RESUMO
Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft-tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment-refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing.
Assuntos
Adenoviridae/genética , Terapia Genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Terapia Viral Oncolítica , Sarcoma/terapia , Animais , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Injeções Intralesionais , Mesocricetus , Camundongos , Camundongos Nus , Prognóstico , Sarcoma/sangue , Sarcoma/mortalidade , Taxa de Sobrevida , Células Tumorais Cultivadas , Replicação Viral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chronic kidney disease is frequently associated with protein-energy wasting related to chronic inflammation and a resistance to anabolic hormones such as insulin and growth hormone (GH). In this study, we determined whether a new GH-releasing hormone super-agonist (AKL-0707) improved the anabolism and nutritional status of nondialyzed patients with stage 4-5 chronic kidney disease randomized to twice daily injections of the super-agonist or placebo. After 28 days, this treatment significantly increased 24-h GH secretion by almost 400%, without altering the frequency or rhythmicity of secretory bursts or fractional pulsatile GH release, and doubled the serum insulin-like growth factor-1 level. There was a significant change in the Subjective Global Assessment from 'mildly to moderately malnourished' to 'well-nourished' in 6 of 9 patients receiving AKL-0707 but in none of 10 placebo-treated patients. By dual-energy X-ray absorptiometry, both the mean fat-free mass and the body mineral content increased, but fat mass decreased, all significantly. In the AKL-0707-treated group, both serum urea and normalized protein equivalent of nitrogen appearance significantly decreased with no change in dietary protein intake, indicating a protein anabolic effect of treatment. Thus, our study shows that stimulation of endogenous GH secretion by AKL-0707 overcomes uremic catabolism of patients with advanced chronic kidney disease.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Hormônio Liberador de Hormônio do Crescimento/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Estado Nutricional/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Hormônio Liberador de Hormônio do Crescimento/agonistas , Hormônio do Crescimento Humano/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage. Therefore, the combination of oncolytic immuno-virotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and in vivo in an orthotopic xenograft mouse model, in combination with low-dose CP or its main active metabolite 4-hydroperoxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data on this virus from the Advanced Therapy Access Program (ATAP). Low-dose CP increased the efficacy of Ad5/3-D24-GMCSF in vitro and in a TNBC mouse model. In ATAP, treatments appeared safe and well-tolerated. Thirteen out of 16 breast cancer patients treated were evaluable for possible benefits with modified RECIST 1.1 criteria: 1 patient had a minor response, 2 had stable disease (SD), and 10 had progressive disease (PD). One patient is alive at 1,771 d after treatment. Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.
RESUMO
BACKGROUND: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. METHODS: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT). RESULTS: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. CONCLUSIONS: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. TRIAL REGISTRATION: NCT01598129. Registered 19/04/2012.
RESUMO
Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient's unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colonystimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8+ lymphocytes to tumor, marked induction of systemic antitumor CD8+ T-cells and induction of Th1-type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.
RESUMO
BACKGROUND: Oxidized low density lipoprotein (LDL) plays a key role in processes leading to atherosclerosis. Recent studies show that LDL oxidation in vitro is effectively prevented by estrogen. Yet, the effect of hormonal therapy (HT) on in vivo LDL oxidation has remained open. AIM: We used a novel methodology for the measurement of oxidized LDL in vivo in order to investigate the effects of HT. METHODS: The subjects were derived from two separate trials. In trial 1 (24 months) women (n = 32) used intra-uterine system releasing 10 micrograms/day levonorgestrel, and 2 mg oral estradiol. Trial 2 (12 months) consisted of two groups of subjects. One group (n = 30) used an intrauterine system releasing 20 micrograms/day levonorgestrel, and 2 mg estradiol; the other group (n = 32) received orally a combination of 1 mg norethisterone acetate and 2 mg estradiol. Blood samples were taken at 6 months intervals. Estimation of in vivo LDL oxidation was based on determination of baseline diene conjugation in isolated LDL. RESULTS: Hormonal therapy in trial 1 decreased markedly in vivo LDL oxidation. The effect was seen after 6 months' HT and became more pronounced towards the end of study (41% decrease; P < 0.0001). Contrary to this, in trial 2 the two different kinds of hormonal therapy schemes did not affect in vivo LDL oxidation. CONCLUSIONS: The strong effect seen in trial 1 shows that intrauterine levonorgestrel with 2 mg estradiol can lower LDL oxidation in vivo. The results show that this effect depends on dosage of the progestin.
Assuntos
Terapia de Reposição de Estrogênios , Lipoproteínas LDL/sangue , Pós-Menopausa/efeitos dos fármacos , Progestinas/farmacologia , Índice de Massa Corporal , Anticoncepcionais Femininos/farmacologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/farmacologia , Feminino , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/sangue , Levanogestrel/farmacologia , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Progestinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Útero/efeitos dos fármacosRESUMO
OBJECTIVE: To determine the pharmacokinetics of oxybutynin and its main active metabolite, N-desethyloxybutynin, after multiple dosage (5 mg/30 ml three times daily) of intravesical oxybutynin formulation. Furthermore, to determine the efficacy and safety of intravesical oxybutynin in the symptomatic relief of urge incontinence or urgency in adult patients with detrusor hyperreflexia or instability. MATERIAL AND METHODS: Nine patients were randomly allocated to treatment with a special bladder instillation formulation of oxybutynin or placebo for two 14-day treatment periods in a double-blind, cross-over manner. The third, open study period was designed for pharmacokinetic purposes with all patients on the active drug. The pharmacokinetics was depicted by AUC0-24, Cmax, Cmin, and t(max), The efficacy was evaluated from the data collected from urinary voiding diaries and cystometries. The safety was measured by recording adverse events on questionnaires. Patients who were willing to continue with the intravesical oxybutynin treatment entered the 1-year extension part of the study. RESULTS: Oxybutynin was absorbed from the bladder with a geometric mean Cmax of 9.4 ng/ml and AUC0-24 of 92 ng x h/ml. For N-desethyloxybutynin, the geometric mean Cmax was 14.4 ng/ml and AUC0-24 186 ng x h/ml. Elimination of the drug was protracted, as there were detectable serum concentrations of both oxybutynin and N-desethyloxybutynin even 24 hours post-dose. The mean number of toilet visits/day decreased from the baseline value of 6.9 to 5.7 during oxybutynin treatment, whereas during the placebo period the value increased to 7.4 (p = 0.022). It remained at the same decreased level during the one-year follow-up period. CONCLUSIONS: Oxybutynin is readily absorbed from the bladder after intravesical administration. The serum concentrations of oxybutynin after single 5 mg intravesical doses are at least as high as those reported after oral drug intake, but the parent drug/metabolite ratio is much higher after intravesical administration. The elimination of oxybutynin as well as its metabolite is prolonged after intravesical administration compared with that reported after oral drug intake. The mean number of daily toilet visits decreased significantly in the oxybutynin group.