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1.
Int J Cancer ; 152(2): 259-266, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35913764

RESUMO

Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.


Assuntos
Antineoplásicos , Neuroblastoma , Síndrome da Leucoencefalopatia Posterior , Humanos , Lactente , Camundongos , Animais , Idoso , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Neuroblastoma/tratamento farmacológico , Imunoterapia , Fatores Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico
2.
J Headache Pain ; 23(1): 139, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333710

RESUMO

BACKGROUND: Controlled and real-world evidence have demonstrated the efficacy of calcitonin gene related peptide (CGRP) monoclonal antibodies (MABs) in migraine. However, data on the over-one-year sustained effectiveness of CGRP MABs in resistant chronic migraine (CM) is sparse.  METHODS: This is a two-year real-world prospective analysis of an ongoing single centre audit conducted in patients with resistant CM. Patients received monthly erenumab for six months before assessing its effectiveness. Responders were considered those who achieved at least 30% reduction in monthly migraine days (MMD) by month 6, compared to baseline. Secondary outcomes were also analysed, including changes of the Headache Impact Test version 6 (HIT-6). RESULTS: One hundred sixty-four patients [135 (82.3%) females; mean age 46 SD 14) years] were included in the audit and 160 patients analysed. Patients had failed a mean of 8.4 preventive treatments at baseline. At month 6, 76 patients (48%) were 30% responders to erenumab, 50 patients (31%) were 50% responders and 25 (15%) were 75% responders. The mean reduction in MMD at month 6 was 7.5 days compared to baseline (P < 0.001). At month 12 and month 18, 61 patients (38%) and 52 patients (33%) remained 30% responders respectively. At month 24, 36 patients (23%) remained 30% responders, 25 patients (16%) and 13 patients (8%) were respectively 50% and 75% responders. Compared to 95% of patients at baseline, at months 6, 12 and 24, 46%, 29% and 16% of responders respectively had severe disability. At least one adverse event at month 6, 12, 18 and 24 was reported by 49%, 19%, 11% and 3% of patients. By month 6, 13% of patients discontinued the treatment because of side effects, often constipation. CONCLUSIONS: Long-term sustained effectiveness of erenumab was reported only by a minority of resistant CM patients. Although more research in resistant migraine is needed, Erenumab can provide long-term meaningful reduction in migraine load and migraine-related disability in some patients.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , Transtornos de Enxaqueca/prevenção & controle , Anticorpos Monoclonais/efeitos adversos
3.
BMC Endocr Disord ; 22(1): 291, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36419114

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy. CASE PRESENTATION: A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0. She developed thyrotoxicosis followed by hypothyroidism induced by consolidation immunotherapy with durvalumab (anti-PD-L1). Analysis of the human leukocyte antigen (HLA) region showed HLA-DR4 (susceptible) and DR13 (protective). The possible mechanisms are subsequently discussed in detail. CONCLUSIONS: The case of a patient with thyroiditis associated with the PD-L1 inhibitor durvalumab is described, highlighting the need for proactive monitoring of thyroid hormone levels. Identifying biomarkers associated with an increased risk of ICI-induced side effects (such as HLA) is of interest for better patient selection, optimal management and improved understanding of the mechanisms involved.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Tireoidite , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Tireoidite/induzido quimicamente , Anticorpos Monoclonais/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico
4.
Front Immunol ; 13: 1026964, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405729

RESUMO

Purpose: Immune-mediated adverse events (imAEs) may be associated with response to immune checkpoint inhibitors. We assessed the relationship between imAE development and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab (anti-programmed cell death ligand-1 [PD-L1]) alone or in combination with tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4). Methods: The analysis used individual patient-level data from 307 and 310 patients in the monotherapy and combination arms of MYSTIC, respectively. We evaluated the association between treatment efficacy and development of imAEs using univariate and multivariate survival analyses. Using machine learning, we built a predictive model utilizing baseline clinical and laboratory features to identify patients at risk of developing imAEs and further evaluated patient survival based on a threshold index extracted from the model. Results: Patients who developed any grade of imAE had improved overall survival versus patients without (hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.41-0.62). imAE development was associated with improved overall survival (HR 0.54; 95% CI 0.44-0.66) in a multivariate Cox proportional hazard model considering patient demographic features and baseline characteristics. Higher odds of imAE development were observed (odds ratio 3.023; 95% CI: 1.56-5.83) in responders versus non-responders in patients treated with immunotherapy. Based on baseline characteristics, the random forest classification algorithm was used to formulate a predictive model to identify patients at increased risk of developing imAEs during treatment. Conclusion: Post-hoc exploratory analysis found that the efficacy of immunotherapy was improved in patients who developed on-treatment imAEs. This was independent of severity of imAEs or the need for steroid treatment, which is important in allowing patients to remain on treatment and derive optimal clinical benefit. Further research is warranted to establish the correlation between incidence of imAEs and efficacy in this patient population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais/efeitos adversos
5.
J Hematol Oncol ; 15(1): 165, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371226

RESUMO

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.


Assuntos
Neoplasias do Sistema Nervoso Central , Neuroblastoma , Humanos , Animais , Camundongos , Distribuição Tecidual , Recidiva Local de Neoplasia/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Neoplasias do Sistema Nervoso Central/radioterapia , Neuroblastoma/radioterapia , Antígenos B7
6.
Curr Opin Organ Transplant ; 27(4): 269-276, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36354253

RESUMO

PURPOSE OF REVIEW: Coronavirus disease-2019 (COVID-19) disproportionately causes severe outcomes in solid organ transplant recipients (SOTR). Antispike monoclonal antibodies have been authorized for therapy and prophylaxis for COVID-19. Here, we review the current state of antispike monoclonal antibodies and their role for SOTRs. RECENT FINDINGS: Bamlanivimab with or without etesevimab, casirivimab-imdevimab and sotrovimab have reduced the rates of hospitalization and severe disease in high-risk patients with mild-to-moderate COVID-19. Multiple retrospective studies have also demonstrated monoclonal antibodies are effective in SOTR populations. However, the evolution of resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns has resulted in revocation of the authorization of bamlanivimab with or without etesevimab, and casirivimab-imdevimab as treatment and postexposure prophylaxis (PEP). Sotrovimab and bebtelovimab are currently authorized for treatment of the predominant circulating SARS-CoV-2 B.1.1.529 (Omicron), but not as pre or PEP. Tixagevimab-cilgavimab, a long-acting antibody combination preparation, is authorized for preexposure prophylaxis in high-risk immunocompromised populations, including SOTRs, who are less likely to mount an effective immune response following vaccination series and booster. SUMMARY: Antispike monoclonal antibodies are useful for the prevention and treatment of mild-to-moderate COVID-19 in SOTRs. However, their clinical use should be determined by the evolving epidemiology of SARS-CoV-2 variants in the community.


Assuntos
COVID-19 , Transplante de Órgãos , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , Estudos Retrospectivos , Anticorpos Monoclonais/efeitos adversos , Transplante de Órgãos/efeitos adversos , Transplantados
7.
Cancer J ; 28(6): 496-507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383913

RESUMO

ABSTRACT: Antibody-drug conjugates (ADCs) have been revolutionary in improving personalized therapy of cancer. Through combining monoclonal antibodies, which are targeted to tumor-specific antigens, and cytotoxic agents, ADCs lead to selective delivery of active components, also called payloads, to cancerous cells while sparing healthy body cells from possible collateral damage. Adverse events, however, can still develop because of early release of the payload or cross-expression of targets by normal cells leading to collateral damage. In this review, we elaborate on the common and serious adverse events for the currently US Food and Drug Administration-approved ADCs in solid tumors and discuss mitigating strategies and dose modification guidance for optimizing efficacy and toxicity.


Assuntos
Antineoplásicos Imunológicos , Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias/terapia , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico
8.
Int J Clin Oncol ; 27(12): 1795-1804, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36342599

RESUMO

BACKGROUND: Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. METHODS: In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. RESULTS: In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. CONCLUSIONS: Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted.


Assuntos
Antineoplásicos , Neoplasias , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Japão , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico
9.
BMC Cancer ; 22(1): 1213, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434554

RESUMO

BACKGROUND: Urothelial carcinoma (UC) is the ninth most commonly diagnosed cancer worldwide, with a 3.8/1 male to female ratio. Platinum-based chemotherapy is the first line standard of care for fit patients with advanced UC. However, despite a response rate (RR) for approximately half of patients receiving standard chemotherapy, durable responses are rare (median progression-free progression (PFS) around 8 months). Recently, immune checkpoint inhibitors (ICI) have emerged as new therapeutic options. Among them, Avelumab, an anti-PD-L1 antibody, was assessed in maintenance treatment, demonstrating an overall survival improvement in the JAVELIN Bladder-100 phase III trial. These findings led to its approval as first line maintenance therapy for patients with locally advanced or metastatic UC who have not progressed on prior platinum-containing chemotherapy. However, disease progression as best response was noticed for 37% of patients under Avelumab as maintenance treatment. UC has targetable genomic alterations, including DNA damage repair (DDR) alterations. DDR deficiency is known to major sensitivity to both platinum-based chemotherapy and PD-1/PD-L1 blockade and the combination of ICI and PARP inhibitors showed promising results. It therefore warrants to assess the interest of combining ICI plus PARP inhibitors as maintenance treatment in UC patients. METHODS: The TALASUR trial is a single-arm multicenter phase 2 study aiming to assess the antitumor activity of the combination of Avelumab with Talazoparib among patients with locally advanced/metastatic UC in maintenance therapy after platinum-based chemotherapy. The primary objective is to determine the efficacy of the combination, assessed through PFS. Secondary objectives are as follows: safety profile of the association, objective response, duration of tumoral response, disease control rate, time to subsequent therapy, quality of life. A blood and tumor collections will be also constituted. Patient will receive the combination therapy of daily oral Talazoparib (1 mg/day) and intra-venous Avelumab 800 mg on days 1 and 15, in a 28-day cycle. Fifty patients will be enrolled. DISCUSSION: Talazoparib with Avelumab combination may have additive activity when administrated jointly. We hypothesize that combination will increase the antitumor activity in UC first line maintenance setting with an acceptable safety profile. TRIAL REGISTRATION: NCT04678362, registered December 21, 2020. PROTOCOL VERSION:  Version 1.3 dated from 2020 09 11.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Masculino , Feminino , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Platina/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases , Qualidade de Vida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
10.
Front Immunol ; 13: 1027235, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439116

RESUMO

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.


Assuntos
Anticorpos Monoclonais , Neoplasias , Humanos , Ligação Proteica , Anticorpos Monoclonais/efeitos adversos , Fadiga , Cefaleia , Neoplasias/tratamento farmacológico , Antígeno CD47
11.
Arterioscler Thromb Vasc Biol ; 42(12): 1447-1457, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36325897

RESUMO

BACKGROUND: Despite progress in treating homozygous familial hypercholesterolemia, most patients do not achieve low-density lipoprotein cholesterol (LDL-C) targets. This study examined efficacy and safety of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, alirocumab, in pediatric patients (aged 8-17 years) with inadequately controlled homozygous familial hypercholesterolemia. METHODS: In this open-label, single-arm, multinational, Phase 3 study, patients (n=18) received alirocumab 75 mg or 150 mg (bodyweight <50 kg/≥50 kg) every 2 weeks as an adjunct to background treatment. The primary endpoint was percent change in LDL-C from baseline to Week 12. Secondary endpoints included changes in LDL-C and other lipid parameters up to 48 weeks, safety/tolerability, and alirocumab pharmacokinetics. RESULTS: The mean age of patients was 12.4 years; 16/18 (89%) had mutations in the low-density lipoprotein receptor gene (LDLR) and 2/18 (11%) had mutations in the LDLR adapter protein 1 gene (LDLRAP1). At baseline, mean LDL-C (standard deviation) was 373.0 (193.5) mg/dL, which decreased by 4.1% at Week 12 (primary endpoint) and 11.4%, 13.2%, and 0.4% at Weeks 4, 24, and 48, respectively. At Week 12, 9/18 (50%) patients achieved LDL-C reductions ≥15%. Mean absolute LDL-C decreases ranged from 25 to 52 mg/dL over follow-up. A post hoc analysis demonstrated heterogeneity of responses according to genotype. There were no unexpected safety/tolerability findings. Free PCSK9 was reduced to near zero for all patients at Weeks 12 and 24. CONCLUSIONS: The study supports the efficacy and safety of alirocumab as a potential adjunct to treatment for some pediatric patients with homozygous familial hypercholesterolemia. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; NCT03510715.


Assuntos
Hipercolesterolemia Familiar Homozigota , Pró-Proteína Convertase 9 , Adolescente , Criança , Humanos , Anticorpos Monoclonais/efeitos adversos , LDL-Colesterol , Método Duplo-Cego , Pró-Proteína Convertase 9/genética
13.
Nihon Yakurigaku Zasshi ; 157(6): 458-463, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36328561

RESUMO

Since the first monoclonal antibody was approved by FDA in 1986, numerous therapeutic antibodies have been developed along with advances in antibody engineering and finally, the number of approved therapeutic antibodies by FDA exceeded 100 in 2021. Although therapeutic antibodies were thought to be safer than conventional small molecule drugs, non-clinical safety evaluations of antibodies become more important because antibody-specific toxicity has been found. The depletion of target molecules for antibody drugs is a problem due to the limited number of promising targets. However, to overcome this, some technologies which can enhance the activity of antibodies and enable to add new functions to antibodies have been developed. In particular, bispecific antibodies and antibody-drug conjugates are considered to be attracting technologies as the next-generation antibody modalities. Several drugs applying these technologies have been approved in a recent decade. On the other hand, there is still plenty of room for improvement in these technologies which sometimes occur unexpected toxicity, so the safety of drugs applying these technologies should be carefully evaluated. Here some important considerations for the non-clinical safety evaluations of bispecific antibodies and antibody-drug conjugates are discussed based on a literature review of these types of antibody drugs (approved or terminated due to toxicity).


Assuntos
Anticorpos Biespecíficos , Imunoconjugados , Anticorpos Biespecíficos/uso terapêutico , Imunoconjugados/uso terapêutico , Anticorpos Monoclonais/efeitos adversos
14.
Zhonghua Yi Xue Za Zhi ; 102(41): 3304-3311, 2022 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-36319183

RESUMO

Objective: To investigate the efficacy and safety of daratumumab in relapsed/refractory multiple myeloma (RRMM) patients. Methods: Fifty-two RRMM patients treated with daratumumab from September 2019 to November 2021 in West China Hospital were retrospectively enrolled, including 31 males and 21 females. The mean age of these patients at the first diagnosis of multiple myeloma was (58±10) years. According to the dosage of daratumumab, patients were divided into low dosage group (n=10) and high dosage group (n=42). Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event rates were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of the 52 patients, 8 received daratumumab monotherapy, 27 received daratumumab plus immuno-modulatory drug (IMiD) treatment, 4 received daratumumab plus proteosome inhibitor (PI) treatment, and 11 received daratumumab plus dexamethasone treatment. The diagnosis age of high dosage group patients was (57±9) years, which was significantly younger than that of low dosage group [(66±10) years] (P=0.009). The baseline creatinine level of high dosage group patients [M (Q1, Q3)] was 91 (68, 196) µmol/L, which was significantly higher than that of low dosage group [66 (51, 76) µmol/L] (P=0.021). There was no significant difference in other baseline clinical characteristics, previous treatment regimens, previous lines of treatment, and regimen and cycles of daratumumab between the high dosage group and low dosage group (all P>0.05). The ORR for the 52 patients was 71.2% (37/52). The ORR for daratumumab plus IMiD group was 81.5% (22/27), which was significantly higher than that in monotherapy or dexamethasone group [ORR: 52.6% (10/19), P=0.036). With a median follow-up [M (Q1, Q3)] of 7 (5, 26) months, the median PFS for overall cohort was 17 (95%CI: 9.6-24.4) months. The median PFS for daratumumab plus IMiD group was 26 (95%CI: 6.0-46.0) months, which was significantly better than that in monotherapy or dexamethasone group [12 (95%CI: 3.5-20.5) months] (HR=0.231, 95%CI: 0.075-0.715, P=0.011). Higher diagnosis age was the risk factor of progression (HR=1.085, 95%CI: 1.016-1.158, P=0.014), while more cycles of daratumumab treatment was the protective factor of progression (HR=0.669, 95%CI: 0.495-0.904, P=0.009). There was no significant influence of daratumumab dosage on progression (high dosage vs low dosage, HR=1.016, 95%CI: 0.221-4.668, P=0.984). The median OS for overall cohort was 26 (95%CI: 13.1-38.9) months. Higher serum calcium was the independent risk factor of death (HR=12.190, 95%CI: 1.170-127.048, P=0.037). There was no significant influence of daratumumab dosage on death (high dosage vs low dosage, HR=0.818, 95%CI: 0.171-3.917, P=0.802). Adverse events included infections (43.2%, 16/37), infusion-associated reactions (29.7%, 11/37), and thrombocytopenia (27.0%, 10/37). Conclusions: Daratumumab is effective to treat RRMM. The dosage of daratumumab has no significant influence on prognosis when used in combined treatment. The incidence of adverse events is relatively low, with a favorable safety profile.


Assuntos
Mieloma Múltiplo , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Estudos Retrospectivos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico
15.
Front Endocrinol (Lausanne) ; 13: 1010279, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36204105

RESUMO

Immune checkpoint inhibitors, namely anti-CTLA-4, anti-PD-1 and anti-PD-L1 monoclonal antibodies, have emerged in the last decade as a novel form of cancer treatment, promoting increased survival in patients. As they tamper with the immune response in order to destroy malignant cells, a new type of adverse reactions has emerged, known as immune-related adverse events (irAEs), which frequently target the endocrine system, especially the thyroid and hypophysis. Thyroid irAEs include hyperthyroidism, thyrotoxicosis, hypothyroidism and a possibly life-threatening condition known as the "thyroid storm". Early prediction of occurrence and detection of the thyroid irAEs should be a priority for the clinician, in order to avoid critical situations. Moreover, they are recently considered both a prognostic marker and a means of overseeing treatment response, since they indicate an efficient activation of the immune system. Therefore, a multidisciplinary approach including both oncologists and endocrinologists is recommended when immune checkpoint inhibitors are used in the clinic.


Assuntos
Antineoplásicos Imunológicos , Neoplasias , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Glândula Tireoide
16.
Comput Math Methods Med ; 2022: 7095423, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199771

RESUMO

Objective: This research is aimed at studying the effect of microwave ablation combined with the antiprogrammed death- (PD-) 1 monoclonal antibody on T cell subsets and long-term prognosis in patients suffering from non-small-cell lung cancer (NSCLC). Methods: Employing the random number table technique, a total of 122 NSCLC patients who received treatment at our hospital between May 2015 and June 2019 were selected and assigned to the observation group and the control group, and each group comprised 61 patients (n = 61). While the control group received only anti-PD-1 monoclonal antibody treatment, the observation group received microwave ablation in combination with anti-PD-1 monoclonal antibody. The clinical efficacy was observed for both groups. The levels of T cell subsets (CD3+, CD4+, and CD8+), serum tumor markers (squamous cell carcinoma antigen (SCCA), cytokeratin Ig fragment (CYFRA21-1), and serum carcinoembryonic antigen (CEA)), nuclear factor kappa B (NF-κB), protease C (PKC), and mitogen-activated protein kinase (MAPK) mRNA expression between the two groups were compared. The frequency of adverse reactions was observed in both groups. The survival time of both the groups was recorded over the course of three years of follow-up. The Kaplan-Meier method was employed for analyzing the survival of both the control and the observation group. Results: The response rate (RR) of the observation group (80.33%) was considerably greater in comparison to that of the control group (62.30%) (P < 0.05). Following treatment, the observation group's levels of CD3+, CD4+, CD8+, SCCA, CyFRA21-1, and CEA and the mRNA expressions of NF-κB, PKC, and MAPK were superior to those of the control group, with statistical significances (all P < 0.05). Between the two groups, there was no significant difference in the occurrence of adverse reactions (P > 0.05). The observation group had greater 1-, 2-, and 3-year survival rates (57.38%, 39.34%, and 29.51%) than the control group (32.79%, 18.03%, and 8.20%), with statistically significant differences (all P < 0.05). Conclusion: Microwave ablation in combination with an anti-PD-1 monoclonal antibody could effectively improve the level of T cell subsets and serum tumor markers in NSCLC patients, resulting in a long-term prognosis of patients with good therapeutic effect and safety.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais/efeitos adversos , Antígenos de Neoplasias , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Fragmentos de Imunoglobulinas/uso terapêutico , Queratina-19 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Micro-Ondas/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno , NF-kappa B , Prognóstico , RNA Mensageiro , Subpopulações de Linfócitos T
18.
BMC Cancer ; 22(1): 1104, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307775

RESUMO

BACKGROUND: An over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC).  METHODS: This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5-15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study.  RESULTS: From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type KRAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T1/2) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%-44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%-68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6-5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached). CONCLUSIONS: SCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov ( NCT02211443 ).


Assuntos
Antineoplásicos , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mutação , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genética
19.
Ann Saudi Med ; 42(5): 309-318, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36252145

RESUMO

BACKGROUND: The introduction of biological treatments has revolutionized the management of moderate-to-severe psoriasis. Multiple clinical trials have established the efficacy of biological agents in the treatment of moderate-to-severe psoriasis. Nevertheless, there are no clear indications for optimal monitoring intervals during treatment. OBJECTIVES: Collect and analyze laboratory evaluation data from patients receiving biological therapy to provide a better understanding of the need for laboratory investigations before and during treatment with biological agents, and to analyze adverse events and other factors. DESIGN: Retrospective cohort SETTINGS: Tertiary care center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: Data were collected from the electronic medical records of patients attending the dermatology, rheumatology, and gastroenterology clinics from June 2014 to June 2019. The laboratory parameters of patients who have received one of the TNF-alpha inhibitors (adalimumab, etanercept, or infliximab) were collected starting at baseline and up to at least one year from treatment initiation. MAIN OUTCOME MEASURES: The time points at which patients developed significantly abnormal laboratory results during treatment with one of the TNF-alpha inhibitors. SAMPLE SIZE: 250 patients RESULTS: Most patients were treated with adalimumab (38.4%); a similar proportion (38%) with infliximab, whereas only 23.6% were treated with etanercept. The majority of the significant abnormal laboratory results occurred at baseline, 3-6 and 9-12 months. Most abnormalities were among patients using infliximab, followed by etanercept, and then adalimumab. The median number of laboratory abnormalities for dermatology patients was significantly lower than that for gastroenterology patients (P<.001), and for rheumatology patients (P=.002). CONCLUSIONS: Because dermatology patients showed a lower median number of laboratory abnormalities than patients treated by other specialties in our study, we believe that dermatology patients require less frequent laboratory monitoring. Therefore, we recommend laboratory evaluation at baseline, after 3-6 months, 1 year from the beginning of treatment, and annually thereafter for patients using TNF-alpha inhibitor agents. However, more frequent testing might be warranted according to patient comorbidities, concomitant medications, and physician judgment. LIMITATIONS: Single center and retrospective design. CONFLICT OF INTEREST: None.


Assuntos
Antirreumáticos , Psoríase , Inibidores do Fator de Necrose Tumoral , Humanos , Adalimumab/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Etanercepte/efeitos adversos , Infliximab/efeitos adversos , Psoríase/tratamento farmacológico , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral/efeitos adversos
20.
J Immunother Cancer ; 10(10)2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36316061

RESUMO

BACKGROUND: OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS: Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS: Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION: No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT02923349.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Dose Máxima Tolerável , Receptores OX40
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