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PURPOSE: The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. METHODS: Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. RESULTS: To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. CONCLUSION: The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.
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Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.
Assuntos
Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/genética , Talidomida/uso terapêutico , Talidomida/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Feminino , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Recidiva , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , IdosoRESUMO
BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).
Assuntos
Antineoplásicos , Dexametasona , Mieloma Múltiplo , Ubiquitina-Proteína Ligases , Humanos , Anticorpos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Administração Oral , RecidivaRESUMO
AIMS: A parent-metabolite population pharmacokinetic (popPK) model of iberdomide and its pharmacologically active metabolite (M12) was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from 3 clinical studies of iberdomide (dose range, 0.1-6 mg) in healthy subjects (n = 81) and patients with relapsed and refractory multiple myeloma (n 245). METHODS: Nonlinear mixed effects modelling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies. RESULTS: The pharmacokinetics (PK) of iberdomide were adequately described with a 2-compartment model with first-order absorption and elimination. A first-order conversion rate was used to link the 1-compartment linear elimination metabolite model with the parent model. Subject type (multiple myeloma patients vs. healthy subject) was a statistically significant covariate on apparent clearance and apparent volume of distribution for the central compartment, suggesting different PK between patients with multiple myeloma and healthy subjects. Aspartate aminotransferase and sex were statistically but not clinically relevant covariates on apparent clearance. Metabolite (M12) PK tracked the PK of iberdomide. The metabolite to parent ratio was consistent across doses and combinations. CONCLUSION: The parent-metabolite population PK model adequately described the time course PK data of iberdomide and M12. Iberdomide and M12 PK exposure were not complicated by demographic factors (age [19-82 y], body weight [41-172 kg], body surface area [1.4-2.7 m2 ], body mass index [16.4-59.3 kg/m2 ]), combination (in combination with dexamethasone and daratumumab), mild hepatic, or mild and moderate renal impairments. The model can be used to guide the dosing strategy for special patient population and inform future iberdomide study design.
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Mieloma Múltiplo , Humanos , Voluntários Saudáveis , Índice de Massa Corporal , Peso Corporal , Modelos BiológicosRESUMO
Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Terapia de Salvação , Sulfonamidas/farmacologia , Idoso , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Medula Óssea/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Terapia Combinada , Dexametasona/administração & dosagem , Feminino , Seguimentos , Genes bcl-2 , Doenças Hematológicas/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecções/etiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Recidiva , Transdução de Sinais , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Translocação Genética , Proteína bcl-XRESUMO
BACKGROUND: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. FINDINGS: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. INTERPRETATION: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. FUNDING: AbbVie and Genentech.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Dexametasona/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Intervalo Livre de Progressão , Inibidores de Proteassoma/efeitos adversos , Sulfonamidas/efeitos adversos , Fatores de TempoAssuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Bioensaio/métodos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Prognóstico , Sulfonamidas/farmacologia , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
Despite advances in the treatment of multiple myeloma, the disease still remains incurable for the majority of patients. The overexpression of anti-apoptotic proteins (i.e., Bcl-2, Bcl-XL or Mcl-1) is a hallmark of cancer and favors tumor cell survival and resistance to therapy. The oral drug venetoclax is the first-in-class Bcl-2-specific BH3 mimetic. In myeloma, in vitro sensitivity to venetoclax is mainly observed in plasma cells harboring the t(11;14) translocation, a molecular subgroup associated with high Bcl-2 and low Mcl-1/Bcl-XL expression. In addition with Bcl-2 members expression profile, functional tests as BH3 profiling or in vitro BH3 mimetic drug testing also predict sensitivity to the drug. Phase 1 clinical trials recently confirmed the efficacy of venetoclax monotherapy in heavily pretreated myeloma patients, mostly in patients with t(11;14). In combination with the proteasome inhibitor bortezomib, venetoclax therapy was found to be feasible and allowed promising response rate in relapsed myeloma patients, independent of t(11;14) status. The present review summarizes the current knowledge, "from bench to bedside", about venetoclax for the treatment of multiple myeloma.
Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/genética , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do TratamentoRESUMO
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.
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Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, exhibits multifaceted effects to boost the stimulation of immune responses to a variety of antigens. However, the direct ability of LLO as an adjuvant and whether it acts as a pathogen-associated molecular pattern (PAMP) have not been demonstrated. In this paper, we show that a detoxified, nonhemolytic form of LLO (dtLLO) is an effective adjuvant in tumor immunotherapy and may activate innate and cellular immune responses by acting as a PAMP. Our investigation of the adjuvant activity demonstrates that dtLLO, either fused to or administered as a mixture with a human papillomavirus type 16 (HPV-16) E7 recombinant protein, can augment antitumor immune responses and facilitate tumor eradication. Further mechanistic studies using bone marrow-derived dendritic cells suggest that dtLLO acts as a PAMP by stimulating production of proinflammatory cytokines and inducing maturation of antigen-presenting cells (APC). We propose that dtLLO is an effective adjuvant for tumor immunotherapy, and likely for other therapeutic settings.
Assuntos
Adjuvantes Imunológicos/farmacologia , Toxinas Bacterianas/farmacologia , Vacinas Anticâncer/administração & dosagem , Proteínas de Choque Térmico/farmacologia , Proteínas Hemolisinas/farmacologia , Imunoterapia/métodos , Listeria monocytogenes/química , Adjuvantes Imunológicos/isolamento & purificação , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Toxinas Bacterianas/isolamento & purificação , Vacinas Anticâncer/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Proteínas de Choque Térmico/isolamento & purificação , Proteínas Hemolisinas/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus/imunologiaRESUMO
OBJECTIVE: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme may be involved in carcinogenesis, particularly in lung, gastric, colorectal and breast cancer. METHODS: In the present study, we have evaluated SOD2 protein levels by immunohistochemistry (IHC) in 331 cervical histological samples including 31 low-grade cervical intraepithelial neoplasia (LSIL), 51 high-grade cervical intraepithelial neoplasia (HSIL), 197 squamous cervical carcinomas (SCC) and 52 cervical adenocarcinomas (ADENO). RESULTS: We observed that SOD2 staining increases with cervical disease severity. Intense SOD2 staining was found in 13% of LSIL, 25.5% of HSIL and 40% of SCC. Moreover, 65.4% of ADENO exhibited intense SOD2 staining. CONCLUSIONS: Differences in the expression of SOD2 could potentially be used as a biomarker for the characterization of different stages of cervical disease.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Superóxido Dismutase/genética , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Razão de Chances , Superóxido Dismutase/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/patologiaRESUMO
OBJECTIVE: To develop a DNA cancer vaccine that targets the vascular endothelial growth factor receptor. DESIGN: Mice were vaccinated intramuscularly with listeriolysin O-fetal liver kinase 1 (LLO-Flk1) or controls. Mice were also challenged subcutaneously with the tumor cell line TC-1. Tumor sizes were measured after vaccination. At the conclusion of the experiments, the tumors were harvested for immunohistochemical analysis and determination of hemoglobin content. SETTING: Research laboratory. SUBJECTS: Six- to 8-week-old C57BL/6 mice. INTERVENTION: Fifty micrograms of each vector was administered 3 times at weekly intervals. MAIN OUTCOME MEASURES: Tumor size, mean vessel density of tumors, hemoglobin content of tumor. RESULTS: Mice treated with the LLO-Flk1 vaccine experienced slower tumor growth relative to the other treatment groups. Complete tumor regression was observed in several cases. Immunohistochemical staining of tumors revealed fewer blood vessels in the mice vaccinated with the LLO-Flk1 vaccine relative to the other treatment groups. Finally, colorimetric assessment for hemoglobin suggested decreased vasculature in the tumor bed of these mice relative to the control groups. CONCLUSION: The novel DNA cancer vaccine LLO-Flk1 can slow tumor growth in vivo.
Assuntos
Vacinas Anticâncer/farmacologia , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Vacinas de DNA/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Toxinas Bacterianas/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Feminino , Vetores Genéticos , Proteínas de Choque Térmico/imunologia , Hemoglobinas/metabolismo , Proteínas Hemolisinas/imunologia , Imuno-Histoquímica , Imunoterapia , Injeções Intramusculares , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/prevenção & controle , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Transfecção , Vacinas de DNA/imunologiaRESUMO
Overexpression of kallikrein 7, a proteolytic enzyme important for epithelial cell shedding, may be causally involved in carcinogenesis, particularly in tumor metastasis and invasion. In this study, we have evaluated hK7 (human kallikrein 7) protein levels by immunohistochemistry in 367 cervical histological samples including 35 cases of cervicitis, 31 low-grade cervical intraepithelial neoplasia, 51 high-grade cervical intraepithelial neoplasia (H-SIL), 197 squamous cervical carcinomas (SCC) and 53 cervical adenocarcinomas. We have observed that hK7 staining increased with the severity of cervical disease. Intense hK7 staining was found in 15.2% of cervicitis samples, in contrast to 55% of H-SIL and 68% of SCC. Moreover, 92.5% of adenocarcinomas also exhibited intense hK7 staining. Differences in the expression of hK7 could potentially be used as a biomarker for the characterization of different stages of cervical disease.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Calicreínas/metabolismo , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Cervicite Uterina/metabolismo , Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologia , Cervicite Uterina/patologia , Displasia do Colo do Útero/patologiaRESUMO
Live, attenuated strains of many bacteria that synthesize and secrete foreign antigens are being developed as vaccines for a number of infectious diseases and cancer. Bacterial-based vaccines provide a number of advantages over other antigen delivery strategies including low cost of production, the absence of animal products, genetic stability and safety. In addition, bacterial vaccines delivering a tumor-associated antigen (TAA) stimulate innate immunity and also activate both arms of the adaptive immune system by which they exert efficacious anti-tumor effects. Listeria monocytogenes and several strains of Salmonella have been most extensively studied for this purpose. A number of attenuated strains have been generated and used to deliver antigens associated with infectious diseases and cancer. Although both bacteria are intracellular, the immune responses invoked by Listeria and Salmonella are different due to their sub-cellular locations. Upon entering antigen-presenting cells by phagocytosis, Listeria is capable of escaping from the phagosomal compartment and thus has direct access to the cell cytosol. Proteins delivered by this vector behave as endogenous antigens, are presented on the cell surface in the context of MHC class I molecules, and generate strong cell-mediated immune responses. In contrast, proteins delivered by Salmonella, which lacks a phagosomal escape mechanism, are treated as exogenous antigens and presented by MHC class II molecules resulting predominantly in Th2 type immune responses. This fundamental disparity between the life cycles of the two vectors accounts for their differential application as antigen delivery vehicles. The present paper includes a review of the most recent advances in the development of these two bacterial vectors for treatment of cancer. Similarities and differences between the two vectors are discussed.
Assuntos
Listeria/imunologia , Neoplasias/imunologia , Salmonella/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Vacinas Anticâncer/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Listeria/metabolismo , Modelos Biológicos , Salmonella/metabolismoRESUMO
Neutralizing antibodies are thought to be required at mucosal surfaces to prevent human papillomavirus (HPV) transmission. However, the potential for cell-mediated immunity in mediating protection against HPV infection has not been well explored. We generated recombinant Listeria monocytogenes (Lm) constructs that secrete listeriolysin O (LLO) fused with overlapping N-terminal (LLO-L1(1-258)) or C-terminal (LLO-L1(238-474)) fragments of HPV type 16 major capsid protein L1 (HPV-16-L1). Oral immunization of mice with either construct induced IFN-gamma-producing CD8+ and CD4+ T cells in the spleen and in the Peyer's patches with the C-terminal construct. Oral immunization with both constructs resulted in diminished viral titers in the cervix and uterus of mice after intravaginal challenge with vaccinia virus expressing HPV-16-L1.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas do Capsídeo/imunologia , Imunoterapia Ativa/métodos , Listeria monocytogenes/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/prevenção & controle , Administração Oral , Animais , Toxinas Bacterianas/biossíntese , Toxinas Bacterianas/imunologia , Proteínas do Capsídeo/biossíntese , Proteínas do Capsídeo/metabolismo , Colo do Útero/virologia , Feminino , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/biossíntese , Proteínas Hemolisinas/imunologia , Proteínas Hemolisinas/metabolismo , Humanos , Imunidade Celular , Imunidade nas Mucosas , Camundongos , Proteínas Oncogênicas Virais/biossíntese , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Human papillomavirus (HPV) infection is linked to the development of cervical cancer, and several cofactors contribute to the risk of disease. Research on the intratypic variability of HPVs has defined variants that are associated with persistent infections and are potentially more oncogenic, translating to a higher risk of malignant disease. The genetic variability of the host also plays a role in the risk of cervical cancer, especially genes controlling the immune response, such as HLA class I and II. These highly polymorphic genes are important risk determinants of HPV persistence and disease progression. The interaction between host and viral factors is complex and needs to be further investigated, paving the way to better define the patients at the highest risk of developing malignant diseases linked to HPV infection.
Assuntos
Genes MHC da Classe II , Genes MHC Classe I , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Feminino , Genes Virais , Humanos , Papillomaviridae/genética , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Polimorfismo Genético , Fatores de Risco , Neoplasias do Colo do Útero/imunologia , Proteínas ViraisRESUMO
Thirty years after angiogenesis was shown to play an enabling role in cancer, modern medicine is still trying to develop novel compounds and therapeutics to target the tumor vasculature. However, most therapeutics require multiple rounds of administration and can have toxic side effects. In this study, we use anti-angiogenesis immunotherapy to target cells actively involved in forming new blood vessels that support the growth and spread of breast cancer. Targeting a central cell type involved in angiogenesis, endothelial cells, we immunized against host vascular endothelial growth factor receptor 2 to fight the growth of Her-2/neu(+) breast tumors. Using the bacterial vector, Listeria monocytogenes (Lm), we fused polypeptides from the mouse vascular endothelial growth factor receptor 2 molecule (fetal liver kinase-1) to the microbial adjuvant, listeriolysin-O, and used Lm to deliver the Ags and elicit potent antitumor CTL responses. Lm-listeriolysin-O-fetal liver kinase-1 was able to eradicate some established breast tumors, reduce microvascular density in the remaining tumors, protect against tumor rechallenge and experimental metastases, and induce epitope spreading to various regions of the tumor-associated Ag Her-2/neu. Tumor eradication was found to be dependent on epitope spreading to HER-2/neu and was not solely due to the reduction of tumor vasculature. However, vaccine efficacy did not affect normal wound healing nor have toxic side effects on pregnancy. We show that an anti-angiogenesis vaccine can overcome tolerance to the host vasculature driving epitope spreading to an endogenous tumor protein and drive active tumor regression.
Assuntos
Inibidores da Angiogênese/imunologia , Vacinas Anticâncer/imunologia , Listeria monocytogenes/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Receptor ErbB-2/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Sequência de Aminoácidos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/genética , Animais , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Feminino , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/genética , Inibidores do Crescimento/imunologia , Proteínas de Choque Térmico/administração & dosagem , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Proteínas Hemolisinas/administração & dosagem , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/imunologia , Listeria monocytogenes/genética , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Dados de Sequência Molecular , Neovascularização Patológica/imunologia , Neovascularização Patológica/fisiopatologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Invasive carcinoma of the cervix (ICC) is the second most common cancer in women worldwide. Lm-LLO-E7 vaccine is a live-attenuated Listeria monocytogenes (Lm) that secretes the HPV-16 E7 antigen fused to a non-hemolytic fragment of the Lm protein listeriolysin O (LLO). In this Phase I trial, the safety of Lm-LLO-E7 was assessed in 15 patients with previously treated metastatic, refractory or recurrent ICC. Patients received 1 of 3 dose levels of Lm-LLO-E7 (1 x 10(9)CFU, 3.3 x 10(9)CFU or 1 x 10(10)CFU) as an intravenous infusion, followed by a second dose 3 weeks later. All patients experienced a flu-like syndrome which responded to non-prescription symptomatic treatment. Severe (grade 3) adverse events related to Lm-LLO-E7 were reported in 6 patients (40%), but no grade 4 adverse events were observed. At the highest dose some patients had severe fever and dose limiting hypotension. By the end of the study protocol, 2 patients had died, 5 had progressed, 7 had stable disease and 1 qualified as a partial responder. This study shows for the first time that a live-attenuated Lm is safe to be administered to late stage ICC patients.