RESUMO
TMPRSS2 is utilized by SARS-CoV-2 for cellular entry. Androgen-Androgen receptor directed therapy (A/ARDT) downregulates expression of TMPRSS2. We hypothesized A/ARDT might protect prostate cancer (PCa) patients from poor COVID-19 outcome. A retrospective analysis of PCa patients with COVID-19 infection was performed. 146 PCa cases were identified, 17% were on A/ARDT. Hospitalization rates were same 52% (OR = 0.99, 0.41-2.24). Mean hospitalization was 9.2 (Range: 1-25) and 14.9 (Range: 2-47) days in A/ARDT and non-A/ARDT groups, respectively. While definitive conclusions cannot be made regarding outcome differences between groups due to lack of statistical significance, these data generate hypothesis that A/ARDT might shorten hospitalization stay.
Assuntos
COVID-19 , Neoplasias da Próstata , Masculino , Humanos , Receptores Androgênicos , Androgênios , Estudos Retrospectivos , SARS-CoV-2 , Neoplasias da Próstata/metabolismoRESUMO
PURPOSE OF REVIEW: We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer. RECENT FINDINGS: Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.
Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos , Ribose/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Antineoplásicos/uso terapêutico , Difosfato de Adenosina/uso terapêutico , Ensaios Clínicos Fase II como AssuntoRESUMO
LESSONS LEARNED: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation. BACKGROUND: Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC. METHODS: Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate. RESULTS: Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea. CONCLUSION: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.
Assuntos
Adenocarcinoma , Neoplasias Ovarianas , Neoplasias Pancreáticas , Feminino , Humanos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Ftalazinas/efeitos adversos , Piperazinas , Quinazolinas , Fator A de Crescimento do Endotélio VascularRESUMO
OBJECTIVE: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. PATIENTS AND METHODS: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. RESULTS: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). CONCLUSION: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.
Assuntos
Anilidas/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/administração & dosagem , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Piridinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prednisona/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/patologia , Piridinas/efeitos adversos , Resultado do TratamentoRESUMO
We investigated the effect of aging on the multi-dimensional characteristics and heterogeneity of human peripheral CD8+ T cells defined by the expression of a set of molecules at the single cell level using the recently developed mass cytometry or Cytometry by Time-Of-Flight (CyTOF) and computational algorithms. CD8+ T cells of young and older adults had differential expression of molecules, especially those related to cell activation and migration, permitting the clustering of young and older adults through an unbiased approach. The changes in the expression of individual molecules were collectively reflected in the altered high-dimensional profiles of CD8+ T cells in older adults as visualized by the dimensionality reduction analysis tools principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). A combination of PhenoGraph clustering and t-SNE analysis revealed heterogeneous subsets of CD8+ T cells that altered with aging. Furthermore, intermolecular quantitative relationships in CD8+ T cells appeared to change with age as determined by the computational algorithm conditional-Density Resampled Estimate of Mutual Information (DREMI). The results of our study showed that heterogeneity, multidimensional characteristics, and intermolecular quantitative relationships in human CD8+ T cells altered with age, distinctively clustering young and older adults through an unbiased approach.
Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Envelhecimento/metabolismo , Algoritmos , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular , Análise por Conglomerados , Feminino , Citometria de Fluxo , Humanos , Ativação Linfocitária , Masculino , Análise de Componente Principal , Análise de Célula Única , Subpopulações de Linfócitos T/metabolismo , Adulto JovemRESUMO
PURPOSE OF REVIEW: Inhibition of immune escape mechanisms, such as the programed death-ligand 1 pathway, has demonstrated rapid, durable responses in multiple tumor types, including advanced urothelial carcinoma. This review discusses emerging immunotherapies for urothelial carcinoma in various stages of clinical development. RECENT FINDINGS: Urothelial carcinoma has a high mutational burden, which may increase the number of tumor antigens and potentially enhance the ability of the immune system to recognize tumor cells as foreign. However, urothelial carcinoma can evade the immune system by downregulating tumor-antigen presentation, upregulating various immune checkpoints, and inactivating cytotoxic T cells. Immunotherapies for urothelial carcinoma target each of these steps to restore immune-mediated cytotoxicity. Many of these agents are in clinical trials for urothelial carcinoma. SUMMARY: Immunotherapies are active in urothelial carcinoma, but only in a fraction of patients, implying the presence of persistent immune escape. Identifying the mechanisms of immune escape and developing rational combinatorial regimens may make the benefit of immunotherapy accessible to a broader population.
Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Imunoterapia , Linfócitos T Citotóxicos/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/patologia , Antineoplásicos , Vacinas Anticâncer , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/patologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T Citotóxicos/efeitos dos fármacos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
Immune checkpoints, such as programmed death ligand 1 (PD-L1) or its receptor, programmed death 1 (PD-1), appear to be Achilles' heels for multiple tumor types. PD-L1 not only provides immune escape for tumor cells but also turns on the apoptosis switch on activated T cells. Therapies that block this interaction have demonstrated promising clinical activity in several tumor types. In this review, we will discuss the current status of several anti-PD-1 and anti-PD-L1 antibodies in clinical development and their direction for the future.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/análise , Carcinoma de Células Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/secundário , Nivolumabe , Receptor de Morte Celular Programada 1/análiseRESUMO
PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non-small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation-based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Neoplasias Pancreáticas , Neoplasias de Mama Triplo Negativas , Humanos , DNA Tumoral Circulante/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Poli(ADP-Ribose) Polimerases/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genéticaRESUMO
BACKGROUND: There is lack of consensus about the effectiveness of neoadjuvant platinum-based chemotherapy in patients with micropapillary variant urothelial carcinoma (MVUC) prior to radical cystectomy. We studied the association between neoadjuvant chemotherapy (NAC) and pathologic response (PR) among patients with micropapillary versus non-variant bladder urothelial carcinoma (UC). METHODS: We queried the National Cancer Database to identify patients with localized UC and MVUC from 2004 to 2017. We restricted our analysis to patients who underwent radical cystectomy with or without NAC. We compared clinical, demographic, and pathologic characteristics associated with NAC. We used multivariable logistic regression and propensity score matching to examine the association between NAC and the occurrence of a pathologic complete response (pT0) and pathologic lymph node positivity (pN+). Kaplan Meier analyses and Cox proportional hazards models were used to assess overall survival (OS). We performed analyses among subsets of patients with clinical stage II (cT2) disease, as well as the entire cohort (cT2-T4). RESULTS: We identified 18,761 patients, including 18,027 with non-variant UC and 734 patients with MVUC. Multivariable analysis revealed that NAC use was associated with greater odds of pT0 (9.64[7.62-12.82], P<0.001), and the association did not differ significantly between MVUC and non-variant UC. In a propensity matched analysis of patients with MVUC, NAC use was associated with higher odds of pT0 (OR 4.93 [2.43-13.18] P<0.001), lower odds of pN+ (OR 0.52 [0.26-0.92] P=0.047) and pathologic upstaging (OR 0.63 [0.34-0.97] P=0.042) in all stages. Similar findings were observed with cT2 disease. No significant association was seen between NAC and OS with MVUC (HR 0.89 [0.46-1.10] P=0.63), including the subset of patients with cT2 (HR 0.83 [0.49-1.06] P=0.58). CONCLUSIONS: NAC is associated with similar pathologic and nodal responses in patients with localized MVUC and non-variant UC. Improvements in pathologic findings did not translate into OS in this retrospective hospital-based registry study.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Terapia Neoadjuvante , Estudos Retrospectivos , Estadiamento de Neoplasias , Cistectomia/efeitos adversos , Quimioterapia AdjuvanteRESUMO
PURPOSE: Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS: Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS: In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION: Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Estados Unidos , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , National Cancer Institute (U.S.) , Fator A de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ftalazinas/efeitos adversosRESUMO
BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.
Assuntos
Antineoplásicos Imunológicos , Carcinoma de Células Escamosas , Neoplasias Penianas , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Nivolumabe/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/etiologia , Neoplasias Penianas/patologia , Antineoplásicos Imunológicos/efeitos adversos , Estudos Retrospectivos , Carcinoma de Células Escamosas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. PATIENTS AND METHODS: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. RESULTS: All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. CONCLUSIONS: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Idoso , Anticorpos Monoclonais Humanizados , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de SobrevidaRESUMO
Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.
Assuntos
Vacinas Anticâncer , Sarcoma , Adjuvantes Imunológicos , Antígenos de Neoplasias/genética , Vacinas Anticâncer/efeitos adversos , Humanos , Proteínas de Membrana/genéticaAssuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/terapia , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias Ósseas/secundário , Humanos , Ipilimumab , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Vísceras/patologiaRESUMO
PURPOSE: The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. PATIENTS AND METHODS: Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing). RESULTS: The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 µg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6-30+ months). CONCLUSIONS: NHS-IL12 was well tolerated up to a dose of 16.8 µg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.See related commentary by Lyerly et al., p. 9.
Assuntos
Imunoglobulina G/administração & dosagem , Interleucina-12/imunologia , Segunda Neoplasia Primária/tratamento farmacológico , Neoplasias/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Idoso , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Influenza Humana/induzido quimicamente , Influenza Humana/patologia , Interleucina-12/administração & dosagem , Interleucina-12/efeitos adversos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Segunda Neoplasia Primária/imunologia , Segunda Neoplasia Primária/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/efeitos adversos , Transaminases/metabolismoRESUMO
PURPOSE: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1-expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors. PATIENTS AND METHODS: Adults with previously treated, advanced, NY-ESO-1-positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses). RESULTS: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti-NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti-NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis. CONCLUSIONS: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Células Dendríticas/transplante , Vetores Genéticos/administração & dosagem , Lentivirus/genética , Proteínas de Membrana/imunologia , Neoplasias/terapia , Sarcoma/terapia , Adulto , Idoso , Antígenos de Neoplasias/biossíntese , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Estudos de Coortes , Células Dendríticas/citologia , Células Dendríticas/imunologia , Intervalo Livre de Doença , Feminino , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Humanos , Lentivirus/imunologia , Masculino , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Neoplasias/imunologia , Sarcoma/imunologia , Taxa de SobrevidaRESUMO
BACKGROUND: Radium223 (Ra223) delivers high-energy radiation to osteoblastic metastasis of prostate cancer, resulting in irreparable double-stranded DNA damage. The effects of Ra223 on CD8+ T cell subsets in patients with prostate cancer is unknown. PATIENTS AND METHODS: Fifteen men with metastatic prostate cancer with clinical indication for Ra223 without any autoimmune or immune deficiency conditions were enrolled. Patients received a course of Ra223 50 kBq/kg. Concurrent use of prednisone ≤ 10 mg a day was allowed. Peripheral blood samples were collected before and 3 to 4 weeks after the first dose of Ra223 50 kBq/kg. Peripheral blood mononuclear cells were purified and analyzed for the phenotypic and functional characteristics of CD8+ T cells using flow cytometry. RESULTS: One Ra223 treatment did not result in significant change in the overall frequencies of CD8+ T cells and their subsets including naive, central memory, and effect memory cells. However, the mean frequency of programmed cell death protein 1-expressing EM CD8+ T cells decreased after 1 Ra223 treatment from 20.6% to 14.6% (P = .020), whereas no significant change was observed in the frequencies of CD27-, CD28-, or CTLA4-expressing T cells. One Ra223 treatment was not associated with any significant change in the frequencies of CD8+ T cells producing IFN-γ, TNF-α, and IL-13. CONCLUSION: One Ra223 treatment is associated with a decreased mean frequency of programmed cell death protein 1-expressing effect memory CD8+ T cell without affecting other immune checkpoint molecules or cytokine production. Further investigations are warranted to elucidate the immunologic and clinical significance of our observations and its long-term effects after multiple treatments.
Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/administração & dosagem , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-13/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/imunologia , Rádio (Elemento)/farmacologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
IMPORTANCE: Atezolizumab (anti-programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. OBJECTIVE: To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). INTERVENTIONS: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. MAIN OUTCOMES AND MEASURES: Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. RESULTS: Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. CONCLUSIONS AND RELEVANCE: Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01375842.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Carcinoma de Células de Transição/mortalidade , Estudos de Coortes , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Fatores de Tempo , Neoplasias da Bexiga Urinária/mortalidade , Urotélio/patologiaRESUMO
PURPOSE: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. RESULTS: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. CONCLUSION: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.