Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Immunotherapy with an alum-adsorbed Parietaria-pollen allergoid: a 2-year, double-blind, placebo-controlled study. Aggressive coseasonal immunotherapy in mountain cedar pollen allergy. Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite. CONSORT adoption and quality of reporting of randomized controlled trials: a systematic analysis in two dermatology journals. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer. Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise. Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial. Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial. Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II). Effect of allergen specific immunotherapy (IT) on natural killer cell activity (NK), IgE, IFN-gamma levels and clinical response in patients with allergic rhinitis and asthma. Early effects of rush immunotherapy with Dermatophagoides pteronyssinus in asthmatics. Allergen-specific immunotherapy with recombinant grass pollen allergens. Safety and immunological changes during sublingual immunotherapy with standardized quality grass allergen tablets. Controlled evaluation of allergoid in the immunotherapy of ragweed hay fever. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Cellular and humoral responses after multiple injections of unconjugated chimeric monoclonal antibody MOv18 in ovarian cancer patients: a pilot study. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: a single-blinded, randomized, and controlled trial. Functional mimicry of an anti-idiotypic antibody to nominal antigen on cellular response. Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae results in decreased bronchial hyperreactivity. Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species. II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Regulation of the human immune response to ragweed pollen by immunotherapy. A controlled trial comparing the effect of immunosuppressive peptic fragments of short ragweed with standard treatment. Double-blind placebo-controlled study of sublingual immunotherapy with house dust mite extract (D.pt.) in children.
Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen. NY-ESO-1 is a "cancer-testis" antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO(157-170), is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO(157-170) mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO(157-170) epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC. A double-blind, placebo-controlled study was performed in order to confirm the safety, suitability, and efficacy of an alum-adsorbed Parietaria judaica-pollen allergoid, Allergovit, for allergen-specific immunotherapy. Parietaria pollen is an important cause of pollinosis, particularly in the Mediterranean zone, where it may be encountered for up to 8-9 months of the year. It is an aggressive allergen, and the doses tolerated during immunotherapy are less than those achieved with grass pollen. This factor increases the desirability of using therapeutic preparations with minimal IgE-binding activity, such as allergoids, in order to reduce the risk of side-effects and enable patients to tolerate a higher dose of allergen, thereby increasing the chances of successful specific immunotherapy. Forty patients with rhinitis and/or asthma were allocated at random to active- or placebo-treatment groups at the beginning of the study. All patients received the active preparation during the second year of the study. Immunotherapy was well tolerated by all patients and the incidence of side-effects was low. Treatment resulted in significant reductions in specific cutaneous reactivity and increases in nasal tolerance. A progressive improvement in nasal inspiratory peak flow in association with the immunotherapy indicated a reduction in nasal inflammation. These objective assessments of efficacy endorsed the results from the patients' diary cards, which indicated significant improvements in symptoms and reductions in the use of medication. The immunologic activity of the therapeutic preparation was demonstrated by the induction of a significant specific-IgG antibody response, with increases in IgG4 during the second year of treatment. We conclude that the safety and efficacy of immunotherapy with the Parietaria allergoid make it suitable for consideration in the treatment of patients with Parietaria-pollen-induced rhinitis or asthma. Ninety adults with "mountain cedar" pollen allergy were started on coseasonal immunotherapy regimens in December 1979. At season's end, there were 20 whose starting antigen dose was based on serial dilution end point titration (SDET), 1:2,500 or 1:12,500 weight by volume (w/v); 28 in a "traditional" group started at 1:62,500 w/v; and 28 who had been double-blind placebo control subjects. Injections twice weekly were pushed aggressively toward maintenance. The SDET group received 11 times more antigen than the traditional group; both showed a trend for fewer symptoms than the placebo group. As compared with the other groups, SDET subjects had substantially blunted total and specific IgE responses in season, lower specific IgE level at season's end and less shift of skin end point toward higher dilutions. The findings demonstrate that substantial immunologic effects are possible in the first months of aggressive coseasonal immunotherapy. Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown.
                A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance.
                After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines.
                The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine.
                These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM. CONSORT (Consolidated Standards for Reporting Trials) guidelines were constructed to ensure optimal reporting quality of randomized controlled trials (RCTs).
                To determine the effect of the adoption of CONSORT on the reporting quality of RCTs, we performed a systematic evaluation of RCTs published in two dermatology journals pre- and post-CONSORT adoption.
                The journals selected for the study were the Journal of the American Academy of Dermatology and the British Journal of Dermatology. We selected RCTs published in 1997 and 2006 using both Medline and hand searching. The following critical CONSORT criteria were recorded: sample size, type of disease studied, type of control, single-centre or multicentre study, type of funding, blinding, methods and type of randomization, definition of a primary endpoint, justification for sample size selection and power calculation, population for analysis, and adequacy of group comparison. A multivariable analysis was conducted to determine factors associated with optimal reporting quality.
                In total, 98 studies were included. Improvement in reporting quality was evident for the specification of the randomization method (20% in 1997 vs. 45% in 2006, P < 0.01) and for the justification of sample size (22% in 1997 vs. 43% in 2006, P = 0.027). The percentage of studies with optimal reporting quality increased from 11% in 1997 to 28% in 2006 (P = 0.03). Factors significantly associated with a good methodological quality were pharmaceutical industry funding and publication in 2006 vs. 1997.
                There is a need to improve the reporting quality of RCTs published in dermatology journals. Immunotherapy with the SQ-standardized grass tablet Grazax is efficacious and well-tolerated in adult patients with rhinoconjunctivitis. Allergic asthma and rhinoconjunctivitis are closely linked, and a strategy combining treatment of the upper and lower airways is recommended.
                To investigate the efficacy of treatment with the grass tablet on grass pollen-induced rhinoconjunctivitis and asthma as well as the immunologic response and the safety profile in children.
                A total of 253 children age 5 to 16 years, with grass pollen-induced rhinoconjunctivitis with/without asthma, were randomized 1:1 to active treatment or placebo. Treatment was initiated 8 to 23 weeks before the start of the grass pollen season 2007 and continued throughout the entire season. Symptomatic medication was provided as relief medication to both groups in a stepwise fashion. Primary endpoints were rhinoconjunctivitis symptom and medication scores.
                The rhinoconjunctivitis symptom and medication scores and the asthma symptom score were all statistically significantly different between the 2 treatment groups. The differences in medians relative to placebo were 24%, 34%, and 64% in favor of active treatment. The immunologic response was similar to that observed in adults. The most common adverse reaction was oral pruritus, reported by 40 subjects (32%) in the active and 3 (2%) in the placebo group. Six subjects withdrew because of adverse events. No serious adverse events were assessed as treatment-related.
                Immunotherapy with the grass tablet reduced grass pollen-induced rhinoconjunctivitis and asthma symptoms in a pediatric population and introduced an immunomodulatory response, consistent with treatment of the underlying allergic disease. The treatment was well tolerated. We evaluated the therapeutic efficiency of the murine monoclonal antibody-B43.13 in the treatment of patients with recurrent ovarian cancer.
                This was a retrospective study of immune responses and survival in 44 patients who were treated with technetium 99m-labeled monoclonal antibody-B43.13, a murine monoclonal antibody that is directed against the tumor-associated antigen CA125. Most patients were pretreated heavily. Biologic activity was quantified by the assay of immune responses to the human anti-murine antibodies against the monoclonal antibody-B43.13 variable region (Ab(2)) and antibodies that target the CA 125 antigen itself (anti-CA 125 antibody).
                More than one half of patients (56.8%) survived for >12 months after the first dose of monoclonal antibody B43.13; 34.1% of the patients survived >24 months. To date, 6 of the 44 patients are alive, with survival times of 4 to 7.5 years after the start of the antibody treatment. More than 60% of the evaluable patients met predefined criteria for robust, treatment-emergent human anti-murine antibodies and Ab(2) responses, and these responses were associated with improved survival rates. Median survival time increased approximately 3-fold for human anti-murine antibody responders (22.6 months) versus nonresponders (7.2 months; P <.0016, log-rank test) and 2-fold for Ab(2) responders (18.3 months) versus nonresponders (9.3 months). No serious drug-associated adverse events were reported.
                The associations between multiple types of immune response and improved clinical outcomes suggest that monoclonal antibody-B43.13 should be further evaluated for potential use as an immunotherapy for CA125-expressing malignancies. We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients. The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.
                (c) 2009 UICC. The local (noninjection) routes of immunotherapy are presently regarded as viable therapeutic options for respiratory allergy, and their mechanisms of action are currently undergoing investigation.
                We evaluated the clinical efficacy of a preseasonal rush sublingual-swallow immunotherapy and its effects on allergic inflammation in patients with seasonal rhinoconjunctivitis caused by Parietaria species.
                Thirty patients with Parietaria species-induced rhinoconjunctivitis (13 with mild intermittent asthma) were randomly assigned sublingual-swallow immunotherapy or placebo in a rush preseasonal course. We assessed the seasonal symptom-drug intake score by diary card and the inflammatory infiltration and the intercellular adhesion molecule 1 expression on nasal epithelium after specific allergenic challenge before and after treatment.
                The investigated immunotherapy was well tolerated, and no side effects were recorded. A significant reduction of the symptom score (P =.016) and drug intake score (P =. 008) after immunotherapy was observed only in the active group. A decrease of the cumulative score was observed also in the placebo group (P =.046), but the significance was clearly higher (P =.006) in the active group. In the active group a reduction of neutrophils (P =.001), eosinophils (P =.01), and intercellular adhesion molecule 1 expression (P =.04) after specific nasal challenge was also detected.
                The present results suggest that this sublingual-swallow immunotherapy administered through a rush schedule is clinically effective and safe and that it decreases the immune-mediated inflammatory responses to the allergen. A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity.
                Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses.
                In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1') and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred.
                Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated. Allergen specific immunotherapy (IT) has been widely used for many years as a specific treatment of allergic diseases. A variety of changes in immunological parameters have been described but it still remains uncertain as to which of them is responsible for the improvement of symptoms. The aim of our study was to evaluate the effect of IT on natural killer (NK) cell activity, IL-4, IFN-gamma, IgE levels and skin test reactivity in addition to clinical efficacy. Thirty-one patients with allergic rhinitis and asthma were selected according to positive history, skin prick tests to Dermatophagoides pteronyssinus (Der p) or grass pollens, presence of specific IgE antibodies in sera and clinical findings, and were submitted to one year of placebo-controlled IT. Total IgE, specific IgE, IL-4 and IFN-gamma levels were measured by using ELISA method. Standard chromium 51 release assay was used to measure NK cell cytotoxic activity against the human leukemic cell line, K562 target cells. Mean symptom and medication scores, skin test reactivity and histamine sensitivity were significantly decreased in the patients given IT at the end of the first year when compared with the placebo group. However, there was neither a significant reduction in total and specific IgE levels nor a significant increase in IFN-gamma levels at the first year of IT. IL-4 levels were only measured at the beginning of the study because of the very low levels. A decrease in NK cell activity was found in patients treated with grass pollen extracts after 12 months when compared with Der p and placebo group. No signs of major local or systemic side effects due to IT were seen in patients during the study. Although significant clinical efficacy of specific IT with standardized extracts has been demonstrated in allergic rhinitis and asthmatic patients at the end of the first year of IT, no significant changes in immunological parameters were observed. However we conclude that a decrease in NK cell cytotoxic activity during IT has to be taken into account in the follow-up of patients. In this study we assessed the effects of Dermatophagoides pteronyssinus (Dpt) rush immunotherapy in comparison with placebo treatment in our asthmatic patients. Fourteen highly Dpt-susceptible adults were randomized in two groups (immunotherapy and placebo) and treated in single-blind manner. Patients were selected according to the recommendation of the immunotherapy position paper (1993). To minimize side effects we modified the protocol by adjusting allergen doses for each patient separately. Immunologic (total and Dpt-specific serum IgE and IgG antibodies/EIA, Pharmacia) and clinical parameters (spirometry, medication score and skin testing) were recorded before treatment, after 2 weeks, at the second month and after 4 months of immunotherapy onset. None of the patients had life-threatening side effects in the course of the treatment. The results obtained demonstrated significant influence of immunotherapy on Dpt-specific serum IgG synthesis (Kruskal Wallis test, p < 0.05) and on the late phase skin reaction with Dpt (U-test, p < 0.05) at the end of the second month of immunotherapy onset. In the immunotherapy group, we also registered a negative correlation between concentrations of Dpt-specific serum IgE and IgG antibodies (p = -0.83; p < 0.05), at the end of the second month. In addition, diversities among patients, expressed by immunologic parameters, were related to the amount of delivered allergen. There were no significant differences between groups concerning medication score from opposite to better FEV, PEFR and dPEFR results (Kruskal Wallis, p < 0.05) in the placebo group. In conclusion, Dpt-specific serum IgG concentration, immunologic score and late phase skin reactivity to allergen appeared to be the valid parameters of rush-immunotherapy achievement, while delivered allergen dose also seemed to be an influencing factor. Allergen-specific immunotherapy uses aqueous extracts of natural source materials as a basis for preparations to down regulate the allergic response. Recombinant DNA technology has enabled the cloning of many allergens, thus facilitating investigations aimed at improving efficacy and safety of immunotherapy.
                To determine the effectiveness of a mixture of 5 recombinant grass pollen allergens in reducing symptoms and need for symptomatic medication in patients allergic to grass pollen.
                A randomized, double-blind, placebo-controlled study of subcutaneous injection immunotherapy was performed in subjects with allergic rhinoconjunctivitis, with or without asthma. Primary endpoint was a symptom medication score compiled from separate symptom and medication scores. Secondary endpoints included a rhinitis quality of life questionnaire, conjunctival provocation, and specific antibody responses.
                The symptom medication score showed significant improvements in subjects receiving recombinant allergens as opposed to placebo, with reductions in both symptoms and medication usage. The rhinitis quality of life questionnaire revealed clinically relevant significant improvements in overall assessment and in 5 of 7 separate domains, and conjunctival provocation showed a clear trend in favor of active treatment. All treated subjects developed strong allergen-specific IgG(1) and IgG(4) antibody responses. Some patients were not sensitized to Ph l p 5 but nevertheless developed strong IgG antibody responses to that allergen.
                A recombinant allergen vaccine can be a effective and safe treatment to ameliorate symptoms of allergic rhinitis. The clinical benefit is associated with modification of the specific immune response with promotion of IgG(4) and reduction of IgE antibodies consistent with the induction of IL-10-producing regulatory T cells. Immunotherapy is the only treatment for allergy that has the potential to alter the natural course of the disease. Sublingual immunotherapy for grass pollen-induced rhinoconjunctivitis has been developed to make immunotherapy available to a broader group of allergic patients. Here, a safe dose range and the safety during daily sublingual administration were investigated for a new tablet-based sublingual immunotherapy for grass pollen allergy. Simultaneously, immunological changes were monitored. A randomized, double-blind, placebo-controlled phase I trial was undertaken, with stepwise dose-escalation during the dose-finding period, and afterwards with daily dosing 8 weeks prior to and 15 weeks during the grass pollen season (2500, 25000, or 75000 standardized quality tablet [SQ-T] units, or placebo). Fifty-two participants with grass pollen-induced rhinoconjunctivitis and a positive skin prick test and specific IgE to Phleum pratense entered the trial. During the daily-dose treatment periods, 67% of the participants reported adverse events. The most frequent were itching in the mouth, eyes, or throat, and rhinitis, and most were mild and resolved within 1 day. Two participants withdrew due to adverse events (sting and blisters in the mouth and itching in the mouth). Time- and dose-dependent increases of P pratense-specific IgG, IgA, IgE, and IgE-competing components were found in serum during the first 8 weeks of daily dosing, indicating that the treatment had a significant allergen-specific effect on the immune system. In conclusion, the grass allergen tablet, administered in a dose of 75000 SQ-T once daily, was well tolerated and displayed systemic immunogenicity. Immunotherapy with ragweed allergoid administered in a clustered regimen, placebos in a clustered regimen, and unaltered ragweed extract (allergen) in a weekly regimen were compared in three groups of hay fever patients carefully matched for ragweed sensitivity. The allergoid and placebo comparison was performed double-blind and the unaltered ragweed extract comparison was single-blind. In terms of antigen E (AgE) equivalents, doses were about 50 times higher in the allergoid-treated group than in the allergen-treated group. Whereas there was no immunologic response to placebos, the allergoid regimen produced a more rapid serum IgG antibody response, with significantly higher posttreatment levels than those in the allergen regimen. Initial IgE antibody rises and subsequent slow declines were similar. Symptom-medication scores were similar in the two specifically treated groups and significantly less than scores reported by the placebo group (p less than 0.01). Due to an overestimate of the initial allergoid doses, systemic reactions occurred mostly in the early visits with allergoid treatment, whereas systemic reactions appeared late in the allergen treatment. The overall incidence was similar. In a second year, after 8 mo of no injections, a preseasonal booster regimen with both materials produced virtually no untoward reactions. During the period of no injections, IgG antibody declines were modest and, after boosters, IgG antibody levels rose promptly. Clinical results in both groups were again excellent, with an advantage for allergoid. Postsurgical recurrence of hepatocellular carcinoma (HCC) is frequent and fatal. Adoptive immunotherapy is active against HCC. We assessed whether postoperative immunotherapy could lower the frequency of recurrence.
                Between 1992 and 1995, we did a randomised trial in which 150 patients who had undergone curative resection for HCC were assigned adoptive immunotherapy (n=76) or no adjuvant treatment (n=74). Autologous lymphocytes activated vitro with recombinant interleukin-2 and antibody to CD3 were infused five times during the first 6 months. Primary endpoints were time to first recurrence and recurrence-free survival and analyses were by intention to treat.
                76 patients received 370 (97%) of 380 scheduled lymphocyte infusions (mean cell number per patient 7.1x10(10) [SD 2.1]; CD3 and HLA-DR cells 78% [16]), and none had grade 3 or 4 adverse events. After a median follow-up of 4.4 years (range 0.2-6.7), adoptive immunotherapy decreased the frequency of recurrence by 18% compared with controls (45 [59%] vs 57 [77%]) [corrected] patients. Time to first recurrence in the immunotherapy group was significantly longer than that in the control group (48% [37-59] vs 33% [22-43] at 3 years, 38% [22-54] vs 22% [11-34] at 5 years; p=0.008). The immunotherapy group had significantly longer recurrence-free survival (p=0.01) and disease-specific survival (p=0.04) than the control group. Overall survival did not differ significantly between groups (p=0.09).
                Adoptive immunotherapy is a safe, feasible treatment that can lower recurrence and improve recurrence-free outcomes after surgery for HCC. Vaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu- or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-gamma staining and (51)Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu-derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines. Chimeric antibody MOv18 (c-MOv18) mediates antibody-dependent cellular cytotoxicity (ADCC) in vitro. To study the toxicity of c-MOv18 and its immunological effects, five ovarian cancer patients received intravenous injections for 4 weeks.
                ADCC activity of c-MOv18 was tested in a (51)Cr-release assay using IGROV1 and KB cells. Patients' peripheral blood mononuclear cells (PBMC) were phenotyped for CD3, CD4, CD8, and CD25 by FACS analysis and tested for T-cell proliferation in vitro in the presence of c-MOv18 with and without IL-2.
                Toxicity was mild and transient. No human anti-chimeric antibodies were found. Increased ADCC levels corresponding with a slight increase in CD4+ and CD8+ fractions were observed after the first injection, while the CD4/CD8 ratio and the levels of CD25 remained unchanged. c-MOv18 did not have a mitogenic effect on patients' PBMC and adding IL-2 did not change the degree of proliferation. In three patients stable disease was achieved for up to 4 months, 9 months and 14 months, respectively.
                Immunotherapy aiming at the patient's immunological capacity has minor effects in ovarian cancer patients that have been heavily pretreated with chemotherapy. Such strategies should be evaluated in patients who are more immunocompetent, i.e., before excessive chemotherapy and after achieving microscopic or small volume disease. Warts occur commonly in humans. Destructive modalities are generally the first physician-administered therapy. Other treatment options include immunotherapy. Intralesional immunotherapy using mumps, Candida, or Trichophyton skin test antigens has proved efficacy in the treatment of warts.
                To determine rates of wart resolution in response to injection of antigen alone, antigen plus interferon alfa-2b, interferon alfa-2b alone, and normal saline; and to compare response according to viral type, major histocompatibility complex antigens, and peripheral blood mononuclear cell proliferation to autologous human papillomavirus antigen before and after injection.
                Randomized, single-blinded, placebo-controlled, clinical trial.
                Medical school-based dermatology department.
                Two hundred thirty-three patients clinically diagnosed as having 1 or more warts. Main Outcome Measure Clinical resolution of warts in response to intralesional immunotherapy.
                Responders were observed in all treatment arms, but were significantly more likely to have received antigen (P<.001). Resolution of distant untreated warts was observed, and was significantly more likely in subjects receiving antigen (P<.001). Interferon did not significantly enhance the response rate (P = .20) and did not differ from normal saline (P = .65). No viral type or major histocompatibility complex antigen correlated with response or lack of response (P>.99 and P = .86, respectively). A positive peripheral blood mononuclear cell proliferation assay result (2 times pretreatment levels) was significantly more likely among responders (P = .002). While there was no significant difference in response based on sex (P = .56), older subjects (>40 years) were less likely to respond (P = .01).
                Intralesional immunotherapy using injection of Candida, mumps, or Trichophyton skin test antigens is an effective treatment for warts, as indicated by significantly higher response rates and distant response rates in subjects receiving antigen. Viral type and major histocompatibility complex antigens did not seem to influence treatment response. Response is accompanied by proliferation of peripheral blood mononuclear cells to human papillomavirus antigens, suggesting that a human papillomavirus-directed cell-mediated immune response plays a role in wart resolution. One concept for immune therapy of cancer involves induction of antigen mimic antibodies to trigger the immune system into a response against the tumor cells. Anti-idiotypic antibodies (Ab2) directed against the antigen-combining site of other antibodies (Ab1) may functionally and even structurally mimic antigen and induce anti-anti-idiotypic immune response. We report here the generation of murine monoclonal antibody (mAb) WJ02 (Ab2) raised against the murine monoclonal immunoglobulin MJ01 (Ab1), which defines ovarian cancer antigen CA125. In enzyme immunoassays the binding of Ab2 to the variable region of Ab1 could be inhibited by CA125. In addition, the mimicry of mAb WJ02 to CA125 on cellular immune response was detected by human peripheral blood cells. The T cells primed by mAb WJ02 or CA125 proliferated in the presence of CA125 or mAb WJ02, respectively. Furthermore, T cells specific to mAb WJ02 could lyse ovarian cancer cells OVCAR-3 that express CA125. Finally, we proved that a patient immunized with mAb MJ01 could induce T cells that recognize mAb WJ02. In summary, we conclude that mAb WJ02 mimics CA125 on cellular response and such functional mimicry is one of the most important criteria to select Ab2 for cancer therapy. To evaluate the tolerability and efficacy of specific immunotherapy with mite extracts, we performed a double-blind, placebo-controlled immunotherapy study in 30 patients with proven allergy to mite allergens. The specific immunotherapy with standardized extracts of Dermatophagoides pteronyssinus and D. farinae by a clustered rush protocol was well tolerated. After 1 year of treatment, the actively treated group showed a significant improvement compared to their starting value as well as to the placebo-treated patients with regard to skin prick test, conjunctival provocation test, and subjective rhinitis score. The subjective asthma score and bronchial hyperreactivity, measured by the methacholine provocation test, was improved in comparison to the starting value, but not to the placebo group, after 12 months. However, a further, open comparison of the placebo- and verum-treated groups at 18 months revealed a significant reduction. The drug intake was not increased in the verum-treated group. Exposure to mite levels was constant throughout this time period, as revealed by antigen measurement. We conclude that specific immunotherapy in perennial, mite-allergen-induced asthma may reduce not only immediate, IgE-mediated symptoms but, after a rather long time period of 12-18 months, also the inflammatory component of bronchial asthma, thus leading to a reduction of unspecific hyperreactivity. The IgE response of patients only allergic to grass pollens differs from response of patients allergic to multiple-pollen species. The IgE immunoblots to orchard-grass pollens confirmed that polysensitized patients had more proteins revealed than patients only allergic to grass pollens. To determine if both groups of patients present a different response toward specific immunotherapy (IT), a double-blind, placebo-controlled study was performed in 70 patients. Patients receiving the active treatment had a rush IT with either a standardized orchard grass-pollen extract or with a standardized mixed-pollen extract prepared, depending on the sensitivity of the patients. The maintenance dose was defined as that dose effective in grass-pollen IT in previous experiments. The same equipotent maintenance dose was administered for all pollen species. Symptom-medication scores during the pollen season and nasal challenge with orchard grass-pollen grains demonstrated that grass pollen-allergic patients had a significantly improved efficacy by comparison to placebo treatment, whereas polysensitized patients had a nonsignificant improvement. Serum grass-pollen IgG was significantly increased after IT in both treated groups. This study demonstrate that the response toward specific IT differs in patients only allergic to grass pollens by comparison to polysensitized patients. Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points.
                We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination.
                The vaccine was well tolerated. Apart from injection-site reaction, no grade > or =2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis.
                This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. A new allergenic preparation consisting of peptic fragments of short ragweed has been tested for its clinical effectiveness. Such enzymatically derived fragments have been shown in prior murine studies to retain the T epitopes of the original allergen but to have a severe reduction in the number of B epitopes. Three groups of ragweed hayfever patients were placed on pre-seasonal immunotherapy. One group received a conventional ragweed preparation that had been enriched for antigen E (Amb a I), designated as Pool 2. The second group was given fragments of Pool 2 (fSRW) prepared by peptic digestion and the third group was injected with histamine as a placebo. Groups treated with the fSRW and Pool 2 had significantly reduced symptom-medication scores compared with the placebo-treatment group. However, fSRW-treated patients fared significantly better than Pool 2 patients (P less than 0.02). fSRW injections caused a significant rise in preseasonal specific IgG, antibodies as well as suppression of the seasonal anamnestic specific IgE increase. Similar, but not quite as marked changes occurred with Pool 2 treatment. fSRW was well tolerated and non-toxic. Thus, allergen modification by enzymatic degradation, as demonstrated here, appears to be a promising new approach for allergen immunotherapy. Safety and efficacy of sublingual (sublingual-swallow) immunotherapy (IT) with house dust mite extract were evaluated in 30 children (6-15 2/3 years of age) over the first 12 months of an ongoing study. The cumulative dose was 570 micrograms Der p I (five times that administered with subcutaneous therapy). Safety: One patient on active treatment dropped out after 8 weeks because of a subjective feeling of severe weakness, questionably induced by the therapy. Five patients on active therapy and one patient on placebo reported minor local side effects. Efficacy: Pulmonary symptoms were reduced after 12 months in actively treated asthmatics, but this was not consistent with the lack of improvement in bronchial reactivity, skin sensitivity and specific IgG and IgG4 against D.pt. in this group. In patients with rhinitis nasal sensitivity was reduced in the placebo group without concomitant improvement in the nasal symptom score. Specific IgE (D.pt. and D.f.) increased significantly more in the active treatment group after 3 and 12 months. We conclude that sublingual IT over 12 months with the fivefold Der p 1 dose of subcutaneous IT was well tolerated, but there was no consistent clinical or immunological benefit compared to placebo.
We conclude that despite promising immunological responses no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Furthermore, the adoption of guidelines to ensure uniformity in trial conduct, response definitions and trial reporting is recommended to improve quality and comparability of immunotherapy trials.