RESUMO
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (Assuntos
Desoxicitidina
, Gencitabina
, Imunoterapia
, Terapia Neoadjuvante
, Neoplasias da Bexiga Urinária
, Humanos
, Neoplasias da Bexiga Urinária/tratamento farmacológico
, Neoplasias da Bexiga Urinária/imunologia
, Neoplasias da Bexiga Urinária/terapia
, Neoplasias da Bexiga Urinária/patologia
, Terapia Neoadjuvante/métodos
, Desoxicitidina/análogos & derivados
, Desoxicitidina/uso terapêutico
, Desoxicitidina/administração & dosagem
, Imunoterapia/métodos
, Masculino
, Cisplatino/uso terapêutico
, Cisplatino/administração & dosagem
, Feminino
, Anticorpos Monoclonais Humanizados/uso terapêutico
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Inibidores de Checkpoint Imunológico/uso terapêutico
, Idoso
, Pessoa de Meia-Idade
, Invasividade Neoplásica
, Interleucina-9/metabolismo
, Antígeno B7-H1/metabolismo
, Biomarcadores Tumorais/sangue
, Resultado do Tratamento
RESUMO
PURPOSE: Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab. PATIENTS AND METHODS: 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations. RESULTS: Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (-3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT). CONCLUSIONS: Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Imunoterapia/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. SIGNIFICANCE: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.
Assuntos
Citarabina , Leucemia Mieloide Aguda , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Linfócitos T CD8-Positivos , Citarabina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Staphylococcus aureus is a major human pathogen that causes an array of infections ranging from minor skin infections to more serious infections, including osteomyelitis, endocarditis, necrotizing pneumonia and sepsis1. These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment1. Phagocytosis by macrophages and neutrophils is the primary mechanism through which S. aureus infection is controlled by the immune system2. Macrophages have been shown to be a major reservoir of S. aureus in vivo3, but the role of macrophages in the induction of antibiotic tolerance has not been explored. Here, we show that macrophages not only fail to efficiently kill phagocytosed S. aureus, but also induce tolerance to multiple antibiotics. Reactive oxygen species generated by respiratory burst attack iron-sulfur cluster-containing proteins, including TCA-cycle enzymes, result in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that respiratory burst induces antibiotic tolerance in the spleen during a murine systemic infection. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics.
Assuntos
Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Animais , Linhagem Celular , Ciclo do Ácido Cítrico , Modelos Animais de Doenças , Farmacorresistência Bacteriana/imunologia , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/deficiência , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/imunologia , Fagocitose , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/imunologiaRESUMO
Aminoglycoside antibiotics require proton motive force (PMF) for bacterial internalization. In non-respiring populations, PMF drops below the level required for drug influx, limiting the utility of aminoglycosides against strict and facultative anaerobes. We recently demonstrated that rhamnolipids (RLs), biosurfactant molecules produced by Pseudomonas aeruginosa, potentiate aminoglycoside activity against Staphylococcus aureus. Here, we demonstrate that RLs induce PMF-independent aminoglycoside uptake to restore sensitivity to otherwise tolerant persister, biofilm, small colony variant, and anaerobic populations of S. aureus. Furthermore, we show that this approach represses the rise of resistance, restores sensitivity to highly resistant clinical isolates, and is effective against other Gram-positive pathogens. Finally, while other membrane-acting agents can synergize with aminoglycosides, induction of PMF-independent uptake is uncommon, and distinct to RLs among several compounds tested. In all, small-molecule induction of PMF-independent aminoglycoside uptake circumvents phenotypic tolerance, overcomes genotypic resistance, and expands the utility of aminoglycosides against intrinsically recalcitrant bacterial populations.