RESUMO
BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.
Assuntos
Adenocarcinoma/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Próstata/terapia , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Humanos , Imunoterapia , Ipilimumab , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: This first-in-human phase I/IIA study was designed to evaluate the safety and pharmacokinetics (PKs) of AGS-PSCA a fully human monoclonal antibody directed to prostate stem cell antigen (PSCA) in progressive castration-resistant prostate cancer. PATIENTS AND METHODS: Twenty-nine patients were administered infusions of AGS-PSCA (1-40 mg/kg) every 3 weeks for 12 weeks; 18 final patients received a 40-mg/kg loading dose followed by 20-mg/kg repeat doses. Primary end points were safety and PK. Immunogenicity, antitumor activity and circulating tumor cells were also evaluated. RESULTS: No drug-related serious adverse events were noted. Dose escalation stopped before reaching the maximum tolerated dose as target concentrations were achieved. Drug levels accumulated linearly with dose and the mean terminal half-life was 2-3 weeks across dose levels. The 40-mg/kg loading dose followed by repeated 20-mg/kg doses yielded serum drug concentrations above the projected minimum therapeutic threshold after two to three doses without excessive drug accumulation or toxicity. Significant antitumor effects were not seen. CONCLUSIONS: A 40-mg/kg loading dose followed by 20-mg/kg infusions every 3 weeks is the recommended phase II dose of AGS-PSCA. PSCA is a promising drug target and studies in prostate and other relevant solid tumors are planned.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Proteínas de Neoplasias/imunologia , Orquiectomia , Neoplasias da Próstata/terapia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Proteínas Ligadas por GPI/imunologia , Meia-Vida , Humanos , Masculino , Células Neoplásicas CirculantesRESUMO
BACKGROUND: Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer. PATIENTS AND METHODS: Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks. RESULTS: Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%). CONCLUSIONS: The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Epotilonas/administração & dosagem , Epotilonas/farmacologia , Estramustina/administração & dosagem , Estramustina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias Ósseas/secundário , Castração , Relação Dose-Resposta a Droga , Epotilonas/efeitos adversos , Estramustina/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Microtúbulos/efeitos dos fármacos , Pessoa de Meia-Idade , Antígeno Prostático Específico/análise , Resultado do TratamentoRESUMO
Prostate cancer is a important tumor in which to evaluate vaccine strategies. It is associated with two well-characterized serum biomarkers, prostate specific antigen (PSA) and prostatic acid phosphatase, which enables the investigator to monitor the progress of the disease. There are well-studied but less well-known glycoprotein and glycolipid antigens on the surface of prostate cancer cells that may function as targets for immune recognition and attack. Conventional treatments such as chemical castration are often poorly tolerated. When initiation of hormonal therapy is controversial, alternative therapies with minimal side effects are a desirable approach. Vaccines represent a means by which the immune system can be stimulated in order to affect an antitumor response by means of recruiting a variety of different effector arms of the immune system. The varying approaches toward vaccine construction as treatment strategies for relapsed prostate cancer are described.
Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Imunoterapia Ativa , Neoplasias da Próstata/terapia , Terapia de Salvação , Adenocarcinoma/imunologia , Adjuvantes Imunológicos , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Sequência de Carboidratos , Carboidratos/análise , Carboidratos/imunologia , Ensaios Clínicos Fase I como Assunto , Citocinas/genética , Citocinas/fisiologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Gangliosídeos/imunologia , Técnicas de Transferência de Genes , Terapia Genética , Glicolipídeos/imunologia , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Mucinas/imunologia , Metástase Neoplásica , Proteínas de Neoplasias/química , Proteínas de Neoplasias/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias da Próstata/imunologia , Ratos , Timidina Quinase/genética , Transfecção , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/uso terapêutico , Proteínas Virais/genéticaRESUMO
BACKGROUND: There are limited data available regarding the cost of care in patients with androgen independent prostate carcinoma (AIPC), and there are no data on the impact of direct nonmedical and indirect costs (DNM/IC). This lack of data, along with the feasibility of collecting DNM/IC, was examined in patients with AIPC who took part in a randomized trial using a newly developed questionnaire, the Collection of Indirect and Nonmedical Direct Costs (COIN) form. METHODS: Patients with AIPC were randomized to one of three treatment arms: 1) strontium only (strontium 4 Mci in Week 1 and Week 12) (STRONT); 2) vinblastine 4 mg/m(2) per week for 3 weeks then 1 week off and estramustine, 10 mg/kg per day (CHEMO); or 3) a combination of treatments outlined in the arms for CHEMO and STRONT (CHEMO/STRONT). Direct medical costs were collected through the hospital billing system. DNM/IC data were obtained prospectively using the COIN form. Cost data were analyzed for a period of 6 months. RESULTS: Twenty-nine patients were randomized, after which the protocol was closed because of poor accrual. The median survival of the patients was 22.3 months. The mean and median total costs for the 20 of 29 patients with complete cost information were $12,647 and $11,257 over 6 months, respectively. DNM/IC represented 11% of the total cost (range, from < 1% to 42%); in 20% of participating individuals, these costs accounted for 35-42% of total costs. Failure to collect complete cost information was due to early death, administrative difficulties, and loss to follow-up. CONCLUSIONS: In this pilot project, the collection of these cost data using the COIN form was feasible and practical and was limited primarily by logistic, not form specific, issues. DNM/IC were found to be a significant proportion of total costs (up to 42%) in selected patients, and this information proved to be a useful addition to the cost analysis. Approximately 98 patients would be required to detect a 20% difference in total costs between arms in a properly powered, randomized trial. Considering the potentially significant impact on total costs, DNM/IC data should be included in future cost-analysis studies of patients with AIPC and other diseases.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/economia , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/economia , Efeitos Psicossociais da Doença , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Adenocarcinoma/secundário , Idoso , Neoplasias Ósseas/secundário , Custos de Medicamentos , Estramustina/economia , Estramustina/uso terapêutico , Custos de Cuidados de Saúde , Gastos em Saúde , Custos Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Dor/economia , Dor/etiologia , Projetos Piloto , Neoplasias da Próstata/patologia , Estrôncio/economia , Estrôncio/uso terapêutico , Vimblastina/economia , Vimblastina/uso terapêuticoRESUMO
In the past, the treatment options for patients with metastatic prostate cancer that progressed despite castrate levels of testosterone was limited, and no therapies provided an improvement in survival. The majority of these patients had extensive osseous disease, multiple comorbidities, and poor performance status. With the widespread use of prostate-specific antigen (PSA) to monitor their clinical course, patients have presented with less extensive disease and a better performance status. Clinical trial methodology has improved as well, through incorporation of post-therapy changes in PSA to evaluate novel agents. This approach allows more patients to enter clinical trials, and the results show that the majority of these patients will have significant reduction in pain, regression of measurable disease, and suppression of PSA. These data suggest that prostate cancer is not as resistant to chemotherapy as it was once thought to be.
Assuntos
Androgênios/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Antígeno Prostático Específico/análise , Neoplasias da Próstata/tratamento farmacológico , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Determinação de Ponto Final , Estramustina/farmacologia , Estramustina/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/patologia , Testosterona/sangueRESUMO
We have previously reported on a carbohydrate-based vaccine program for immunotherapy in cancer patients. One such vaccine, based on the globo H antigen conjugated to the protein keyhole limpet hemocyanin (KLH), has been in clinical evaluation. Although this and other carbohydrate vaccines have been shown to induce antibody responses, there are currently no quantitative data on the antibody levels achieved in immunized patients by these or other anti-cancer vaccines. We report herein an efficient route to complex synthetic oligosaccharides attached to an affinity matrix for identifying and isolating antibodies elicited against such a carbohydrate-based vaccine in humans. Pre- and postvaccination profiles from serum samples of patients immunized with globo H-KLH were compared. All anti-globo H antibody activity was efficiently separated from other serum constituents. The isolated antibodies were readily quantified, and their specificities were analyzed. Since no comparable data were available on antibodies resulting from the vaccination of other cancer patients, we compared the observed levels with those quoted in studies with bacterial polysaccharide vaccines that had been quantified. Remarkably, cancer patients immunized with globo H-KLH produce anti-globo H antibody levels often exceeding those formed by immunization with bacterial polysaccharides. In addition, substantial quantities of both IgG and IgM antibodies were elicited, clearly indicating a class switch to IgG. Taken together, these analyses serve to clarify several aspects of the immune response to the vaccine and give several new insights to the carbohydrate-based vaccination strategy. Furthermore, antibodies so isolated could well have applications in clinical therapy.
Assuntos
Anticorpos/isolamento & purificação , Vacinas Anticâncer/imunologia , Vacinas Conjugadas/imunologia , Vacinas Sintéticas/uso terapêutico , Especificidade de Anticorpos , Vacinas Anticâncer/isolamento & purificação , Sequência de Carboidratos , Cromatografia de Afinidade , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/imunologia , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Masculino , Dados de Sequência Molecular , Neoplasias da Próstata/imunologia , Vacinas Conjugadas/isolamento & purificaçãoRESUMO
Men with rising prostate-specific antigen (PSA) levels after primary therapies such as prostatectomy or radiotherapy represent a unique group for whom no standard treatment option exists. A variety of approaches including expectant monitoring, dietary modification, hormonal therapy, and alternative medicines have shown an impact on the rate of increase in PSA, but the overall effect on survival remains controversial. At Memorial Sloan-Kettering Cancer Center, we have focused our treatment approach on this cohort of patients in a series of phase I monovalent carbohydrate and glycoprotein-conjugate vaccine trials using the patients' immune system to generate an antitumor response. These synthetic vaccines are conjugated to keyhole limpet hemocyanin (KLH) and given with the immunologic adjuvant QS21 as five subcutaneous vaccines over 26 weeks. All patients generated specific high-titer immunoglobulin M (IgM) and/or IgG antibodies, some of which were able to mediate complement lysis. Preliminary data suggest that these vaccines may impact on the rate of increase in posttreatment PSA slopes compared with pre-PSA values. The impact of vaccine therapy on the PSA slope and its effect on the time to radiographic progression are the current focus of a forthcoming phase II trial. Vaccines may offer an alternative treatment option for the patient who has relapsed early following primary therapies.
Assuntos
Vacinas Anticâncer/imunologia , Neoplasias da Próstata/terapia , Formação de Anticorpos , Vacinas Anticâncer/uso terapêutico , Carboidratos/imunologia , Ensaios Clínicos como Assunto , Glicoproteínas/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Mucinas/imunologia , Vacinas Conjugadas , Vacinas Sintéticas/imunologiaRESUMO
Prostate cancer that has relapsed biochemically after primary therapies, such as prostatectomy or radiation, remains a therapeutic challenge in that no standard treatment option exists for this patient. These patients are often young and may be offered androgen ablation as the mainstay of treatment. Many patients do not wish to undergo a regimen that may be associated with a variety of side effects that will impact on their quality of life. Delaying hormonal treatment in this group does not compromise survival and patients may try a variety of approaches in an attempt to control rising PSAs. Therefore, these patients are an interesting subgroup for whom immunological and alternative therapies may prove to be beneficial. We review new approaches for this population of men, which result in antitumor effects with minimal toxicities.
Assuntos
Recidiva Local de Neoplasia/terapia , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/terapia , Vacinas Anticâncer , Dieta com Restrição de Gorduras , Terapia Genética , Humanos , Masculino , FitoterapiaRESUMO
The complex carbohydrate molecule globo H hexasaccharide has been synthesized, conjugated to keyhole limpet hemocyanin, and administered with the immunologic adjuvant QS-21 as a vaccine for patients with prostate cancer who have relapsed after primary therapies such as radiation or surgery. Globo H is one of several candidate antigens present on prostate cancer cells that can serve as targets for immune recognition and treatment strategies. The vaccine, given as five subcutaneous vaccinations over 26 weeks, has been shown to be safe and capable of inducing specific high-titer IgM antibodies against globo H. Its immunogenicity was confirmed in prostate cancer patients with a broad range of stages and tumor burdens. Observations of several patients who had evidence of disease relapse restricted to a rising biochemical marker, prostate-specific antigen (PSA), indicated that a treatment effect could occur within 3 months after completion of the vaccine therapy. This effect was manifested as a decline of the slope of the log of PSA concentration vs. time plot after treatment compared with values before treatment. Five patients continue to have stable PSA slope profiles in the absence of any radiographic evidence of disease for more than 2 years. The concept of using PSA slope profiles in assessing early treatment effects in biological therapies such as vaccines awaits further validation in phase II and III trials. The use of a variety of lesser known candidate glycoprotein and carbohydrate antigens in prostate cancer serves as a focus for the development of a multivalent vaccine of the treatment of relapsed prostate cancer in patients with minimal tumor burden.
Assuntos
Biomarcadores Tumorais/sangue , Vacinas Anticâncer/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapia , Vacinas Conjugadas/uso terapêutico , Idoso , Anticorpos/sangue , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Sequência de Carboidratos , Proteínas do Sistema Complemento/imunologia , Testes Imunológicos de Citotoxicidade , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Seleção de Pacientes , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/prevenção & controle , Fatores de Tempo , Vacinação , Vacinas Conjugadas/química , Vacinas Conjugadas/imunologiaRESUMO
To assess the tumor targeting, safety, and efficacy of monoclonal antibody 131I-labeled CC49 in patients with androgen-independent prostate cancer, 16 patients received 75 mCi/m2 of the radiolabeled antibody after 7 days of IFN-gamma pretreatment. Sequential tumor biopsies in three patients showed a median 5-fold (range, 2-6-fold) increase in the proportion of cells staining positively for the TAG-72 antigen, whereas one showed a decrease in staining. Fourteen patients received 131I-labeled CC49, whereas 2 showed a disease-related decrease in performance status, precluding antibody treatment. The antibody localized to sites of metastatic androgen-independent prostate cancer in 86% (12 of 14; 95% confidence interval, 57-95%) of cases. Both osseous and extraosseous sites were visualized, and in six (42%) patients, more areas were visible when the radioimmunoconjugate was used than were apparent when conventional scanning techniques were used. The localization of the conjugate in the marrow cavity was usually a site not visualized by the radionuclide bone scan, in which the isotope localizes primarily to the tumor-bone interface. The dose-limiting toxicity was thrombocytopenia because five (36%) patients showed grade IV and seven (50%) showed grade III effects. In addition, six (42%) patients, four of whom were hospitalized, showed a flare in baseline pain, and four showed a decrease in pain. No patient showed a >50% decline in prostate-specific antigen, although radionuclide bone scans remained stable in four cases for a median of 4 months. The results are consistent with dosimetry estimates showing that the delivered dose to tumor was subtherapeutic and suggest that approaches that exclusively target the bone tumor interface or the marrow stroma may be unable to completely eradicate disease in the marrow cavity. For CC49, improving outcomes would require repetitive dosing, which was precluded by the rapid development of a human antimouse antibody response.
Assuntos
Interferon gama/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Neoplasias Hormônio-Dependentes/terapia , Neoplasias da Próstata/terapia , Radioimunoterapia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Antígenos de Neoplasias/análise , Medula Óssea/imunologia , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Terapia Combinada , Glicoproteínas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/radioterapia , Dor , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Tomografia Computadorizada de Emissão , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do TratamentoRESUMO
Defining the expression of tumor-associated antigens on primary and metastatic prostate cancer is the crucial first step in selecting appropriate targets for immune attack. In this study, the distribution of the tumor-associated antigens GM2, Tn, sTn, Thompson-Friedenreich antigen (TF), Globo H, Le(y), MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, carcinoembryonic antigen, beta chain of human chorionic gonadotropin (hCG beta), HER2/neu, PSMA, and KSA on primary and metastatic prostate cancer and 16 types of normal tissues was compared by immunohistochemistry, using a panel of well-characterized monoclonal antibodies. Our results show that GM2, KSA, and MUC2 were strongly expressed on 8 or 9 of 9 metastatic prostate cancer biopsy specimens and, with PSMA, hCG beta, TF, Tn, and sTn, on 8 or more of 11 primary prostate cancer specimens. Tn, MUC1, and PSMA were expressed on 4-6 of 9 metastatic specimens. The remaining antigens were expressed on no more than three of nine metastatic specimens. Normal tissues were also tested with all antibodies. With regard to the eight antigens most widely expressed on prostate cancers, PSMA was not expressed significantly on any of the normal tissues except prostate epithelium. Tn, sTn, hCG beta, and MUC2 were detected on up to 3 of 10 types of normal epithelia. GM2, TF, MUC1, and KSA were more broadly distributed on normal epithelia, all primarily at the secretory borders. STn, KSA, and hCG beta were also detected in the testis, and GM2 was expressed on gray matter of brain. From the 30 antigens that we have screened, this study provides the basis for selecting GM2, TF, Tn, sTn, hCG beta, MUC1, MUC2, KSA, and PSMA as target antigens for specific immunotherapy of prostate cancer.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/biossíntese , Antígenos de Superfície/biossíntese , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Sequência de Aminoácidos , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Sequência de Carboidratos , Epitopos , Humanos , Masculino , Dados de Sequência Molecular , Metástase Neoplásica , Neoplasias da Próstata/imunologiaRESUMO
Conventional therapies for patients with early-stage relapsed prostate cancer often do not provide an acceptable quality of life. These patients often have increasing PSAs as the sole manifestation of their disease recurrence and represent a unique subgroup of patients for whom alternative treatment strategies are needed. The patients are asymptomatic and may be an appropriate population for targeted immunological approaches. Vaccine therapies, based on synthetically constructed, naturally occurring prostate-associated antigens or genetically modified immune cells, offer exciting new approaches toward treating this disease with resulting antitumor effects and minimal toxicities. The results of clinical trials using these technologies reinforces the use of immunological approaches for the treatment of prostate cancer.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Células Dendríticas/imunologia , Terapia Genética/métodos , Humanos , Masculino , Antígeno Prostático Específico/sangue , Qualidade de Vida , RecidivaRESUMO
Carcinoma of the prostate represents a wide range of diseases with differing prognoses. A key to selecting treatment depends on the ability to predict the natural history of the disease for the individual. Thus far, non-hormonal approaches have not demonstrated a survival advantage in randomized comparisons and, clearly, innovative approaches are needed. The clinical trials program developed at Memorial Sloan-Kettering Cancer Center is based on specific manifestations and specific targets of the disease and the predicted prognosis, using prostate-specific antigen and acid phosphatase changes as biomarkers of progression and response. In patients with minimal disease who have received local treatments but progressed systemically, we are studying methods aimed at stimulating their immune systems either by nonspecific immunopotentiation or specific immunization to specific glycoprotein or carbohydrate targets on the cancer cells, or to anti-growth factor receptor antibody aimed at blocking the specific signalling pathways that contribute to hormonal failure. These and other approaches provide an opportunity to treat this disease while maintaining an acceptable quality of life for patients.
Assuntos
Antineoplásicos/farmacologia , Imunoterapia , Neoplasias Hormônio-Dependentes/terapia , Neoplasias da Próstata/terapia , Radioimunoterapia , Receptores de Fatores de Crescimento/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais , Humanos , Masculino , Neoplasias Hormônio-Dependentes/imunologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/imunologiaRESUMO
Peripheral blood lymphocytes (PBL), when cultured in vitro in the presence of autologous irradiated tumor and interleukin-2 (IL-2), become more restricted in the spectrum of their cytotoxicity. The cells continue to exhibit cytotoxicity for autologous tumor cells and major histocompatibility complex (MHC)-concordant allogeneic tumor cells of similar histologic type but not for the natural killer target cell line, K562. Furthermore, the addition of autologous tumor at different time points after the initiation with IL-2 alone of conventional lymphokine-activated killer cell cultures modifies both the specificity and the degree of cytotoxicity of these lymphocytes for tumor targets. By varying the culture conditions it may be possible to generate killer cells that will exhibit similarly enhanced and more restricted antitumor effects in vivo.
Assuntos
Células Matadoras Ativadas por Linfocina/imunologia , Células Tumorais Cultivadas/imunologia , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Linhagem Celular , Citotoxicidade Imunológica , Antígenos HLA/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-2/farmacologia , Complexo Principal de Histocompatibilidade/imunologia , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
The recent explosion of knowledge in the field of immunology has resulted in the development of many new and exciting forms of treatment for cancer patients. The identification of murine MoAbs with reactivity against antigens found on sarcomas has been accomplished in recent years. However, many problems exist with these reagents. As these antibodies are raised in mice, they represent foreign proteins for humans. As such, the development of immunity against the antibodies has been one of the major problems in applying this modality in the clinic. Other problems, such as specificity, antigenic modulation, tumor cell heterogeneity, and trafficking of the antibody to the tumor, remain to be resolved. Current research involving the development of chimeric or human MoAbs may overcome some of these obstacles. Cell-mediated approaches to therapy have met with enthusiasm and modest success so far. Although LAK cell therapy has not resulted in tumor regressions in the small number of sarcoma patients treated, further studies to define the true response rate are underway. It is possible that treatment with tumor-specific cells such as TIL or "educated" lymphocytes will be more effective in attaining regression in patients with metastatic bone and soft tissue sarcomas.
Assuntos
Neoplasias Ósseas/terapia , Imunização Passiva , Imunoterapia , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Humanos , Interferons/uso terapêutico , Células Matadoras Naturais/transplante , Linfocinas/imunologiaRESUMO
Human T cell clones cytotoxic for autologous sarcoma cell lines have been developed from patient JM with an osteogenic sarcoma, and from patients EG and RM with malignant fibrohistiocytoma. These clones were derived from the cocultivation of peripheral blood lymphocytes (PBL) with the respective patient's autologous irradiated established tumor cell lines (AIT). After two cycles of stimulation for 5 days in bulk culture, these "educated" lymphocytes were seeded at a density of 1 X 10(6) cells/well in 24-well plates and were cultured in the presence of highly purified natural IL 2 and AIT, the latter serving as a feeder layer. Cell numbers were reduced from the initial seeding density by one log each week until reaching a density of 10(2) cells. These cells were found to be stable in viability and cytotoxic activity, after which limiting dilution was then performed. Within 4 to 6 wk, clones were isolated with unique specificities. These clones were capable of proliferating to a total density of 10(9) cells/ml and maintained their specific cytotoxicity for more than 6 mo. Testing with a panel of target cells of various histotypes, cold-target inhibition assays, and blocking of cytotoxicity with anti-HLA monoclonal antibodies showed that the T cell clones recognize a common sarcoma-associated antigen and that the lysis is HLA restricted. Phenotypically, cytotoxic clones derived from JM were Leu-1+, Leu-2+, and Leu-3-, whereas those derived from EG exhibited either Leu-24 or Leu-3+ markers, the latter phenotype lacking cytotoxicity. RM exhibited mainly Leu-3+ clones with strong cytotoxicity. All were HNK-1- and HLA class II+, with less than 1% of cells of each clone stained by anti-TAC monoclonal antibody. The clones from each patient did not lyse autologous or allogeneic PBL, mitogen-induced T lymphoblasts, normal fibroblasts, cells isolated from benign neoplasms, carcinoma cells, Daudi B lymphoid cells, or K562 cells. With the exception of EG, all clones produced immune interferon in a range from 12 to 50 U/ml. The generation of long-term specific T cell clones can be used to further dissect the cellular immune response to sarcomas. Cytotoxic T cell clones have potential application for tumor immunotherapy.
Assuntos
Sarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos de Neoplasias/imunologia , Células Cultivadas , Células Clonais , Antígenos HLA/imunologia , Antígenos HLA-DR/imunologia , Humanos , Imunidade Celular , Interferon gama/metabolismo , Interleucina-2/farmacologiaRESUMO
After nearly a decade of controversy, the concept of adoptive immunotherapy in humans is gaining greater acceptance. More recently, investigators have made use immunotherapeutically of T-lymphocytes nonspecifically activated in vitro by a number of agents, including lymphokines, lectins, and autologous and allogeneic tumor cells. The limitations for the investigational use of these highly specialized and "educated" lymphocytes have been the inability to generate sufficient numbers of cells in vitro for adoptive transfer experiments and to sustain their growth over long periods of time. While marked success has been demonstrated over the years in tumor-bearing animal models, the feasibility of such work in humans has been greatly improved by the experimental expansion and maintenance of immune lymphocytes (those exposed to antigenic challenge) in vitro using either highly purified or recombinant, interleukin 2. As a result, large numbers of lymphocytes can successfully be infused into patients, and whole body scans can show migration of these labeled cells to the lung, liver, and spleen. The use of nontoxic, nonspecific activated "killer" lymphocytes is an innovative approach with enormous potential. This report presents discussion of these findings and addresses the issue of an alternative approach to cancer treatment therapy, the in vivo use of cloned cytotoxic T-lymphocytes sensitized to the autologous tumor.