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1.
Clin Cancer Res ; 25(19): 5818-5831, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31273010

RESUMO

PURPOSE: The CANON [CAVATAK in NON-muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer. PATIENTS AND METHODS: Fifteen patients enrolled in this "window of opportunity" phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue. RESULTS: Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy. CONCLUSIONS: The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in "immunological heat" within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.


Assuntos
Imunoterapia/métodos , Molécula 1 de Adesão Intercelular/imunologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Imunoterapia/efeitos adversos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Terapia Viral Oncolítica/efeitos adversos , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/virologia
2.
BJU Int ; 95(4): 522-5, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15705072

RESUMO

OBJECTIVE: To present our results on managing loco-regional recurrence of renal cell carcinoma (RCC) with surgical excision, as local recurrence at the site of a previous nephrectomy is resistant to both systemic therapy and radiotherapy. PATIENTS AND METHODS: In all, 16 patients were operated on between 1994 and 2003 for local recurrence of RCC. The median (mean, range) age at the time of local recurrence was 57.9 (57.4, 28.9-71.7) years, and the median interval from primary surgery 2.22 (3.88, 0.27-14.46) years. Before surgery eight patients had been given systemic immunotherapy, with no response of their local recurrence. RESULTS: Two patients were deemed inoperable because of direct invasion of the great vessels and the liver by tumour. The remaining 14 patients had recurrence in residual adrenal tissue (two), para-aortic nodes (three), para-caval nodes (two), retrocaval nodes (one), renal bed (six), liver, spleen and stomach (one each), and diaphragm (two). Although complete macroscopic en-bloc clearance was achieved in these patients, only eight had tumour-free margins on histological examination. The histology was consistent with RCC recurrence in all cases. All of the patients were followed with computed tomography at regular intervals. At a median follow-up of 1.0 (1.65, 0.25-6.5) years, five patients remain disease-free, four have local and distant relapse, and five developed distant metastasis only. The presence of tumour at the resection margin was a significant factor in predicting local and distant disease-free survival (P < 0.05). CONCLUSIONS: En bloc excision of isolated locally recurrent RCC is possible, and complete surgical extirpation can lead to prolonged disease-free survival.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/cirurgia , Nefrectomia/métodos , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do Tratamento
3.
BJU Int ; 94(6): 845-7, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15476520

RESUMO

OBJECTIVE: To assess the use of sodium pentosan polysulphate (SPP) for haemorrhagic cystitis (HC), a potentially life-threatening side-effect in patients treated with pelvic radiotherapy or cyclophosphamide, and which can be difficult to manage as patients often have significant comorbidity. PATIENTS AND METHODS: Between September 1991 and December 2000, 60 consecutive patients (24 women and 36 men) with haemorrhagic cystitis were primarily treated with SPP; 53 patients had had radical radiotherapy for pelvic malignancy and seven systemic cyclophosphamide. All patients were screened for blood dyscrasia and residual/primary urothelial malignancy with imaging, urine cytology and cystoscopy. RESULTS: In all, 51 patients were available for follow-up; the median (range) interval between completing treatment and developing haematuria was 4.5 (0.08-39.4) years, the duration of treatment 180 (21-1745) days and patients were followed for 450 (19-4526) days from the onset of haematuria. All patients were started on SPP at an initial dose of 100 mg three times daily. In 21 patients the dose was gradually reduced to a maintenance dose of 100 mg and in 10 further patients SPP was stopped because the haematuria stopped completely. Twenty patients died while on treatment from causes not directly related to their haematuria. CONCLUSION: We recommend the use of SPP as the primary method of managing haemorrhagic cystitis associated with pelvic radiotherapy or systemic chemotherapy.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Cistite/tratamento farmacológico , Hemorragia/prevenção & controle , Poliéster Sulfúrico de Pentosana/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Bexiga Urinária/efeitos da radiação , Cistite/etiologia , Feminino , Hematúria/tratamento farmacológico , Hematúria/etiologia , Hemorragia/etiologia , Humanos , Masculino , Neoplasias Pélvicas/radioterapia , Radioterapia/efeitos adversos , Estudos Retrospectivos
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