RESUMO
Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline ß2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.
Assuntos
Linfoma Folicular , Protocolos de Quimioterapia Combinada Antineoplásica , Progressão da Doença , Humanos , Imunoterapia , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Masculino , Prognóstico , Fatores de RiscoRESUMO
Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced-dose FCR (FCR-Lite) plus lenalidomide (FCR(2) ) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR(2) . Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR(2) . Twenty patients were evaluable. After four cycles of FCR(2) , response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR(2) . After 17.4 months of median follow-up, one progression and one death occurred. Our findings suggest that FCR(2) combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Rituximab , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, â¼50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.
Assuntos
Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
Interleukin-15 (IL-15) has a major role in NK-cell homeostasis. Modulation of the relative frequency and expression intensity of the NK-cell receptors by IL-15 may increase NK cell-mediated cytotoxicity in cancer patients. We investigated the receptor repertoire and measured NK-cell activity in newly diagnosed AML patients and evaluated the ex vivo effects of IL-15. The expression of the activating NK cell receptors was significantly decreased in the AML patients compared to that in NK cells of healthy donors. When NK cells obtained from AML patients were cultured with IL-15, expression of the activating receptors was significantly upregulated compared to pre-culture levels. Concomitantly, cytotoxic activity of NK cells against autologous leukemic blasts increased following IL-15 stimulation. This IL-15 induced increase in activity was blocked by neutralizing antibodies specific for the NK cell activating receptors. These pre-clinical data support the future use of IL-15 for NK cell- based therapies for AML patients.
Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Interleucina-15/farmacologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/metabolismo , Receptores de Células Matadoras Naturais/biossíntese , Células Cultivadas , Humanos , Interleucina-15/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Mieloide Aguda/imunologia , Regulação para CimaRESUMO
PURPOSE: Regulatory CD4(+)CD25(high)Foxp3(+) T cells (Treg) control peripheral immune tolerance. Patients with cancer, including those with hematologic malignancies, have elevated numbers of Treg in the peripheral circulation and in tumor tissues. However, mechanisms of suppression and clinical significance of Treg, especially in patients with acute myelogenous leukemia (AML), has not been well defined. EXPERIMENTAL DESIGN: We prospectively evaluated the phenotype, function, and mechanisms of suppression used by Treg in newly diagnosed untreated AML patients. The relationship between the frequency of circulating Treg and the disease status as well as treatment outcome was also evaluated. RESULTS: The percentage of circulating Treg was higher (P < 0.0001) and their phenotype was distinct in AML patients relative to normal controls. Suppression mediated by Treg coincubated with proliferating autologous responder cells was also higher (P < 0.001) in AML than that mediated by control Treg. Using Transwell inserts, we showed that interleukin-10 and transforming growth factor-beta1 production as well as cell-to-cell contact were necessary for Treg-mediated suppression. Also, the pretreatment Treg frequency predicted response to chemotherapy. Unexpectedly, patients who achieved complete remission still had elevated frequency of Treg, which mediated high levels of suppressor activity. CONCLUSIONS: Treg accumulating in the peripheral circulation of AML patients mediate vigorous suppression via contact-dependent and contact-independent mechanisms. Patients with lower Treg frequency at diagnosis have a better response to induction chemotherapy. During the post-induction period, the Treg frequency and suppressive activity remain elevated in complete remission, suggesting that Treg are resistant to conventional chemotherapy.
Assuntos
Leucemia Mieloide/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Trifosfato de Adenosina/metabolismo , Antígenos CD4/imunologia , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/imunologia , Leucemia Mieloide/sangue , Leucemia Mieloide/patologia , Prognóstico , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismoRESUMO
Immunostimulatory DNA containing unmethylated cytosine-guanine (CpG) motifs have been successfully used as adjuvants to enhance the immunity of vaccines designed to trigger antitumor T-cell responses. We examined the effect of a CpG oligodeoxynucleotide (CpG ODN) for its ability to potentiate the activity of tumor antigen-pulsed dendritic cells (DC) in a clinically relevant mouse model, which is transgenic for both carcinoembryonic antigen (CEA) and HLA-A2 for the treatment of colon carcinoma in a therapeutic setting. The systemic administration of CpG ODN 1826 alone had modest effect on tumor growth when tumors were palpable and had no effect with larger tumor burden. However, coadministration of CpG ODN 1826 with the vaccine provided significant increase in tumor-free survival compared with mice immunized with DC-based vaccines alone. The DC/CpG combined vaccination strategy resulted in increased secretion of Th1 cytokines and HLA-A2-restricted CEA-specific CTL responses were also enhanced. Both tumor regression and extended tumor-free survival resulting from DC/CpG combination therapy required the participation of T cells. Tumor-free mice were resistant to tumor rechallenge and immunity conferred by the vaccine was transferable in athymic nude mice. These results provide evidence that vaccination with antigen-pulsed DC with CpG ODN as adjuvant can lead to effective tumor regression and long-term survival in a murine model of colon carcinoma.
Assuntos
Antígeno Carcinoembrionário/genética , Neoplasias do Colo/terapia , DNA/farmacologia , Células Dendríticas/citologia , Antígeno HLA-A2/genética , Imunoterapia/métodos , Oligodesoxirribonucleotídeos/genética , Animais , Células Apresentadoras de Antígenos , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Epitopos/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T Citotóxicos/citologiaRESUMO
In chronic lymphocytic leukemia (CLL), malignant B cells and nonmalignant T cells exhibit dysfunction. We previously demonstrated that infection of CLL cells with modified vaccinia Ankara (MVA) expressing the costimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM) increased expression of these costimulatory molecules on the surface of CLL cells and thus augmented their antigen-presenting capability. Here, we evaluate the effect of MVA-TRICOM-modified CLL cells on T cells. Following incubation with irradiated MVA-TRICOM-modified CLL cells, allogeneic and autologous CD4(+) and CD8(+) T cells expressed significantly higher levels of B7-1, ICAM-1, and LFA-3. We show that this increase was the result of physical acquisition from the antigen-presenting cells (APCs), and that purified T cells that acquired costimulatory molecules from MVA-TRICOM-modified CLL cells were able to stimulate the proliferation of untreated T cells. These results demonstrate for the first time that T cells from CLL patients can acquire multiple costimulatory molecules from autologous CLL cells and can then act as APCs themselves. Given the immunodeficiencies characteristic of CLL, enhancing the antigen-presenting function of CLL cells and T cells simultaneously could be a distinct advantage in the effort to elicit antitumor immune responses.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígeno B7-1/metabolismo , Antígenos CD58/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos T/imunologia , Antígeno B7-1/genética , Antígenos CD58/genética , Humanos , Molécula 1 de Adesão Intercelular/genética , Leucemia Linfocítica Crônica de Células B/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Vaccinia virus/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Leucemia Linfocítica Crônica de Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Rituximab , Análise de Sobrevida , Fatores de Tempo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
PURPOSE: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. EXPERIMENTAL DESIGN: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [(18) F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. RESULTS: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P=0.010). CONCLUSIONS: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RituximabRESUMO
Induction of active tumor-specific immunity in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies is compromised by the deficit of endogenous dendritic cells (DCs). In attempt to develop improved vaccination strategies for patients with CLL and other tumors with poorly identified rejection antigens, we tested the ability of ex vivo-generated DCs to cross-present the antigens expressed by CLL cells and to induce CLL-specific, functional CTL responses. Monocyte-derived DCs from CLL patients were induced to mature using a "standard" cytokine cocktail (in IL-1beta, TNF-alpha, IL-6, and PGE2) or using an alpha-type 1-polarized DC (alphaDC1) cocktail (in IL-1beta, TNF-alpha, IFN-alpha, IFN-gamma, and polyinosinic:polycytidylic acid) and were loaded with gamma-irradiated, autologous CLL cells. alphaDC1 from CLL patients expressed substantially higher levels of multiple costimulatory molecules (CD83, CD86, CD80, CD11c, and CD40) than standard DCs (sDCs) and immature DCs, and their expression of CCR7 showed intermediate level. alphaDC1 secreted substantially higher (10-60 times) levels of IL-12p70 than sDCs. Although alphaDC1 and sDCs showed similar uptake of CLL cells, alphaDC1 induced much higher numbers (range, 2.4-38 times) of functional CD8+ T cells against CLL cells. The current demonstration that autologous tumor-loaded alphaDC1 are potent inducers of CLL-specific T cells helps to develop improved immunotherapies of CLL.
Assuntos
Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos da radiação , Diferenciação Celular/efeitos da radiação , Células Dendríticas/metabolismo , Células Dendríticas/efeitos da radiação , Raios gama , Humanos , Interleucina-12/metabolismo , Fenótipo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Raios UltravioletaRESUMO
Induction of potent and sustained antitumor immunity depends on the efficient activation of CD8(+) and CD4(+) T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4(+) T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2-restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA(691) (YMIGMLVGV)-pulsed dendritic cells or CAP1-6D (YLSGADLNL, agonist peptide for CAP-1)-pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptide-pulsed dendritic cells alone (P < 0.02). IFN-gamma ELISPOT and (51)Cr-release assays showed that HLA-A2-restricted, CEA-specific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4(+) T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications.
Assuntos
Vacinas Anticâncer/imunologia , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Antígeno HLA-A2/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/farmacologia , Antígeno Carcinoembrionário/genética , Células Dendríticas/imunologia , Epitopos/imunologia , Feminino , Antígeno HLA-A2/genética , Memória Imunológica , Imunoterapia Adotiva/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/farmacologiaAssuntos
Leucemia Linfocítica Crônica de Células B/terapia , Guias de Prática Clínica como Assunto/normas , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Diagnóstico Diferencial , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Neoplasia Residual/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodosAssuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/administração & dosagem , Adulto , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Estudos de Coortes , Recall de Medicamento , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/efeitos adversos , Feminino , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Indução de Remissão , Suspensão de TratamentoRESUMO
In this study, using the carcinoembryonic antigen (CEA)-expressing C15 murine colon carcinoma system in syngeneic C57BL/6 mice, we have evaluated the efficacy of bone marrow-derived dendritic cells (DCs) pulsed with the murine anti-idiotype antibody 3H1 as a tumor vaccine. Anti-idiotype 3H1 mimics a distinct and specific epitope of CEA and can generate anti-CEA immunity in mice, rabbits, monkeys, and humans when used with a conventional immune adjuvant. Our goal was to determine whether the use of DC as direct antigen-presenting cells would improve the potency of 3H1 as vaccine. Bone marrow-DC pulsed with 3H1 and injected into naïve mice induced both humoral and cellular anti-3H1, as well as anti-CEA immunity. Specific killing of C15 cells in in vitro antibody-dependent cellular cytotoxicity has been observed by immune sera. Immune-splenic lymphocytes when stimulated in vitro with 3H1 or CEA, showed increased proliferative CD4(+) Th1 type T-cell response and secreted significantly high levels of Th1 cytokines [IFN-gamma, interleukin (IL)-2] and low levels of Th2 cytokines (IL-4, IL-10). This vaccine also induced MHC class I antigen-restricted CD8(+) T-cell responses. The up-regulation of activation markers CD69 and CD25 on CD8(+) CTLs correlated with antigen-specific strong CTL responses in vitro. The immunity induced in mice resulted in a complete rejection of CEA-expressing C15 tumor cells in 100% of experimental mice, whereas no protection was observed when 3H1-pulsed DC-vaccinated mice were challenged with CEA-negative MC-38 cells. The tumor rejection in 3H1-pulsed DC-treated mice was associated with the induction of a memory response that helped those mice to survive a second challenge with a lethal dose of C15 cells.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Vacinas Anticâncer/imunologia , Neoplasias do Colo/imunologia , Células Dendríticas/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/prevenção & controle , Citocinas/biossíntese , Células Dendríticas/metabolismo , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Memória Imunológica/imunologia , Interleucina-12/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Tumorais CultivadasRESUMO
In this report, we have studied the immunogenicity of the nominal antigen, carcinoembryonic antigen (CEA), and that of an anti-idiotype antibody, 3H1, which mimics CEA and can be used as a surrogate for CEA. We have demonstrated that immunization of CEA transgenic mice with bone marrow-derived mature dendritic cells (DC) loaded with anti-idiotype 3H1 or CEA could reverse CEA unresponsiveness and result in the induction of CEA-specific immune responses and the rejection of CEA-transfected MC-38 colon carcinoma cells, C15. Immunized mice splenocytes proliferated in an antigen-specific manner by a mechanism dependent on the functions of CD4, MHC II, B7-2, CD40, CD28, and CD25. However, immune splenic lymphocytes isolated from 3H1-DC-vaccinated mice when stimulated in vitro with 3H1 or CEA secreted significantly higher levels of Th1 cytokines than did CEA-DC vaccinated mice. DC vaccination also induced antigen-specific effector CD8+ T cells capable of expressing interleukin-2, IFN-gamma, and tumor necrosis factor (TNF)-alpha and displayed cytotoxic activity against C15 cells in an MHC class I-restricted manner. 3H1-DC vaccination resulted in augmented CTL responses and the elevated expression of CD69, CD25, and CD28 on CD8(+) CTLs. The immune responses developed in 3H1-DC-immunized mice resulted in rejection of C15 tumor cells in nearly 100% of experimental mice, whereas only 40% of experimental mice immunized with CEA-DC were protected from C15 tumor growth. These findings suggest that under the experimental conditions used, 3H1-DC vaccination was better than CEA-DC vaccination in breaking immune tolerance to CEA and inducing protective antitumor immune responses in this murine model transgenic for human CEA.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/imunologia , Células Dendríticas/imunologia , Imunoterapia Adotiva/métodos , Animais , Neoplasias do Colo/prevenção & controle , Neoplasias do Colo/terapia , Citocinas/biossíntese , Citocinas/imunologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Regulação para CimaRESUMO
PURPOSE: To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. RESULTS: Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. CONCLUSION: ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
Assuntos
Anticorpos Monoclonais/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Fosfatase Alcalina/sangue , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/toxicidade , Carcinoma de Células Renais/metabolismo , Toxidermias/etiologia , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Panitumumabe , SegurançaRESUMO
This phase 2 study assessed the safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m(2) weekly for 4 weeks. Grade 3/4/5 adverse events (AEs) were reported in 11/1/1 patients, respectively. Serious AEs were reported by 11/50 patients, and three discontinued due to AEs. One patient died from aspiration pneumonia due to possibly drug-related nausea and vomiting. Investigator-assessed response rate was 30% (15/50), including four complete responses (CR), three CR unconfirmed (CRu) and eight partial responses (PR). Investigator-assessed median Progression-free survivial (PFS) was 38.3 weeks. Ocaratuzumab's pharmacokinetic profile was similar to that reported for rituximab. Lymphocyte subset analysis showed significant, selective reduction of B-cells during and after ocaratuzumab treatment. Ocaratuzumab at this dose and schedule is active and well tolerated in patients with previously treated FL with low affinity FcγRIIIa genotypes. ClinTrials registry number: NCT00354926.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Receptores de IgG/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Feminino , Heterozigoto , Humanos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Retratamento , Resultado do TratamentoRESUMO
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, with an extracellular ligand-binding domain and intracellular tyrosine kinase domain. Ligand binding induces EGFR dimerization and autophosphorylation on several tyrosine residues in the intracellular domain, leading to mitogenic signal transduction. EGFR overexpression correlates with a poor prognosis and is often associated with malignant transformation in a variety of epithelial cancers. ABX-EGF is a high-affinity (dissociation constant K(D) = 5 x 10(-11) M) fully human IgG2 monoclonal antibody against human EGFR. ABX-EGF binds EGFR and blocks receptor binding of EGF and transforming growth factor-alpha, inhibiting EGFR tyrosine phosphorylation and tumor cell activation. ABX-EGF prevents tumor formation and eradicates large, established A431 tumors in xenograft models. Tumor growth inhibition occurs at relatively low doses, without concomitant chemotherapy or radiotherapy. When combined with chemotherapeutic agents, ABX-EGF has resulted in additive antitumor activity. A Phase I clinical trial has demonstrated activity in several tumor types, and the results from a Phase II trial for renal cell cancer also showed modest activity. Therapy was generally well tolerated without statistically significant adverse events. Monoclonal antibody blockade of EGFR represents a new and exciting direction in cancer therapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Receptores ErbB/metabolismo , Humanos , Neoplasias Renais/tratamento farmacológico , Camundongos , Proteínas de Neoplasias/metabolismo , Panitumumabe , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
The use of anti-idiotype (Id) antibodies as vaccines to stimulate antitumour immunity is one of several promising immunologic approaches to the therapy of cancer. Extensive studies in animal tumour models have demonstrated the efficacy of anti-Id vaccines in preventing tumour growth and curing mice with established tumours. A number of monoclonal anti-Id antibodies that mimic distinct human tumour-associated antigens (TAAs) have been developed and tested in the clinic, and demonstrate encouraging results. In general, the antigen mimicry by anti-Id antibodies has reflected structural homology in the majority of the cases, and amino acid sequence homology in a few of them. The greatest challenge of immunotherapy by means of anti-Id vaccines is to identify the optimal anti-Id antibody that will function as a true surrogate antigen for a TAA system, and ideally will generate both humoral and cellular immune responses. Although several clinical studies have shown enhanced survival of patients receiving anti-Id vaccines, the efficacy of these vaccines will depend on the results of several randomised Phase III clinical trials that are currently planned or ongoing.
Assuntos
Anticorpos Anti-Idiotípicos/uso terapêutico , Imunoterapia Ativa/métodos , Neoplasias/terapia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.