adjuvant prevents the development of chronic pain and transient release of cerebrospinal fluid substance P in adjuvant-induced arthritis in rats.

Parallel time courses of preclinical and behavioural pain-related parameters and levels of substance P-like immunoreactivity in plasma (plasma-SPLI) and cerebrospinal fluid (CSF-SPLI) were studied in 2 groups of rats injected with an arthritogenic solution (concentrated Freund adjuvant) over a 9-week post-infection (PI) period; 1 group was pretreated with saline (control) and 1 pretreated with diluted Freund adjuvant (immunized). In control rats all symptoms of adjuvant-induced arthritis (AIA) developed while in immunized rats AIA symptoms were significantly reduced or did not appear. A significant increase in plasma-SPLI was obvious as early as the 2nd week PI and remained at this level in both groups of animals until the end of the 9-week PI observation period, but with a significantly higher increase in control versus immunized group at all stages. In contrast, CSF-SPLI transiently peaked only in the control group at 3 weeks PI whereas CSF-SPLI values did not differ from one week to another in both groups of rats. These results suggest that successive injections of diluted Freund adjuvant impairs the development of chronic inflammation and pain in AIA in rats, as well as the transient increase in SP release in CSF at 3 weeks PI, but not the long-lasting increased SP release in plasma. Since there is a clear dissociation between our biochemical and preclinical and behavioral data, this study does not provide evidence for the role of substance P as a possible biologic marker of chronic pain either in plasma or in CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

ISCOMATRIX adjuvant: an adjuvant suitable for use in anticancer vaccines.

Human Papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are associated with cervical cancer development and progression and can therefore be used as target antigens for cancer immunotherapy. In this study we evaluated the immunogenicity in mice, of different vaccine formulations using recombinant HPV16 derived E6E7 or E7GST fusion proteins. When co-administered with ISCOMATRIX adjuvant, these E6E7 proteins consistently induced E7 specific CTL, in vivo tumor protection, antibody and DTH responses. ISCOMATRIX adjuvant has been developed for use in the formulation of novel human vaccines and has been evaluated for safety and toxicity in human trials. A formulation containing aluminum hydroxide (Al(OH)3) gave a lesser degree of E7 specific antibody, and no local E7 specific CTL response but similar DTH and tumor protection. These findings demonstrate the potential of ISCOMATRIX adjuvant to stimulate both cellular and humoral immune responses to endogenously processed target antigens, and hence is the preferred adjuvant when CTL responses are desirable.

Adjuvants, Immunologic↗

Is the pretreatment effect of low dose Freund's adjuvant on adjuvant arthritis due to an activation of the nervous system?

It has been recently shown that pretreatment with a low dose of Freund's adjuvant decreases the severity of adjuvant arthritis in rats. To study the involvement of the central and peripheral nervous systems in the pretreatment effect, concentrations of substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivities (-LI) were measured in the cerebrospinal fluid, plasma and synovial fluid 2 and 24 h after a single s.c. injection of 0.05 mg Freund's adjuvant. Increased concentrations of CGRP-LI were found in the cerebrospinal fluid, plasma and synovial fluid. NPY-LI was decreased in the cerebrospinal fluid while NKA-LI was decreased in plasma. In the synovial fluid, SP-LI was increased at 24 h and NKA-LI was increased at 2 h following treatment. Our results indicate that part of pretreatment effect of low dose of subcutaneous Freund's adjuvant in the rat may be attributed to neurogenic mechanisms.

Animals↗