RESUMEN
The purpose of this study was to evaluate the toxicity and potential efficacy of administering the THERATOPE STn-KLH cancer vaccine to ovarian and breast cancer patients after an autologous stem cell transplant. Forty patients (11 high-risk stage II/III breast cancer, 22 stage IV breast cancer, and seven stage III/IV ovarian cancer patients) were treated with high-dose chemotherapy followed by autologous/syngeneic stem cell rescue and vaccination with THERATOPE STn-KLH (Sialyl-Tn-KLH with Detox-B Stable Emulsion). Each patient was scheduled to receive a total of five vaccinations beginning on days 30-151 after stem cell infusion. The vaccine was well tolerated. Induration and erythema at the site of injection were the most common side-effects. When one compares the outcome of patients vaccinated with 66 breast and ovarian cancer patients who were not, following risk-adjustment analysis, vaccinated patients appeared more likely to survive (P = 0.07) and less likely to relapse (P = 0. 10). Vaccinated patients with the greatest specific lytic activity against STn+OVCAR tumor cells relative to nonspecific killing of Daudi cells tended to remain in remission longer than patients who displayed less specific immune activity (P = 0.057). We conclude that the THERATOPE STn-KLH cancer vaccine is well tolerated in breast and ovarian cancer patients after autologous transplant and, while not statistically significant, the trends in data support the concept that THERATOPE vaccine may decrease the risk for relapse and death and thus warrants further study. Bone Marrow Transplantation (2000) 25, 1233-1241.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Hemocianinas/administración & dosificación , Neoplasias Ováricas/terapia , Adulto , Neoplasias de la Mama/patología , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Trasplante Autólogo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Hemocianinas/inmunología , Neoplasias Ováricas/terapia , Linfocitos T/inmunología , Antígenos de Carbohidratos Asociados a Tumores/administración & dosificación , Antígenos de Carbohidratos Asociados a Tumores/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Trasplante de Células Madre Hematopoyéticas , Hemocianinas/administración & dosificación , Hemocianinas/uso terapéutico , Humanos , Inmunoglobulinas/sangre , Inmunoterapia , Interferón gamma/biosíntesis , Interleucina-2/farmacología , Activación de Linfocitos/efectos de los fármacos , Mucinas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Células Tumorales CultivadasRESUMEN
Sixteen metastatic breast cancer patients were immunized with a low dose (5 micrograms) of a 16 amino acid MUC1 peptide (GVTSAPDTRPAPGSTA) conjugated to KLH (BP16-KLH) plus DETOX adjuvant and evaluated for antibody titers against MUC1 peptide and KLH and for cytotoxic lymphocyte (CTL) activity using class 1 HLA-matched MUC1-positive tumor targets. All patients generated strong anti-KLH IgG responses. Only 3 patients developed an anti-MUC1 IgG response, which was weak in magnitude. As it is controversial whether human cancer patients generate class-1-restricted CTL against MUC1, we examined anti-MUC1 CTL activity of PBLs following 4 immunizations with BP16-KLH. The generation of MUC1-specific CTLs required only a 6-day in vitro stimulation of patients' T-cells with synthetic MUC1-peptide-pulsed autologous APCs. The assay for CTL activity was a 4 hour 51Cr release from labeled adenocarcinoma target cells. Eleven of the 16 immunized patients were tested for CTL activity using class-1-matched adenocarcinoma target cell lines. Evidence for class-1-restricted killing of MUC1-expressing tumor cell lines was obtained in 7 of these 11 patients.
Asunto(s)
Neoplasias de la Mama/inmunología , Antígenos de Histocompatibilidad Clase I/fisiología , Mucina-1/inmunología , Linfocitos T Citotóxicos/fisiología , Femenino , Humanos , Inmunización , Inmunoglobulina G/sangre , Metástasis de la NeoplasiaRESUMEN
UNLABELLED: PURPOSE. This article reports the pharmacokinetics, radiation dosimetry and radioimmunoscintigraphy (RIS) of two (99m)Tc-labelled monoclonal antibodies (MAb) used to detect cancer. METHODS: The effects of circulating antigen in female cancer patients are explored and their effects on the ability of these MAbs to effectively perform as RIS agents noted. To illustrate the effects of circulating antigen, data using MAb B43.13 (OVAREX, AltaRex Corp., Waltham, MA, USA) from a Pilot study in ovarian cancer patients are presented. The results from a Phase II study of MAb 170H.82 (Tru-Scint AD, BIOMIRA INC., Edmonton, Alberta, Canada) in patients with primary and locally recurrent breast cancer were used to portray the biodistribution patterns when no circulating antigen is present. Data from planar gamma camera images were obtained for both groups and used for pharmacokinetic and radiation dosimetry analyses. RESULTS: A pharmacokinetic analysis indicated a shorter residence time and higher clearance of (99m)Tc-MAb-B43.13 that was ascribed in part to the circulating CA 125 antigen in this group of ovarian cancer patients. CONCLUSION: These clearance patterns resulted in acceptable, though higher radiation doses to the spleen and urinary bladder wall for these patients when compared to the MAb-170H.82 group. Both MAbs were found to produce acceptable radioimmunoscintigraphic images
Asunto(s)
Adenocarcinoma/metabolismo , Anticuerpos Monoclonales/farmacocinética , Neoplasias de la Mama/metabolismo , Antígeno Ca-125/sangre , Compuestos de Organotecnecio/farmacocinética , Neoplasias Ováricas/metabolismo , Radiofármacos/farmacocinética , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/inmunología , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/inmunología , Antígeno Ca-125/inmunología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Persona de Mediana Edad , Neoplasias Ováricas/inmunología , Cintigrafía , Distribución TisularRESUMEN
Fifty-three women with clinical evidence of adenocarcinoma of the breast were studied with technetium-99m labelled monoclonal antibody (MAb) 170H.82 at protein doses of 1, 2 and 4 mg. An overall per lesion efficacy of 83.5% sensitivity and 97.7% positive predictive value was obtained. Efficacy appears higher in lesions restricted to the breast and local regional disease than systemic metastases. For the 2 mg dose the breast/local regional disease efficacy was 90% sensitivity and 90.2% positive predictive value. The biodistribution of this MAb was best represented by a two-compartment model with a distribution-phase half-life of 4.0+/-1.4 h, followed by an elimination-phase half-life of 39.6+/-6.6 h. In all six patients studied, the critical organ was the kidney, with a mean radiation absorbed dose of 37+/-6.9 mGy/GBq. The accuracy of this imaging technique allows the development of diagnostic strategies for the routine use of the compound in patients with breast cancer.
Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Radioinmunodetección , Tecnecio , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Dosis de Radiación , Sensibilidad y Especificidad , Distribución TisularRESUMEN
The TRUQUANT BR radioimmunoassay, which uses monoclonal antibody B27.29 to quantitate CA27.29 mucin antigen (MUC-1 gene product) in serum, has recently received Food and Drug Administration approval for predicting recurrent breast cancer in patients with stage II and III disease. The purpose of this study was to determine whether the new radioimmunoassay for serum MUC-1 has prognostic significance for patients with metastatic adenocarcinoma receiving active specific immunotherapy (ASI). Using 40 U/ml as the upper limit of "normal," patients with metastatic breast and ovarian cancer with a preimmunotherapy serum CA27.29 mucin > 40 U/ml (CA27.29 Hi patients) had a poorer survival than CA27.29 Lo patients (< or = 40 U/ml) after ASI. There was no significant correlation between preimmunotherapy CA27.29 serum levels and measurable tumor burden. The preimmunotherapy CA27.29 serum level was a predictor of poor survival of metastatic colorectal and pancreatic cancer patients independent of other prognostic factors. There seemed to be two populations of pancreatic cancer patients, separated at 60 U/ml serum CA27.29 (CA27.29 Hi versus Lo patients). A CA27.29 serum level of 22 U/ml separated patients with CA27.29 Hi vs. Lo colorectal cancer. Patients with CA27.29 Lo colorectal and pancreatic cancer survived longer after ASI compared with patients with CA27.29 Hi colorectal and pancreatic cancer, respectively. We suggest that various CA27.29 serum levels define poor prognosis patients (CA27.29 Hi secretors) versus good prognosis patients (CA27.29 Lo secretors) for different cancer types.
Asunto(s)
Adenocarcinoma/terapia , Neoplasias de la Mama/terapia , Inmunoterapia , Mucina-1/sangre , Neoplasias Ováricas/terapia , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias Colorrectales/terapia , Femenino , Humanos , Tolerancia Inmunológica , Inmunoglobulina G/biosíntesis , Inmunohistoquímica , Hibridación de Ácido Nucleico , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Pancreáticas/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
THERATOPE (Biomira Inc., Edmonton, AB, Canada) STn-KLH cancer vaccine induces strong antibody titers against both the synthetic STn epitope and against a natural mucin, OSM, which expresses STn-like epitopes. In prospective, randomized studies in patients with metastatic breast cancer treated at two cancer centers, the effect of different low-dose, immunomodulatory cyclophosphamide (cyclo) pretreatments on the response to THERATOPE STn-KLH was compared. Patients were randomized to receive either intravenous cyclo 300 mg/m2 on day -3, or oral cyclo 50 mg daily from days -14 to -3 inclusive, or no cyclo, before THERATOPE treatments. The anti-STn and anti-OSM antibody titers were higher in the patients who received cyclo intravenously before THERATOPE. Patients treated with cyclo intravenously and THERATOPE STn-KLH cancer vaccine lived significantly longer (projected median survival of 19.7 months versus actual median survival of 12.6 months, p = 0.0176) than those treated with the same STn vaccine with oral or no cyclo. Although it is not clear how the anti-STn antibody response modifies tumor biology, we noted that patients in the intravenously administered cyclo group had a lower percentage of patients showing progressive disease at 9 weeks, and that there was an inverse correlation between serum anti-STN antibody titer and growth of measurable tumors. There was no correlation between tumor growth and anti-KLH antibody titers. These data are consistent with a therapeutic effect of THERATOPE STn-KLH cancer vaccine and support development of a phase III study to explore this further.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Ciclofosfamida/uso terapéutico , Hemocianinas/uso terapéutico , Premedicación , Adenocarcinoma/terapia , Administración Oral , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Persona de Mediana Edad , Metástasis de la Neoplasia , PronósticoRESUMEN
Patients with metastatic breast, colorectal or ovarian cancers received active specific immunotherapy (ASI) with Theratope sialyl-Tn-KLH (keyhole limpet hemocyanin) cancer vaccine emulsified in Detox adjuvant. The median log2 anti-STn IgG titer generated by ASI, estimated by enzyme-linked immunosorbent assay with solid-phase ovine submaxillary mucin, was 5.322 (range = 0 - 9.322). Following ASI, 51 patients who generated titers higher than the median value for anti-STn+ mucin IgG survived longer than 46 patients who generated lower titers below the median. 38 of the patients were phenotyped for CD69 prior to ASI. The patients with lower numbers of CD69+ peripheral blood lymphocytes prior to immunotherapy (pre-ASI) also had low serum CA27.29 cancer antigen (MUC-1) levels, and had longer times to disease progression and improved survival following ASI. Elevated pre-ASI serum CA27.29 tumor antigen levels were associated with higher numbers of CD69+ PBL, with decreased anti-STn antibody production and decreased survival following ASI. The data are compatible with the hypothesis that elevated serum MUC-1 mucin is specifically immunosuppressive.
Asunto(s)
Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Hemocianinas/inmunología , Inmunoterapia Activa , Linfocitos/inmunología , Mucina-1/sangre , Neoplasias/terapia , Femenino , Humanos , Tolerancia Inmunológica , Inmunoglobulina G/sangre , Lectinas Tipo C , Neoplasias/inmunología , Receptores de Interleucina-2/análisisRESUMEN
The humoral immune response of 85 metastatic breast, ovarian, and colorectal cancer patients was analyzed after immunization with THERATOPE STn-KLH (KLH, keyhole limpet hemocyanin) cancer vaccine emulsified in DETOX adjuvant. Enzyme-linked immunosorbent assay (ELISA) antibody titers against the synthetic sialyl-Tn (STn) epitope were estimated by using solid phase STn-HSA and compared with antibody titers generated to the more biologically relevant natural mucin STn epitopes by using ovine submaxillary mucin (OSM) as a solid phase. Anti-KLH antibody titers were compared with anti-STn antibody titers as a specificity control. All but two patients generated increased anti-OSM antibody titers after immunization with STn-KLH. Breast and colorectal cancer patients who had the highest anti-OSM antibody titers, determined 4 weeks after the fourth immunization with STn-KLH (post-4 ASI), survived longer than the patients who had lower post-4 active specific immunotherapy (ASI) anti-OSM antibody titers. In contrast, there was no correlation of anti-KLH antibody titers with survival, demonstrating the specificity of the association of anti-OSM antibodies with survival. Cox multivariate survival analysis models were used to attempt to determine whether the induction of high-titer antibodies after immunization is a prognostic indicator independent of age, level of various tumor markers, extent of disease, lactate dehydrogenase (LDH) level, and route of administration of low-dose cyclophosphamide before ASI. Increased pre-ASI CA-125 serum levels in the ovarian cancer patients were predictors of poor survival, independent of all of the other prognostic factors. The postimmunization increase in anti-OSM immunoglobulin M (IgM) titer was independently associated with longer survival of the colorectal cancer patients. Increased anti-OSM IgG titers were associated with a marked increased survival of the breast cancer patients, which was independent of all other prognostic factors except the size of measurable metastatic lesions at trial entry and the route of administration of cyclophosphamide. In a randomized trial design, breast cancer patients who received low-dose intravenous cyclophosphamide just before ASI showed longer survival and generated higher anti-OSM antibody titers than did patients who received low-dose oral cyclophosphamide before ASI.
Asunto(s)
Adenocarcinoma/secundario , Anticuerpos Antineoplásicos/análisis , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Antígenos de Carbohidratos Asociados a Tumores/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Hemocianinas/uso terapéutico , Inmunoterapia Activa , Mucinas/inmunología , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/secundario , Neoplasias de la Mama/terapia , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/secundario , Neoplasias Colorrectales/terapia , Femenino , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/secundario , Neoplasias Ováricas/terapia , Pronóstico , Análisis de SupervivenciaRESUMEN
Sixty patients presenting with poor prognosis squamous cell cancer of the cervix have been studied in a phase II clinical trial. Patients were treated with radiotherapy and concurrent cisplatin chemotherapy every 10 days. Treatment was well tolerated with all patients completing radiotherapy as prescribed. There was one case of grade 4 acute bowel toxicity. Significant late morbidity was acceptable for this group of patients being restricted to two cases (3.3%) of grade 4 toxicity to the bowel. Pelvic control rates of 78% have been observed. There have been no pelvic recurrences after 26 months, although recurrences beyond the pelvis have occurred up to 4 years later. Actuarial 4-year survival is encouraging at 60%.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Análisis Actuarial , Adulto , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/secundario , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Recurrencia Local de Neoplasia/epidemiología , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patologíaRESUMEN
Lymphocyte activation markers CD69 and HLA-DR were studied in metastatic breast and ovarian cancer patients who received active specific immunotherapy (ASI) using cancer vaccines containing the synthetic tumor-associated antigen sialyl-Tn or the Thomsen-Friedenreich antigen conjugated to KLH plus DETOX adjuvant. Breast cancer patients who showed prolonged survival following ASI had lower numbers of total CD69+ and CD4+CD69+ cells prior to ASI compared to patients who died. However, following ASI, the surviving patients showed an increase in CD69+ and CD4+CD69+ cells and the deceased patients showed a decrease. A greater than 50% increase in the percentage of cells bearing the activation marker CD69 is associated with an increase in survival in both ovarian and breast cancer patients. In the surviving breast cancer patients there was a significant decrease in the percentage of non-B lymphocyte HLA-DR+ (CD20-HLA-DR+) cells following cyclophosphamide treatment. A strong positive correlation was found between lymphocyte populations CD20- HLA-DR+ and CD8+CD57+, a putative suppressor cell population. Breast cancer patients who showed a greater than median decrease in CD20-HLA-DR+ lymphocytes following cyclophosphamide treatment had a survival advantage over patients who had less than the median decrease in the percent CD20-HLA-DR+ lymphocytes.
Asunto(s)
Adenocarcinoma/sangre , Adenocarcinoma/terapia , Antígenos CD/sangre , Antígenos de Diferenciación de Linfocitos T/sangre , Antígenos de Neoplasias/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/terapia , Antígenos HLA-DR/sangre , Inmunoterapia Activa , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos/inmunología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/terapia , Adenocarcinoma/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales , Neoplasias de la Mama/mortalidad , Complejo CD3/inmunología , Antígenos CD4/sangre , Antígenos CD57 , Antígenos CD8/sangre , Femenino , Humanos , Lectinas Tipo C , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Ováricas/mortalidad , Fenotipo , Sensibilidad y EspecificidadRESUMEN
There has been progress over the last decade in addressing three questions: Are there cancer-associated antigens that could be targets for immunotherapy? Can the human immune system recognize cancer-associated antigens? Can an anti-cancer immune response affect cancer cells and lead to increased survival? Results from animal model studies have been interpreted by optimists as encouraging, and by pessimists as being irrelevant to human cancer. Earlier studies on "cancer vaccines" utilized heterogeneous cell extracts of cell components. Monoclonal antibodies have enabled identification of relevant cancer-associated antigens or epitopes, such as the ganglioside GM2, the carbohydrates TF and STn, and the peptide sequences of MUC-1. In parallel with research on immune adjuvants and measures designed to inhibit suppressor activity, these epitopes are being tested for their potential in the immunotherapy of solid tumors. It is clear that some of these cancer-associated epitopes are immunogenic in humans. Mixed responses may relate to cancer heterogeneity and may indicate the importance of multi-epitopic vaccines. Responses are encouraging, but are they relevant? Prolonged disease stability challenges us to re-think the goals of cancer therapy. Recent advances in the knowledge of the effect of cytokines on tumor antigen expression and the regulation of the immune response, coupled with advances in active specific immunotherapy, provide hope that biomodulation may become an important part of the therapy of solid tumors in the next century.
Asunto(s)
Inmunoterapia , Neoplasias/terapia , Animales , Antígenos de Neoplasias/inmunología , Epítopos/inmunología , Humanos , Inmunidad Celular/inmunología , Factores Inmunológicos/uso terapéutico , Neoplasias/inmunologíaAsunto(s)
Adenocarcinoma/terapia , Antígenos de Neoplasias/uso terapéutico , Inmunoterapia Activa , Adenocarcinoma/inmunología , Animales , Neoplasias de la Mama/terapia , Modelos Animales de Enfermedad , Epítopos , Femenino , Cobayas , Humanos , Ratones , Neoplasias Ováricas/terapia , Células Tumorales CultivadasRESUMEN
Several investigators have shown that the expression of the sialyl-Tn (STn) epitope on cancer associated mucins is associated with a poor prognosis in several human cancers suggesting that STn may have functional significance in metastasis. We postulate that antibodies against the STn-epitope can inhibit metastasis. We generated a synthetic "mimic", NANA alpha (2-->6)GalNAc alpha-O-Crotyl (STn-crotyl), of the natural O-linked epitope on mucins, NANA alpha (2-->6)GalNAc alpha-O-Serine (STn-serine). STn-crotyl was conjugated to the carrier protein KLH through the crotyl linker arm and a "vaccine" containing STn-KLH plus Detox adjuvant was formulated. The immunogenicity of the vaccine was evaluated in BALB/c mice and in metastatic breast cancer patients. The specificity and titres of IgG antibodies were evaluated by ELISA on ovine submaxillary mucin (OSM) solid phases. OSM is a convenient source of repeating, natural O-linked STn-serine structures. Mice immunized three times with as little as 0.25 microgram of STn-KLH produced a median IgG titre of over 1:5000 on solid phase OSM. Anti-OSM IgG monoclonal antibodies generated from these mice were completely inhibited in their binding to solid phase OSM equally well by STn-serine and STn-crotyl synthetic haptens but not by several other closely related synthetic haptens. Breast cancer patients immunized 2-8 times with 25 or 100 micrograms of the same vaccine produced median peak IgG titres 1:1280 measured on STn-HSA and 1:80 on OSM. Once again, hapten inhibition experiments with the human sera demonstrated the specificities of the IgG antibodies for STn-crotyl and STn-serine, but not against several other related synthetic haptens. We found little or no evidence that the artificial linker arm (crotyl linker) contributed significantly to either the titre or affinity of the antibodies generated in either mice or human breast cancer patients. This suggests that the antibodies recognized the cancer-associated disaccharide NANA alpha (2-->6)GalNAc. Evidence of a clinical response was noted in several of the immunized breast cancer patients with other patients showing prolonged disease stability.
Asunto(s)
Anticuerpos Antineoplásicos/biosíntesis , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/inmunología , Epítopos/inmunología , Hemocianinas/inmunología , Inmunización , Inmunoglobulina G/biosíntesis , Inmunoterapia Activa , Mucinas/inmunología , Metástasis de la Neoplasia/inmunología , Animales , Anticuerpos Antineoplásicos/inmunología , Neoplasias de la Mama/terapia , Conformación de Carbohidratos , Secuencia de Carbohidratos , Ensayo de Inmunoadsorción Enzimática , Epítopos/química , Haptenos/inmunología , Humanos , Inmunidad Celular , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Resultado del TratamientoRESUMEN
We generated a synthetic epitope, NANA alpha(2-6) GalNAc alpha-O-Crotyl (STn-crotyl), designed to "mimic" the natural O-linked epitope expressed on human carcinoma cells, NANA alpha(2-6)GalNAc alpha-O-Serine (STn-serine). STn-crotyl was conjugated to the carrier protein KLH through the crotyl linker arm, and a "vaccine" containing STn-KLH plus DETOX adjuvant was formulated. The immunogenicity of the vaccine was evaluated preclinically in CAF1 mice and subsequently in patients with metastatic breast cancer. The specificity and titers of IgG antibodies were evaluated by kinetic ELISA on synthetic STn-HSA and on ovine submaxillary mucin (OSM) solid phases. Ovine submaxillary mucin is a convenient source of repeating, natural O-linked STn-serine structures. Mice immunized three times with as little as 0.25 micrograms of STn-KLH produced IgG titers ranging from 1:10(4) to 1:10(5) when tested on solid phase OSM. Anti-OSM IgG, both polyclonal and monoclonal antibodies, generated from these mice were completely inhibited in their binding to solid phase OSM equally well by STn-serine and STn-crotyl synthetic haptens but not by several other closely related synthetic haptens. These monoclonal antibodies also bound to STn determinants on human tumor cell surfaces. Breast cancer patients immunized with 100 micrograms of the same vaccine produced median peak IgG titers 1:1280 measured on STn-HSA and 1:160 on OSM. Hapten inhibition experiments with the human sera demonstrated the specificities of the IgG antibodies for STn-crotyl and STn-serine, but not against several other related synthetic haptens. We found little evidence that the artificial linker arm (crotyl linker) contributed substantially to either the titer or affinity of the antibodies generated in either mice or human breast cancer patients. This suggests that the antibodies recognized the cancer-associated disaccharide NANA alpha(2-->6)-GalNAc. Small but not large doses of STn-KLH immunogen induced anti-STn DTH responses in mice that were inversely proportional to the antibody responses. Evidence of a clinical response was noted in some of the immunized breast cancer patients, with other patients showing prolonged disease stability.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/terapia , Mucinas/inmunología , Adyuvantes Inmunológicos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antineoplásicos/inmunología , Especificidad de Anticuerpos , Secuencia de Carbohidratos , Proteínas del Sistema Complemento/inmunología , Citotoxicidad Inmunológica , Epítopos , Humanos , Hipersensibilidad Tardía/inmunología , Inmunoterapia Activa , Ratones , Datos de Secuencia Molecular , Ovinos , Glándula Submandibular/inmunologíaAsunto(s)
Partería/educación , Adolescente , Adulto , Niño , Curriculum , Femenino , Humanos , Recién Nacido , Mortalidad Materna , Atención Posnatal , Embarazo , Embarazo en Adolescencia , Atención PrenatalRESUMEN
We have synthesized various formulations that have potential for active specific immunotherapy (ASI) of human cancers. Sialyl-Tn (STn) is a potentially important target structure for ASI because its expression on mucins is a strong, independent predictor of poor prognosis, suggesting that it may have functional significance in the metastatic process. In this first pilot study of synthetic sialyl-Tn hapten conjugated to keyhole limpet hemocyanin (STn-KLH), with Detox adjuvant, toxicity and humoral immunogenicity were assessed in 12 patients with metastatic breast cancer. Toxicity was minimal, restricted to local cutaneous reactions (apart from transient nausea and vomiting following single low-dose cyclophosphamide treatment). Using STn-conjugated human serum albumin in a solid-phase enzyme-linked immunosorbent assay, it was shown that all patients developed IgM and IgG specific for the synthetic STn hapten. Following immunization, most patients were shown to develop increased titres of complement-mediated cytotoxic antibodies, partially inhibited by synthetic STn hapten, but not by the related TF hapten. We also detected IgM and IgG antibodies reactive with natural STn determinants expressed on ovine submaxillary mucin, the STn specificity of this reactivity being confirmed by hapten inhibition. Evaluation of clinical efficacy in a small pilot study is difficult. Five patients are alive 12 or more months after entry, and another 4 patients are alive 6 or more months after entry into the study. All 3 patients with known widespread bulky disease progressed despite ASI, 2 having died from widespread cancer. Two patients had partial responses, each lasting 6 months. While several patients had disease stability for 3-10 months, 1 patient with pulmonary metastases remains stable 15 months after entry into the program.
Asunto(s)
Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/terapia , Carcinoma/terapia , Adyuvantes Inmunológicos , Anticuerpos Antineoplásicos/inmunología , Especificidad de Anticuerpos , Antígenos de Carbohidratos Asociados a Tumores/administración & dosificación , Carcinoma/inmunología , Proteínas del Sistema Complemento/inmunología , Citotoxicidad Inmunológica , Femenino , Glicoconjugados/inmunología , Haptenos , Humanos , Inmunización , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Células Tumorales CultivadasRESUMEN
Cisplatin-based combination chemotherapy is the current standard chemotherapy for the management of advanced stage, epithelial ovarian cancer. However, correlation has been demonstrated previously between dose intensity and response for cisplatin, but not for the other cytotoxic drugs commonly used. We treated 46 consecutive, newly diagnosed patients following standard debulking laparotomy with cisplatin 60 mg m-2 every 2 weeks for a total of 8 cycles. Survival and toxicity were compared with those of a similar cohort of 24 consecutive, newly diagnosed patients treated with cisplatin 75 mg m-2 plus cyclophosphamide 600 mg m-2 every 4 weeks for 6 cycles, at the same institution immediately prior to the current cohort. The single-agent cisplatin cohort received a mean relative cisplatin-equivalent dose intensity of 1.43 compared with a received mean relative cisplatin-equivalent dose intensity of 0.88 in the combination chemotherapy cohort, a 62.5% increase in the cisplatin dose intensity. At 2 years, 69% of the patients receiving single-agent cisplatin were alive, compared with 38% of the group receiving the combination chemotherapy (P = 0.014). Alopecia (P < 0.00001) and myelosuppression (P < 0.0000001) were markedly less in the patient group receiving single-agent cisplatin. There was no significant difference in the incidence of neurotoxicity (P = 0.28) or nephrotoxicity (P = 0.38) between the two patient groups. In summary, relatively dose intensive, single-agent cisplatin given in a biweekly schedule for the first-line management of advanced stage, ovarian cancer produced a survival advantage compared with the previous combination cyclophosphamide/platinum combination chemotherapy. This novel therapy takes one-third less time to complete and causes fewer side effects than the current standard of combination cyclophosphamide and cisplatin.
RESUMEN
Maternal death is a tragedy which is all too familiar in much of the world. As part of the Safe Motherhood Initiative the World Health Organization is developing and producing a learning package designed specifically for midwives. Through a modular system of learning incorporating aspects of community, prevention, treatment and follow-up the package seeks to address the five main causes of maternal mortality. In this paper the first pre-testing of the educational material in an African country is described. The extent of the evaluation is limited at this early stage but the initial analysis of the results is encouraging and have led to modifications of the original package. The evaluation has confirmed that a tool such as this package can be a valuable resource for midwife teachers attempting to improve the relevance of education for their midwifery students. The midwifery students whilst being 'with woman' in childbirth are also grappling with the realities of death in their everyday practice. The educational package has also reinforced the sense of urgency fundamental to completing this extensive project so that it can be made available to midwives throughout the developing world at the earliest opportunity.