RESUMEN
Progress in our understanding of chronic lymphocytic leukemia and its treatment has resulted in a more tailored approach to patient management, with different therapeutic regimens for different patient populations. The current standard of care has evolved from single-agent therapy with chlorambucil or cyclophosphamide, through the introduction of purine analogs to the more recent introduction of chemoimmunotherapy. Selection of appropriate initial therapy should be based primarily on patient characteristics such as age, performance status and the expected clinical course of the leukemia based on established risk factors. Achieving a complete and durable response is the major goal for fit patients; chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab would be advantageous. Alternatively, in unfit patients, controlling symptoms is the essential treatment goal and a regimen with a more favorable toxicity profile should be applied. This manuscript reviews the data that has lead to current treatment choices, advises on tailored therapies and discusses emerging trends. Data for this review was identified by a search of electronic information including Medline and PubMed databases, conference proceedings and trial registers. Critical analysis of extracted data was undertaken with attention to trial phase, treatment schedules and end points, including response rates, follow-up times, progression-free survival and overall survival.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Clorhidrato de Bendamustina , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Compuestos de Mostaza Nitrogenada/uso terapéutico , Pronóstico , Purinas/administración & dosificaciónRESUMEN
PURPOSE: (90)Yttrium-ibritumomab-tiuxetan (Zevalin) is an effective treatment for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. The purpose of this study is to assess whether tissue and cellular localization of (90)Y-ibritumomab-tiuxetan determined by autoradiography and radioactivity localized to tumor tissue might enhance our understanding of the mechanism of action of radioimmunotherapy. METHODS: Eight eligible patients had CD20+ NHL, a bulky peripheral lymph node, and were scheduled for (90)Y-ibritumomab-tiuxetan treatment. 2-Deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed prior to treatment and at 12 weeks after therapy for assessment of response. Bone marrow, lymph node, and blood samples were collected 114 +/- 3 h after 14.8 MBq/kg (90)Y-ibritumomab-tiuxetan and processed for histology, scintillation counting, and microscopic autoradiography. RESULTS: Pericellular membrane localization of (90)Y-ibritumomab-tiuxetan to lymphoma cells was observed by autoradiography in the involved areas of lymph node with absence of significant localization in histologically normal sections of bone marrow. Pericellular radioactivity and the highest quantitative radioactivity were observed in lymph node samples of responding patients. CONCLUSIONS: (90)Y-ibritumomab-tiuxetan localizes to the surface membrane of CD20+ lymphoma cells in affected lymph nodes. The patients with the highest quantitative concentration of radioactivity to the lymph node as determined by scintillation counting were observed to have a clinical and FDG-PET/CT response.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia/métodos , Radioisótopos de Itrio/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Antígenos CD20/inmunología , Autorradiografía , Humanos , Leucemia Linfocítica Crónica de Células B/radioterapia , Linfoma Folicular/radioterapia , Linfoma de Células B Grandes Difuso/radioterapia , Linfoma de Células del Manto/radioterapia , Linfoma no Hodgkin/patología , Persona de Mediana EdadRESUMEN
B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
We evaluated the efficiency of recombinant vaccinia virus expressing interleukin-2 (rvv-IL-2) as a tumor vaccine in an immunocompetent mouse model of head and neck squamous cell carcinoma (SCC VII/SF). Mice with five-day-old tumors in the floor of the mouth were treated with rvv-IL-2 by intratumoral injections. These treated mice survived longer (P <.03) than mice treated with control vaccines. Splenocytes, bone marrow, and lymph node cells from tumor-bearing mice responded poorly to concanavalin A stimulation, suggesting induction of immunosuppression. The rvv-IL-2 virus grew for 7 days in the tumor following intratumoral injection. We did not detect any virus particles in several normal organs following rvv-IL-2 injection. Comparison of expression levels of several potential immune inhibitory mediators between the tumors growing in mice and cultured tumor cells demonstrated higher expression of IL-10, GM-CSF, TGF-beta, and NO synthetase in tumors. These results suggested possible roles for these molecules in immunosuppression. We conclude that rvv-IL-2 has potential as a therapeutic vaccine for head and neck cancer and that it can be more effective provided the immunosuppression is reversed.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Terapia Genética/métodos , Neoplasias de Cabeza y Cuello/terapia , Interleucina-2/metabolismo , Virus Vaccinia/fisiología , Animales , Médula Ósea/inmunología , Carcinoma de Células Escamosas/inmunología , Concanavalina A/farmacología , Cartilla de ADN/química , Vectores Genéticos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Terapia de Inmunosupresión , Interleucina-10/metabolismo , Interleucina-2/genética , Ganglios Linfáticos/inmunología , Ratones , Trasplante de Neoplasias , Óxido Nítrico Sintasa/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/inmunología , Tasa de Supervivencia , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/metabolismoAsunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Antígenos de Neoplasias/inmunología , Inmunoterapia/métodos , Imitación Molecular/inmunología , Neoplasias/terapia , Secuencia de Aminoácidos , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Secuencia de Bases , Ensayos Clínicos como Asunto , Humanos , Datos de Secuencia MolecularRESUMEN
The anti-idiotypic (Id) monoclonal antibody (MAb) 520C9-6b (IgG1k), raised in syngenic mice against the murine anti-Her2/neu MAb 520C9 (Ab1), functionally mimics a human Her2/neu epitope and serves as a surrogate for the protein antigen. Immunization of allogeneic C57BL/6 mice and rabbits with 520C9-6b (Ab2) induced anti-Her2/neu-specific antibodies that react with antigen-positive SKBr3 cells by ELISA and FACS analysis. The immune sera inhibited binding between Ab1 and Ab2 and vice versa (binding of Ab2 to Ab1), indicating that it was a true anti-anti-Id (Ab3) antibody. The Ab3 sera or purified Ab3 specifically lysed Her2/neu-positive SKBr3 cells, but no significant lysis was observed in antigen-negative LS174T cells in an antibody-dependent cellular cytotoxicity assay. An Id-specific cellular immune response was also demonstrated in an in vitro lymphocyte proliferation assay. Furthermore, a panel of tumor tissues and tumor cells was screened for the presence of the Her2/neu epitope by its reactivity with Ab1 and Ab3 using immunohistochemistry and FACS analysis. Identical results were obtained using either Ab1 or Ab3 (Ab1'). The data indicated that anti-Id 520C9-6b can induce Her2/neu-specific antibody in experimental animals and may serve as a potential network antigen for the treatment of patients bearing Her2/neu-positive tumors.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/inmunología , Antígenos/inmunología , Receptor ErbB-2/inmunología , Animales , Anticuerpos Antiidiotipos/aislamiento & purificación , Anticuerpos Monoclonales/aislamiento & purificación , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Hibridomas/inmunología , Sueros Inmunes/farmacología , Inmunidad Celular , Inmunización , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Conejos , Linfocitos T/inmunología , Células Tumorales CultivadasRESUMEN
Immunologic approaches to therapy for colorectal cancer have evolved substantially. In the past, patients were treated with nonspecific immune stimulants such as bacillus Calmette-Guérin (BCG). The current focus lies in targeting tumor-associated antigens. This is done either through passive immune therapy, with antibodies targeted directly to tumor cells, or by active immune therapy through vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic tumor-associated antigens. These different approaches to immunotherapy are reviewed.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Inmunización Pasiva , Inmunoterapia/métodos , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Carbohidratos , Antígeno Carcinoembrionario/inmunología , Humanos , Mucinas , Péptidos , Radioisótopos/uso terapéutico , Células Tumorales CultivadasRESUMEN
Certain anti-idiotypic antibodies that bind to the antigen-combining sites of antibodies can effectively mimic the three-dimensional structures and functions of the external antigens and can be used as surrogate antigens for active specific immunotherapy. Extensive studies in animal models have demonstrated the efficacy of these vaccines for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections as well as tumors. Several monoclonal anti-idiotype antibodies that mimic distinct human tumor-associated antigens have been developed and characterized. Encouraging results have been obtained in recent clinical trials using these anti-idiotype antibodies as vaccines. In this article, we will review the current literature and discuss the potential of this novel therapeutic approach for various human cancers.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Células Pequeñas/terapia , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/terapia , Femenino , Humanos , Neoplasias Pulmonares/terapia , Melanoma/terapia , Neoplasias/inmunologíaRESUMEN
Immune approaches to the therapy of colorectal cancer and melanoma have substantially evolved over the past years, from treating patients with nonspecific immune stimulants to a focus on the use of tumor-associated antigens (TAAs) either by passive immune therapy with antibodies targeted directly to tumor cells or by active immune therapy via vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic TAAs. We review the different immunotherapeutic approaches to the treatment of melanoma and colorectal cancers, and summarize relevant clinical trials.
Asunto(s)
Neoplasias Colorrectales/terapia , Inmunoterapia/métodos , Melanoma/terapia , Anticuerpos Monoclonales/uso terapéutico , Vacunas contra el Cáncer , Neoplasias Colorrectales/inmunología , Humanos , Melanoma/inmunología , Radioinmunoterapia/métodosRESUMEN
The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.76 months post-ASCT (range, before ASCT-6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Glucolípidos/inmunología , Glicoproteínas/inmunología , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Anticuerpos Monoclonales , Neoplasias de la Mama/inmunología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular , Gotas Lipídicas , Activación de Linfocitos , Persona de Mediana Edad , Tasa de Supervivencia , Linfocitos T/inmunología , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Anti-idiotype antibody, 1A7, functionally mimics the tumor-associated antigen disialoganglioside GD2, which is overexpressed on the surface of a number of neuroectodermal tumors such as melanoma, neuroblastoma, soft tissue sarcoma, and small cell carcinoma of the lung. Immunization of mice with 1A7 generated the production of anti-GD2 antibodies. In a phase I clinical trial, immunization of patients with 1A7, mixed with the adjuvant QS21, demonstrated that 1A7 could act as a surrogate antigen for GD2 and induce strong humoral immune responses in advanced stage melanoma patients. DNA vaccines have recently been shown to invoke humoral as well as cellular responses in injected hosts against the transgene product. To evaluate the efficiency of DNA vaccines encoding anti-idiotype antibodies, we constructed expression plasmids encoding the variable heavy (VH) and variable light (VL) chains of 1A7. The plasmids were made in two configurations, expressing either the VH (pc1A7VHLnVL) or the VL (pc1A7VLLnVH) chain of 1A7 at the amino terminus, linked together by a 15-amino acid linker (Ln). In vitro transcription/translation assays and transfection of CHO-K1 cells with the plasmids demonstrated that a approximately 30-kDa protein was expressed by both configurations of the single-chain variable fragment. This protein can be specifically precipitated by monoclonal anti-GD2 antibody, 14G2a. Following intramuscular injection in mice, the plasmids were detectable in the injected tissues for at least 3 months and the injected plasmids actively transcribed the single-chain variable fragment 1A7 gene at the injected site. A single, intramuscular immunization of a group of C57BL/6 mice with pc1A7VLLnVH in phosphate-buffered saline induced humoral immune responses against 1A7 as well as GD2, the nominal antigen. Multiple immunizations, however, were required to elicit stronger immune responses.
Asunto(s)
Anticuerpos Antiidiotipos/genética , Gangliósidos/genética , Vacunas de ADN , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/metabolismo , Secuencia de Bases , Células CHO , División Celular , Línea Celular , Clonación Molecular , Cricetinae , ADN Complementario/metabolismo , Femenino , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Músculos/metabolismo , Pepsina A/metabolismo , Plásmidos/genética , Plásmidos/metabolismo , Biosíntesis de Proteínas , Linfocitos T/metabolismo , Factores de Tiempo , Transcripción Genética , TransfecciónRESUMEN
Important advances in molecular biology and chelation chemistry have led to new and improved monoclonal antibody reagents. Rituximab (IDEC-C2B8) was approved by the United States Food and Drug Administration for relapsed CD20-positive lymphomas, and denileukin diftitox was approved (DAB389IL-2) for CTCL. Ibritumomab tiuxetan and iodine 131 anti-B1 have excellent activity and acceptable toxicity and likely higher responses than rituximab. These questions should be answered in phase III trials, and preliminary results from the rituximab versus ibritumomab tiuxetan trial suggest higher responses to the latter. Data on radiolabeled Lym-1, T101, LL2, and anti-Tac also look promising. The therapeutic role of immunotoxins has yet to be determined, but encouraging data with DAB389IL-2 and LMB-2 have been reported. Antibody conjugates with drugs, prodrugs, nonprotein toxins, and other agents are also under investigation. Bispecific antibodies for lymphoma may also have a future role in lymphoma therapy. It is anticipated that many of the major advances in lymphoma therapy will be antibody based.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfoma/inmunología , Linfoma/terapia , Anticuerpos Biespecíficos/metabolismo , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Inmunotoxinas/metabolismo , Profármacos/uso terapéuticoRESUMEN
Between April 1997 and March 1998 we evaluated the immune response and outcome in 11 chemosensitive patients who were treated with the anti-idiotype antibody vaccine TriAb after recovery from intensive therapy and autologous stem cell transplant (ASCT). Triab was commenced after recovery from the acute effects of ASCT; a minimum interval of 1 month was required from completion of consolidation radiotherapy, if given. Nine patients (82%) manifest anti-anti-idiotype antibody (Ab3) responses post ASCT. The maximal Ab3 response was seen after a median of 10 doses (range 5-20), which corresponded to a median of 14 months (range 5-19) post ASCT. Evidence of a T cell proliferative response was seen in eight patients; the response was modest in most of these. At a median follow-up of 24 months (range 22-33) after ASCT, four patients are alive without evidence of disease progression. All four of these patients were in the subgroup with more vigorous immune responses. Subsequent efforts have been directed toward the achievement of higher levels of immune responses more rapidly post ASCT. Bone Marrow Transplantation (2000) 26, 729-735.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Anticuerpos Antiidiotipos/toxicidad , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/inmunología , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/toxicidad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Metástasis Linfática/inmunología , Activación de Linfocitos , Persona de Mediana Edad , Factores de Tiempo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Immunization with anti-idiotype (Id) antibodies represents a novel new approach to active immunotherapy. Extensive studies in animal tumor models have demonstrated the efficacy of anti-Id vaccines in preventing tumor growth and curing mice with established tumor. We have developed and characterized several murine monoclonal anti-Id antibodies (Ab2) which mimic distinct human tumor-associated antigens (TAA) and can be used as surrogate antigens for triggering active anti-tumor immunity in cancer patients. Encouraging results have been obtained in recent clinical trials. In this article, we will review the existing literature and summarize our own findings showing the potential of this approach for various human cancers. We will also discuss where anti-Id vaccines may perform better than traditional antigen vaccines.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antiidiotipos/uso terapéutico , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Ensayos Clínicos Fase I como Asunto , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Modelos Animales de Enfermedad , Femenino , Humanos , Idiotipos de Inmunoglobulinas/inmunología , Inmunoterapia Activa , Melanoma/inmunología , Melanoma/terapiaRESUMEN
Anti-idiotype (Id) vaccine therapy has been tested and shown to be effective, in several animal models, for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections. The administration of anti-Id antibodies as surrogate tumor-associated antigens (TAA) also represents another potential application of the concept of the Id network. Limited experience in human trials using anti-Id to stimulate immunity against tumors has shown promising results. In this "counter-point" article, we discuss our own findings showing the potential of anti-Id antibody vaccines to be novel therapeutic approaches to various human cancers and also discuss where anti-Id vaccines may perform better than traditional multiple-epitope antigen vaccines.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/inmunología , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Epítopos/inmunología , Imitación Molecular , Neoplasias/terapia , Adyuvantes Inmunológicos , Compuestos de Alumbre , Animales , Anticuerpos Antiidiotipos/efectos adversos , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/biosíntesis , Anticuerpos Antineoplásicos/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/uso terapéutico , Antígeno Carcinoembrionario/inmunología , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/terapia , Estudios de Evaluación como Asunto , Gangliósidos/inmunología , Glucolípidos/inmunología , Glicoproteínas/inmunología , Humanos , Inmunización , Leucemia-Linfoma de Células T del Adulto/inmunología , Gotas Lipídicas , Melanoma/terapia , Ratones , Ratones Endogámicos C57BL , Modelos Inmunológicos , Neoplasias/prevención & control , Neoplasias Experimentales/terapia , Resultado del TratamientoRESUMEN
PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 microg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti-anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1' because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier-derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Gangliósidos/inmunología , Inmunoglobulina G/inmunología , Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiidiotipos/uso terapéutico , Especificidad de Anticuerpos , Progresión de la Enfermedad , Femenino , Gangliósidos/uso terapéutico , Humanos , Inmunización , Masculino , Melanoma/patología , Melanoma/terapia , Persona de Mediana Edad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Análisis de SupervivenciaRESUMEN
PURPOSE: We generated an anti-idiotype antibody, designated CeaVac, that is an internal image of the carcinoembryonic antigen (CEA). We previously demonstrated that the majority of patients with advanced colorectal cancer generate specific anti-CEA responses. The purpose of the current study was to treat patients with surgically resected colon cancer with CeaVac to determine the immune response and clinical outcome to treatment with vaccine. We also compared the immune responses between patients treated with fluorouracil (5-FU) chemotherapy regimens plus vaccine versus vaccine alone. PATIENTS AND METHODS: Thirty-two patients with resected Dukes' B, C, and D, and incompletely resected Dukes' D disease were treated with 2 mg of CeaVac every other week for four injections and then monthly until tumor recurrence or progression. Fourteen patients were treated concurrently with 5-FU chemotherapy regimens. RESULTS: All 32 patients entered onto this trial generated high-titer immunoglobulin G and T-cell proliferative immune responses against CEA. The 5-FU regimens did not have a qualitative or quantitative effect on the immune response. Three of 15 patients with Dukes' B and C disease progressed at 19, 24, and 35 months. Seven of eight patients with completely resected Dukes' D disease remained on study from 12 to 33 months; one patient with resected Dukes' D disease relapsed at 9 months. One patient with incompletely resected Dukes' D disease remained on study at 14 months without evidence of progression; eight experienced disease progression at 6 to 31 months. CONCLUSION: CeaVac consistently generated a potent anti-CEA humoral and cellular immune response in all 32 patients entered onto this trial. A number of very high-risk patients continue on study. 5-FU regimens, which are the standard of care for patients with Dukes' C disease, did not affect the immune response. These data warrant a phase III trial for patients with resected colon cancer.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Antígeno Carcinoembrionario/inmunología , Antígeno Carcinoembrionario/uso terapéutico , Neoplasias del Colon/terapia , Adyuvantes Inmunológicos/uso terapéutico , Hidróxido de Aluminio/uso terapéutico , Animales , Anticuerpos Antiidiotipos/inmunología , Antimetabolitos Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Fluorouracilo/uso terapéutico , Humanos , Inmunidad Celular , Inmunoglobulina G/inmunología , Ratones , Ratones Endogámicos BALB C , Estadificación de Neoplasias , Saponinas/uso terapéuticoRESUMEN
Anti-idiotype antibody, 11D10 mimics biologically and antigenically a distinct and specific epitope of the high molecular weight human milk fat globule (HMFG), a cancer-associated antigen present in over 90% of breast tumor samples. To augment the immunogenicity of 11D10 without the aid of a carrier protein or adjuvant, we made a chimeric 11D10-GM-CSF fusion protein for use as a vaccine. An expression plasmid for 11D10 was made by ligation of the DNA sequences of the 11D10 light-chain variable region upstream of the human kappa constant region. The heavy-chain plasmid carrying GM-CSF was made by ligation of the heavy-chain variable region sequences upstream of the human gamma1 constant region CH1 fused to the DNA fragment encoding the mature GM-CSF peptide 3' to the CH3 exon. NS1 plasmacytoma cells were transfected with the light and heavy-chain vectors by electroporation. Fusion protein secreted in the culture medium was purified and was characterized by gel electrophoresis as well as by determination of the biological activity of the fused GM-CSF. In nonreducing SDS-polyacrylamide gels, a single band approximately 200 Kd reacted with anti-human kappa, anti-human lambda1 and anti-GM-CSF antibodies. In reducing polyacrylamide gels, a approximately 74 kd protein reacted with anti-human lambda1 and anti-GM-CSF antibodies. The fusion protein induced proliferation of GM-CSF dependent NFS-60 cells. These results suggest that the protein is a chimeric anti-idiotype antibody consisting of 11D10 variable domains, human kappa and lambda1 constant domains and that the GM-CSF moiety fused to the constant region lambda1 is biologically active.