RESUMO
OBJECTIVE: To report on the surgical safety and quality of pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and PLND for muscle-invasive bladder cancer (MIBC) after neoadjuvant chemo-immunotherapy. PATIENTS AND METHODS: The Swiss Group for Clinical Cancer Research (SAKK) 06/17 was an open-label single-arm phase II trial including 61 cisplatin-fit patients with clinical stage (c)T2-T4a cN0-1 operable urothelial MIBC or upper urinary tract cancer. Patients received neoadjuvant cisplatin/gemcitabine and durvalumab followed by surgery. Prospective quality assessment of surgeries was performed via central review of intraoperative photographs. Postoperative complications were assessed using the Clavien-Dindo Classification. Data were analysed descriptively. RESULTS: A total of 50 patients received RC and PLND. All patients received neoadjuvant chemo-immunotherapy. The median (interquartile range) number of lymph nodes removed was 29 (23-38). No intraoperative complications were registered. Grade ≥III postoperative complications were reported in 12 patients (24%). Complete nodal dissection (100%) was performed at the level of the obturator fossa (bilaterally) and of the left external iliac region; in 49 patients (98%) at the internal iliac region and at the right external iliac region; in 39 (78%) and 38 (76%) patients at the right and left presacral level, respectively. CONCLUSION: This study supports the surgical safety of RC and PLND following neoadjuvant chemo-immunotherapy in patients with MIBC. The extent and completeness of protocol-defined PLND varies between patients, highlighting the need to communicate and monitor the surgical template.
Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Cistectomia , Desoxicitidina , Gencitabina , Excisão de Linfonodo , Terapia Neoadjuvante , Neoplasias da Bexiga Urinária , Humanos , Cistectomia/métodos , Excisão de Linfonodo/métodos , Masculino , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Feminino , Idoso , Pessoa de Meia-Idade , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pelve , Estudos ProspectivosRESUMO
Patients with haemato-oncological malignancies are one of the high-risk groups for a severe course in case of COVID-19 infections. Furthermore, vaccination results in significantly lower response rates in haematological malignancies and lower antibody levels in patients with solid cancer. We investigated efficacy and safety of a heterologous booster vaccination with Ad26.COV2.S DNA vector vaccine in haemato-oncological patients without antibody response after double-dose BNT162b2 messenger (m-)RNA COVID-19 vaccine. A total of 32 haemato-oncological non-responders to double-dose BNT162b2 received a heterologous booster vaccination with Ad26.COV2.S. Blood samples were assessed directly before the vaccination (T0) and four weeks after (T1). Safety assessment was performed using a standardised questionnaire. The overall response rate was 31%, with a mean (SD) antibody titre of 693·79 (1 096·99) binding activity units (BAU)/ml. Patients with chronic lymphocytic leukaemia or lymphoma showed a significantly lower response rate (P = 0·048). Adverse events were reported in 29·6% of patients, of which 7·1% were graded as severe, including grade III and IV events following the Common Terminology Criteria of Adverse Events (CTCAE). The heterologous booster vaccination with Ad26.COV2.S led to a serological response in nine out of 29 patients without response after double-dose BNT162b2. Furthermore, the vaccination was safe in our cohort, leading to mainly mild local and systemic reactions. Overall, this vaccination regimen should be further evaluated to increase the response rate in the highly vulnerable population of haemato-oncological patients.
Assuntos
Ad26COVS1/administração & dosagem , Anticorpos Antivirais/sangue , Formação de Anticorpos/efeitos dos fármacos , Vacina BNT162/administração & dosagem , COVID-19 , Neoplasias Hematológicas/sangue , Imunização Secundária , SARS-CoV-2/metabolismo , Idoso , COVID-19/sangue , COVID-19/prevenção & controle , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Haemato-oncological patients are at risk in case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Currently, vaccination is the best-evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato-oncological patients. A total of 259 haemato-oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti-SARS-CoV-2-S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P < 0·001). Haematological patients receiving systemic treatment had a 14·2-fold increased risk of non-responding (95% confidence interval 3·2-63·3, P = 0·001). Subgroups of patients with lymphoma or chronic lymphocytic leukaemia were at highest risk of serological non-response. Low immunoglobulin G (IgG) level, lymphocyte- and natural killer (NK)-cell counts were significantly associated with poor serological response (P < 0·05). Vaccination was well tolerated with only 2·7% of patients reporting severe side-effects. Patients with side-effects developed a higher S/RBD-antibody titre compared to patients without side-effects (P = 0·038). Haematological patients under treatment were at highest risk of serological non-response. Low lymphocytes, NK cells and IgG levels were found to be associated with serological non-response. Serological response in oncological patients was encouraging. The use of BNT162b2 is safe in haemato-oncological patients.
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Neoplasias Hematológicas/imunologia , SARS-CoV-2/imunologia , Idoso , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacina BNT162 , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Imunoensaio/métodos , Imunoglobulina G/sangue , Células Matadoras Naturais/citologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos/citologia , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , SARS-CoV-2/genética , SegurançaRESUMO
Immunotherapy - immune-related adverse events and their management Abstract. Checkpoint-Inhibition has become an important part of modern oncological treatment strategies for many patients with cancer. The development of this new class of anti-cancer drugs has begun for ten years and showed meanwhile a specific new side effect profile. Since the mode of action of checkpoint inhibitors is immune modulation the side effects are particularly different to so far established anti-cancer drugs. Because of the immunological nature of side effects, the spectrum is wide, and the symptoms are amble. Additionally, the side effects can appear at very different time points after the administration of the checkpoint inhibitor. Therefore, the recognition and the management are a new challenge for the care teams. Only if the whole care team is able to understand, diagnose and efficiently manage the side effects the therapeutic potential of this new class of anti-cancer drugs can be made useful for the patients. The article aims to provide information for the care teams to recognize and manage side effects of checkpoint-inhibitors.
Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/terapia , Humanos , Fatores Imunológicos , Oncologia , Síndromes Neurotóxicas/etiologiaRESUMO
Vinorelbine combined with filgrastim at a dose of 10 µg/kg of body weight (BW) per day is a reliable and well-tolerated regimen for mobilization of hematopoietic progenitor cells (HPCs) in patients with multiple myeloma. This prospective, randomized, phase II study was initiated to assess the feasibility of a reduced filgrastim dosage. Vinorelbine was combined with either standard-dose filgrastim (10 µg/kg BW per day) or reduced-dose filgrastim (5 µg/kg BW per day). Leukapheresis sessions were planned to start at day 8 and were continued until the predefined target amount of 4 × 106 HPCs/kg BW was collected. The study demonstrated the feasibility of vinorelbine combined with reduced daily filgrastim with a mean of 1.29 leukapheresis sessions necessary per patient (95% confidence interval, .95 to 1.7). All patients could start leukapheresis as planned at day 8, and the collection success rate was 100% for the whole patient collective after a maximum of 2 leukapheresis sessions. No statistically significant differences with regard to the amount of HPCs collected between the 2 groups were observed (P = .99). Accordingly, no differences were seen with regard to length of hospitalization for autotransplant (P = .34) and duration of neutrophil (P = .93) and platelet engraftment (P = .42). Patients receiving reduced-dose filgrastim reported significantly lower peak pain values in a numeric analogue scale (P = .01), and the costs were significantly lower than in patients undergoing standard-dose chemomobilization (P = .001). Vinorelbine 35 mg/m2 plus filgrastim 5 µg/kg BW once per day until completion of HPC collection is feasible and appears to be advantageous with respect to the severity of pain intensity and treatment costs.
Assuntos
Filgrastim/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Vinorelbina/administração & dosagem , Idoso , Autoenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Estudos ProspectivosRESUMO
Biosimilars are increasingly being licensed as equipotent drugs, although efficacy and safety data are not available for all clinical indications. Accordingly, the efficacy of the biosimilar filgrastim Zarzio® combined with vinorelbine for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma has not been evaluated yet. We compared the efficacy of vinorelbine combined with this biosimilar filgrastim for HPC mobilization to vinorelbine plus original filgrastim (Neupogen®). Overall, 105 multiple myeloma patients received vinorelbine 35 mg/m2 intravenously on day 1 and either original filgrastim (n = 61;58%) or biosimilar filgrastim (n = 44;42%) at a dose of 5 µg per kg body weight (BW) twice daily subcutaneously starting day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and performed for a maximum of three consecutive days until at least 4 × 106 HPC/kg BW were collected. All patients proceeded to leukapheresis. In 102 (97%) patients the leukapheresis sessions were started as planned at day 8. The median number of collected HPC was 7.3 × 106 /kg BW (0.2-18.3) with original filgrastim compared to 9 × 106 /kg BW (4.2-23.8) with the biosimilar filgrastim (P = 0.16). HPC collection was successful in 57 (93%) of 61 patients of the original group and in all 44 (100%) patients of the biosimilar group (P = 0.14). No differences were observed regarding side effects. Duration of neutrophil engraftment after autologous HPC transplantation was similar between the two groups (P = 0.17). Biosimilar and original filgrastim achieve comparable results in combination with vinorelbine regarding HPC mobilization and transplantation outcome in multiple myeloma patients. J. Clin. Apheresis 32:21-26, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Medicamentos Biossimilares/farmacologia , Filgrastim/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Vimblastina/análogos & derivados , Medicamentos Biossimilares/administração & dosagem , Contagem de Células , Protocolos Clínicos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Filgrastim/administração & dosagem , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Estudos Retrospectivos , Vimblastina/administração & dosagem , Vimblastina/farmacologia , VinorelbinaRESUMO
We aimed to assess the efficacy of vinorelbine plus granulocyte colony-stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 µg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW at the first day of leukapheresis and 7.65 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Mieloma Múltiplo/terapia , Vimblastina/análogos & derivados , Adulto , Fatores Etários , Idoso , Antígenos CD34/genética , Antígenos CD34/imunologia , Contagem de Células , Quimioterapia Combinada , Feminino , Filgrastim , Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Lenalidomida , Leucaférese , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Transplante Autólogo , Resultado do Tratamento , Vimblastina/uso terapêutico , VinorelbinaRESUMO
Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor-specific CD8(+) T cells, together with tumor-specific CD4(+) T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1(-/-) recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1(-/-) CD4(+) T cells and gp100-specific TCR transgenic Rag1(-/-) CD8(+) T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm(2)) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8(+) T cells. Mice with recurrent melanoma had increased CD4(+)Foxp3(+) TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8(+) and CD4(+) T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4(+) T cell population to a Foxp3(+)CD4(+) regulatory T cell population.
Assuntos
Antígenos de Neoplasias/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Linfócitos T Reguladores/imunologia , Regulação para Cima/imunologia , Transferência Adotiva , Animais , Antígenos de Neoplasias/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Contagem de Linfócitos , Melanoma Experimental/terapia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Recidiva Local de Neoplasia/terapia , Oxirredutases/biossíntese , Oxirredutases/deficiência , Linfócitos T Reguladores/patologia , Antígeno gp100 de Melanoma/metabolismoRESUMO
Background: Patients with bone metastases from solid tumors often have additional treatment with bone targeted agents (BTAs) to avoid symptomatic skeletal events (SSEs) such as clinically significant pathological fracture leading toradiation therapy or surgery to the bone, spinal cord compression, or hypercalcemia. The absolute value of BTA treatment in the era of immunotherapy (IO) is unknown. Methods: Patients with bone metastases treated with immunotherapy within the Alpine Tumor Immunology Registry were compared based on whether they received an additional BTA such as denosumab or zoledronic acid. The primary endpoint was time to first SSE. Continuous data were summarized as median and range, categorical data using frequency counts and percentages. Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables. Results: One hundred and ninety-seven patients with bone metastases and treatment with immunotherapy such as nivolumab (48 %), pembrolizumab (40 %), atezolizumab (12 %), ipilimumab (9 %) and other immunotherapy (5 %) were included. The most frequent tumor types were lung cancer (50 %), malignant melanoma (11 %), renal cell cancer (10 %) and bladder cancer (9 %), respectively. One hundred and twenty-two patients (62 %) received a BTA treatment (91 % denosumab). The median treatment duration of a BTA was 178 days (min: 1 day, max: 2010 days). Out of the 197 patients, 47 (24 %) experienced at least one SSE, 100 (51 %) had bone pain. Ten of the 122 patients (8 %) receiving a BTA developed osteonecrosis of the jaw (ONJ). The percentage of patients without an SSE at fixed time points was higher if treated with a BTA (e.g., at 6 months, 92 % [95 % CI: 84 % - 96 %] versus 88 % [95 % CI: 77 % - 94 %]), but no significant difference in time to first SSE (HR 0.69; 95 % CI 0.34-1.39, log-rank p = 0.29) or time to first bone pain (HR: 0.85; 95 % CI: 0.51-1.43, p = 0.54) between these two groups could be detected. There were differences in OS between patients treated with a BTA and patients not treated with a BTA (HR: 1.46; 95 % CI: 1.01-2.10, p = 0.043). Conclusion: No significant difference in time to first SSE or bone pain was observed between patients who have received a BTA or not when treated with immunotherapy. Based on these retrospective results the indication of BTAs to reduce SSEs in cancer patients under treatment with immunotherapy needs further evaluation.
RESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is an incurable malignant disease, which results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein (FAP) is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors (CAR) against tumor-associated antigens (TAA) and therefore represent a therapeutic strategy of adoptive immunotherapy. METHODS: To evaluate FAP expression immunohistochemistry was performed in tumor tissue from MPM patients. CD8+ human T cells were retrovirally transduced with an anti-FAP-F19-∆CD28/CD3ζ-CAR. T cell function was evaluated in vitro by cytokine release and cytotoxicity assays. In vivo function was tested with an intraperitoneal xenograft tumor model in immunodeficient mice. RESULTS: FAP was found to be expressed in all subtypes of MPM. Additionally, FAP expression was evaluated in healthy adult tissue samples and was only detected in specific areas in the pancreas, the placenta and very weakly for cervix and uterus. Expression of the anti-FAP-F19-∆CD28/CD3ζ-CAR in CD8+ T cells resulted in antigen-specific IFNγ release. Additionally, FAP-specific re-directed T cells lysed FAP positive mesothelioma cells and inflammatory fibroblasts in an antigen-specific manner in vitro. Furthermore, FAP-specific re-directed T cells inhibited the growth of FAP positive human tumor cells in the peritoneal cavity of mice and significantly prolonged survival of mice. CONCLUSION: FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells.
Assuntos
Gelatinases/metabolismo , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Proteínas de Membrana/metabolismo , Mesotelioma/imunologia , Mesotelioma/terapia , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/terapia , Serina Endopeptidases/metabolismo , Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Citotoxicidade Imunológica , Endopeptidases , Humanos , Imuno-Histoquímica , Mesotelioma Maligno , Camundongos , Peritônio/patologia , Proteínas Recombinantes/metabolismo , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transdução Genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various therapeutic modalities are available for its treatment, including endocrine therapy, chemotherapy, poly (ADP-ribose) polymerase [PARP] inhibition, radionuclide therapy, and radioligand therapy. OBJECTIVES: This review outlines practical aspects and considerations regarding treatment sequencing in mCRPC. MATERIALS AND METHODS: The findings are based on existing prospective phase 3 studies that have demonstrated clinically relevant and statistically significant benefits in radiographically progression-free and/or overall survival. RESULTS: Sequential therapy, aside from numerous patient-specific factors, depends on the treatment patients received in the hormone-sensitive prostate cancer (mHSPC) setting. Following pretreatment with ADT alone or ADT plus docetaxel in the mHSPC context, additional endocrine therapy is the standard approach. In the event of progression under combined endocrine therapy initiated in the mHSPC setting, docetaxel currently serves as the standard for the majority of patients. Patients who received triplet therapy as a pretreatment in the mHSPC scenario can be treated with radioligand therapy or second-line chemotherapy. CONCLUSION: Various active and well-tolerated treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of therapy is primarily determined by previous treatments, but many other individual factors are also taken into consideration.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Estudos ProspectivosRESUMO
INTRODUCTION: The combination of checkpoint inhibition and cisplatin-based chemotherapy is investigated in muscle invasive bladder cancer (MIBC) and results from phase 2 trials have been presented. Intravesical BCG has been used for non-MIBC (NMIBC) in patients with carcinoma in situ and high-grade Ta/T1 tumours. BCG induces innate and adapted immune response and upregulation of PD-L1 in preclinical models. The proposed trial is intended to implement a new immuno-immuno-chemotherapy induction therapy for MIBC. The combination of BCG and checkpoint inhibition with chemotherapy aims at higher intravesical responses and better local and systemic control of disease. METHODS AND ANALYSIS: SAKK 06/19 is an open-label single-arm phase II trial for patients with resectable MIBC T2-T4a cN0-1. Intravesical recombinant BCG (rBCG: VPM1002BC) is applied weekly for three instillations followed by four cycles of neoadjuvant cisplatin/gemcitabine every 3 weeks. Atezolizumab 1200 mg every 3 weeks is started together with rBCG and given for four cycles. All patients then undergo restaging and radical cystectomy and pelvic lymphadenectomy. Atezolizumab is continued as maintenance therapy after surgery every 3 weeks for 13 cycles. Pathological complete remission is the primary endpoint. Secondary endpoints include pathological response rate (Assuntos
Cisplatino
, Neoplasias da Bexiga Urinária
, Humanos
, Cisplatino/uso terapêutico
, Vacina BCG/uso terapêutico
, Cistectomia
, Terapia Neoadjuvante
, Neoplasias da Bexiga Urinária/tratamento farmacológico
, Neoplasias da Bexiga Urinária/patologia
, Imunoterapia
, Administração Intravesical
, Músculos/patologia
, Excisão de Linfonodo
, Estudos Multicêntricos como Assunto
, Ensaios Clínicos Fase II como Assunto
RESUMO
PURPOSE: The integration of immunotherapy in the perioperative setting of muscle-invasive urothelial carcinoma (MIUC) appears promising. SAKK 06/17 investigated the addition of neoadjuvant durvalumab to gemcitabine/cisplatin (GC) chemotherapy followed by radical surgery and adjuvant checkpoint inhibition with durvalumab. PATIENTS AND METHODS: SAKK 06/17 was an investigator-initiated, open-label, single-arm phase II study including cisplatin-fit patients with stage cT2-T4a cN0-1 operable MIUC. Four cycles of neoadjuvant GC in combination with four cycles of durvalumab (start with GC cycle 2) were administered, followed by radical surgery. Adjuvant durvalumab was given for 10 cycles. The primary end point was event-free survival (EFS) at 2 years. RESULTS: Sixty one patients were accrued at 12 sites. The full analysis set consisted of 57 patients, 54 (95%) had bladder cancer. Median follow-up was 40 months. The primary end point was met, with EFS at 2 years of 76% (one-sided 90% CI [lower bound], 67%; two-sided 95% CI, 62 to 85). EFS at 3 years was 73% (95% CI, 59 to 83). Complete pathologic response in resected patients (N = 52) was achieved in 17 patients (33%), and 31 (60%) had pathologic response Assuntos
Carcinoma de Células de Transição
, Neoplasias da Bexiga Urinária
, Humanos
, Neoplasias da Bexiga Urinária/tratamento farmacológico
, Neoplasias da Bexiga Urinária/cirurgia
, Carcinoma de Células de Transição/tratamento farmacológico
, Carcinoma de Células de Transição/cirurgia
, Cisplatino/efeitos adversos
, Desoxicitidina/efeitos adversos
, Músculos
, Imunoterapia
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Terapia Neoadjuvante/efeitos adversos
RESUMO
BACKGROUND: Asbestos is the main cause of MPM in industrialized countries. Even since asbestos is banned in most developed countries, the peak wave of MPM incidence is anticipated for the next years due to the long latency of asbestos induced MPM. MPM patients not eligible for surgical procedures like decortication or pleuro-pneumectomie have a median survival of 12 months with palliative chemotherapy. Therefore, new therapeutic approaches are of crucial need in this clinical situation. METHODS/DESIGN: This is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x106 adoptively transferred FAP-specific re-directed T cells given directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral transfer of a chimeric antigen receptor recognizing FAP which serves as target structure in MPM. At day 0 of the protocol, re-directed T cells will be injected in the pleural effusion and patients will be monitored for 48h under intermediate care conditions. AE, SAE, SADR and SUSAR will be monitored for 35 days and evaluated by an independent safety board to define any dose limiting toxicity (DLT). No further patient can be treated before the previous patient passed day 14 after T cell transfer. The protocol will be judged as save when no DLT occurred in the first 3 patients, or 1 DLT in 6 patients. Secondary objectives are feasibility and immune monitoring. DISCUSSION: Adoptive T cell transfer is a new and rapidly expanding branch of immunotherapies focusing on cancer treatment. Recently, objective responses could be observed in patients with chronic lymphatic leukemia treated with adoptively transferred CD19-specific re-directed T cells. The choice of the target antigen determines the possible on-target off-tissue toxicity of such approaches. There are reports of severe toxicity in patients who received T cells intravenously due to unexpected expression of the target antigen (on-target) in other tissues than the tumor (off-tissue). To minimize the risk of on-target off-tissue toxicity and to maximize the on-target anti-tumor effect we propose a clinical protocol with loco-regional administration of re-directed T cells. FAP-specific T cells will be directly injected in the pleural effusion of patients with MPM. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01722149).
Assuntos
Gelatinases/metabolismo , Imunoterapia Adotiva/métodos , Proteínas de Membrana/metabolismo , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Serina Endopeptidases/metabolismo , Linfócitos T/imunologia , Adolescente , Transferência Adotiva , Adulto , Idoso , Citocinas/metabolismo , Endopeptidases , Feminino , Humanos , Masculino , Mesotelioma/imunologia , Mesotelioma/metabolismo , Pessoa de Meia-Idade , Derrame Pleural , Derrame Pleural Maligno , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/metabolismo , Adulto JovemRESUMO
Hepatic fungal infection is a frequent complication in patients receiving intensive chemotherapy for acute leukaemia. Hepatic lesions may be detected using computerised tomographic (CT) scans, but there is no standardised CT protocol for the diagnosis and follow-up of hepatic fungal infection. We therefore retrospectively analysed the number and the volume of hepatic fungal lesions in 24 CT of 20 consecutive patients treated for acute leukaemia during late-arterial and porto-venous phase. The mean number of lesions per patient was 31 (range: 3-105) in the late-arterial and 26 (3-81) in the porto-venous CT (P = 0.026). The mean total volume of all lesions was 6.45 ml in the late-arterial and 4.07 ml in the porto-venous CT representing a 1.6fold difference between the two CT scans (P = 0.008). The total volume of the lesions negatively correlated to the absolute contrast difference between liver parenchyma and liver vein (Pearson correlation, r = -0.62; P = 0.002). In conclusion, the late-arterial CT provides a superior distinction of hepatic lesions due to a delayed perfusion of the outer rim of the fungal lesions resulting in an extended visibility. The late-arterial CT is superior to the porto-venous CT for initial diagnosis and follow-up of hepatic fungal infection.
Assuntos
Hospedeiro Imunocomprometido , Leucemia/complicações , Hepatopatias/diagnóstico , Fígado/diagnóstico por imagem , Micoses/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Humanos , Leucemia/tratamento farmacológico , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Micoses/diagnóstico por imagem , Micoses/patologia , Estudos RetrospectivosRESUMO
To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n = 46; 50%), or daily filgrastim (n = 46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p = 0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p = 0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p = 0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p = 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Tempo de Internação , Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Formas de Dosagem , Relação Dose-Resposta a Droga , Feminino , Filgrastim , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Polietilenoglicóis , Proteínas Recombinantes , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/estatística & dados numéricos , Transplante Autólogo , Resultado do TratamentoRESUMO
Regulatory T (Treg) cells represent a major roadblock to the induction of antitumor immunity through vaccine approaches. TGF-beta is a cytokine implicated in the generation and maintenance of Treg cells, as well as in their suppressive function. These experiments examined whether the generation of tumor-sensitized Treg cells was TGF-beta dependent and evaluated whether TGF-beta produced by Treg cells blocked the priming of tumor-specific T cells in vaccinated reconstituted lymphopenic mice. We show that tumor-sensitized Treg cells (CD25(+)/FoxP3(+)) obtained from tumor-bearing mice block the generation of tumor-specific T cells in reconstituted lymphopenic mice. Strikingly, this suppression is absent if tumor-sensitized Treg cells are acquired from tumor-bearing mice expressing the dominant-negative TGFbetaRII in T cells. This loss of suppression was a result of the crucial role of TGF-beta in generating tumor-sensitized Treg cells, and not due to the insensitivity of naive or tumor-primed effector T cells to the direct suppressive influence of TGF-beta. We conclude that blocking TGF-beta in a tumor-bearing host can inhibit the induction of highly suppressive tumor-sensitized Treg cells. These data suggest that an integrative strategy combining "up-front" Treg cell ablation followed by vaccination and TGF-beta blockade may limit generation of new tumor-sensitized Treg cells and improve the generation of therapeutic immune responses in patients with cancer.
Assuntos
Neoplasias Experimentais/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Células Cultivadas , Imunidade , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Knockout , Transdução de Sinais/imunologiaRESUMO
INTRODUCTION: Standardized systemic treatment options are lacking for carcinoma ex pleomorphic adenoma, which is a rare and aggressive tumor primarily found in salivary glands.Here we report the case of a 63-year-old male with carcinoma ex pleomorphic adenoma of the left parotid and parapharyngeal space harboring a neurotrophic receptor tyrosine kinase (NTRK) 2 fusion who was treated with a small molecule inhibitor that targets the tropomyosin receptor kinase (TRK) proteins. To the best of our knowledge, no similar case has been described in the literature so far. PATIENT CONCERNS: After multiple surgical resections and radiotherapy for localized cancer disease over several years, our patient again developed an increasing swelling and pain around the left ear and numbness of the left half of the face. DIAGNOSIS: Magnetic resonance imaging and positron emission tomography/computed tomography scans showed tumor recurrence in the left parotid, below the left ear, and in the parapharyngeal space, as well as metastases of the lungs and cervical lymph nodes. As data on the efficacy of systemic therapies for inoperable carcinoma ex pleomorphic adenoma are scarce, we performed a next-generation sequencing that revealed the presence of a hitherto unknown NTRK2 fusion. INTERVENTIONS: Treatment with the TRK inhibitor larotrectinib was initiated, which induced rapid symptom improvement. However, part of the tumor had to be removed shortly afterwards due to local progression. Molecular testing did not demonstrate any alterations accounting for resistance to larotrectinib, with maintenance of the NTRK2 fusion. OUTCOMES: Three months later, imaging confirmed mixed response. While the reason for this remains unknown, the patient is in good condition and continues to receive larotrectinib. CONCLUSION: It remains unclear why our patient showed mixed response to larotrectinib and further studies are needed to explore other possible mechanisms of resistance.
Assuntos
Adenoma Pleomorfo/tratamento farmacológico , Neoplasias Parotídeas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/cirurgia , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas de Fusão Oncogênica/genética , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/cirurgia , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patologia , Receptor trkBRESUMO
OBJECTIVE: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin's and non-Hodgkin's lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. METHODS: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. RESULTS: Fourteen (26%) patients with Hodgkin's lymphoma and 40 (74%) patients with non-Hodgkin's lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 µg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). CONCLUSION: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Neutropenia/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Trombocitopenia/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Esquema de Medicação , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doença de Hodgkin/cirurgia , Humanos , Tempo de Internação , Linfoma não Hodgkin/cirurgia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Polietilenoglicóis , Proteínas Recombinantes , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controle , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[(18)F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15%) patients received statins throughout therapy. Five-year EFS was 67.3% in patients without statins compared with 79% in patients receiving statins during R-CHOP (HR, 0.47; 95% CI, 0.15-1.54, p = 0.2). Five-year OS was 81.4% for patients without statins compared with 93.3% for patients taking statins (HR, 0.58; 95% CI 0.07-4.55, p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75% in the non-statin group versus 86% in the statin group, p = 0.45). A trend toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84% versus 92%, p = 0.068). Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBCL.