RESUMO
Glioblastoma, the most common malignant brain tumor in adults, is associated with a median overall survival duration of less than 2 years. Extraneural metastases occur in less than 1% of all patients with glioblastoma. The mechanism of extraneural metastasis is unclear. We present a case of extensive extraneural, extraosseous, epidural, and soft-tissue metastasis of glioblastoma. The diagnosis of metastatic glioblastoma was made only after next-generation sequencing (NGS) of the metastatic paraspinal lesions was completed. The CDK4, pTERT, PTEN, and TP53 molecular alterations seen in the initial intracranial glioblastoma were found in the paraspinal tumor, along with the addition of MYC, which is implicated in angiogenesis and epidermal-to-mesenchymal transition. Immunohistochemical stains showed that neoplastic cells were negative for GFAP. In conclusion, this case raises awareness about the role of NGS in the diagnosis of extraneural glioblastoma. This diagnosis was not possible with histology alone and only became evident after molecular profiling of the metastatic lesions and its comparison to the original tumor.
RESUMO
BACKGROUND: Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. METHODS: We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). RESULTS: Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40-5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25-0.92, p = 0.026). Both parameters maintained their independent prognostic significance. CONCLUSIONS: ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. CLINICAL TRIAL IDENTIFIER: NCT04805099.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/mortalidade , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
LESSONS LEARNED: Advanced germ cell tumors are aggressive and associated with poor prognosis. Pembrolizumab was overall well tolerated in 12 heavily pretreated patients. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. Published data of immunotherapeutic agents in patients with advanced germ cell tumors are confirmed. The limited antitumor activity of immunotherapy in germ cell tumors is, at least partially, attributed to tumor biology (low tumor mutational burden; low PD-1 expression) and other poor-risk features. Tumor profiling to understand the mechanisms of resistance to pembrolizumab and innovative clinical trials that may include immunotherapy are warranted. BACKGROUND: Advanced germ cell tumors are associated with poor prognosis. We investigated the role of pembrolizumab in patients with advanced germ cell tumors. METHODS: We analyzed a prespecified cohort of an open-label, phase II clinical trial in which patients with advanced germ cell tumors were treated with pembrolizumab (200 mg) intravenously every 21 days. The endpoints of the study were the non-progression rate (NPR) at 27 weeks, safety, and tolerability. An NPR >20% was considered successful and worthy of further pursuit. RESULTS: From August 2016 to February 2018, 12 patients (10 men, 2 women) were treated (median age, 35 years [range, 22-63 years]; median number of prior systemic therapies, 3.5 [range, 2-7]; median number of metastatic sites, 3 [range, 2-8]). Overall, pembrolizumab was well tolerated. One patient experienced both grade 1 immune-related skin rash and grade 3 immune-related pneumonitis. No patient died from toxicity. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. No objective response was noted. The median progression-free survival was 2.4 months (95% confidence interval [CI], 1.5-4.5 months), and the median overall survival was 10.6 months (95% CI, 4.6-27.1 months). The 27-week NPR was 9.0% (95% CI, 0.23-41.2%). CONCLUSION: Overall, pembrolizumab was safe and had limited antitumor activity in these patients. In the advanced, metastatic setting, tumor profiling to understand the mechanisms of resistance to immunotherapy and innovative clinical trials to identify efficacious combination regimens rather than off-label use of pembrolizumab are warranted.
Assuntos
Antineoplásicos Imunológicos , Neoplasias Embrionárias de Células Germinativas , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Intervalo Livre de Progressão , Adulto JovemRESUMO
Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development, namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat diet (HFD)-induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed a normal diet or an HFD for 16 wk. Gravin-t/t mice showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, and very low-density lipoprotein levels in serum as compared with WT mice on HFD. Furthermore, there was less aortic plaque formation coupled with decreased lipid accumulation and liver damage, as the gravin-t/t mice had lower levels of serum alanine aminotransferase and aspartate aminotransferase. Additionally, gravin-t/t HFD-fed mice had decreased expression of liver 3-hydroxy-3-methyl-glutaryl-CoA reductase, an essential enzyme for cholesterol synthesis and lower fatty acid synthase expression. Gravin-t/t HFD-fed mice also exhibited inhibition of sterol regulatory element binding protein-2 (SREBP-2) expression, a liver transcription factor associated with the regulation of lipid transportation. In response to platelet-derived growth factor receptor treatment, gravin-t/t vascular smooth muscle cells exhibited lower intracellular calcium transients and decreased protein kinase A- and protein kinase C-dependent substrate phosphorylation, notably involving the Erk1/2 signaling pathway. Collectively, these results suggest the involvement of gravin-dependent regulation of lipid metabolism via the reduction of SREBP-2 expression. The absence of gravin-mediated signaling lowers blood pressure, reduces plaque formation in the aorta, and decreases lipid accumulation and damage in the liver of HFD mice. Through these processes, the absence of gravin-mediated signaling complex delays the HFD-induced hyperlipidemia and atherosclerosis.NEW & NOTEWORTHY The gravin scaffolding protein plays a key role in the multiple enzymatic pathways of lipid metabolism. We have shown for the first time the novel role of gravin in regulating the pathways related to the initiation and progression of atherosclerosis. Specifically, an absence of gravin-mediated signaling decreases the lipid levels (cholesterol, triglyceride, and VLDL) that are associated with sterol regulatory element binding protein-2 downregulation.
Assuntos
Proteínas de Ancoragem à Quinase A/deficiência , Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proteínas de Ciclo Celular/deficiência , Dieta Hiperlipídica , Hiperlipidemias/prevenção & controle , Lipídeos/sangue , Placa Aterosclerótica , Proteínas de Ancoragem à Quinase A/genética , Animais , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/genética , Proteínas de Ciclo Celular/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Choosing the right drug(s) for the right patient via advanced genomic sequencing and multi-omic interrogation is the sine qua non of precision cancer medicine. Traditional cancer clinical trial designs follow well-defined protocols to evaluate the efficacy of new therapies in patient groups, usually identified by their histology/tissue of origin of their malignancy. In contrast, precision medicine seeks to optimize benefit in individual patients, i.e., to define who benefits rather than determine whether the overall group benefits. Since cancer is a disease driven by molecular alterations, innovative trial designs, including biomarker-defined tumor-agnostic basket trials, are driving ground-breaking regulatory approvals and deployment of gene- and immune-targeted drugs. Molecular interrogation further reveals the disruptive reality that advanced cancers are extraordinarily complex and individually distinct. Therefore, optimized treatment often requires drug combinations and N-of-1 customization, addressed by a new generation of N-of-1 trials. Real-world data and structured master registry trials are also providing massive datasets that are further fueling a transformation in oncology. Finally, machine learning is facilitating rapid discovery, and it is plausible that high-throughput computing, in silico modeling, and 3-dimensional printing may be exploitable in the near future to discover and design customized drugs in real time.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão/métodos , Ensaios Clínicos como Assunto , Oncologia/métodos , Biomarcadores TumoraisRESUMO
BACKGROUND: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. METHODS: A PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed. The objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between biomarker-positive and biomarker-negative groups, using studies that explored the correlation of biomarkers with outcomes. RESULTS: Overall, 174 clinical studies that included 19,178 patients were identified, and 132 studies investigated>30 correlative biomarkers that included PD-L1 expression (≥1%, 111 studies), tumour mutational burden (20 studies) and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46 and 30 cohorts (drugs, tumour types or biomarkers) with 11,692, 3065, and 2256 patient outcomes for ORR, PFS and OS, respectively, were analysed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumours were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p < 0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p < 0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p < 0.0001) compared with those with biomarker-negative tumours. Significance for ORR and PFS was retained in multivariate analysis (p < 0.001) (OS, not included owing to the small number of trials reporting OS). CONCLUSION: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Resultado do Tratamento , Imunoterapia , Biomarcadores , Intervalo Livre de ProgressãoRESUMO
We performed a literature search in PubMed to identify phase I/II clinical trials with immunotherapy drugs approved by the Food and Drug Administration (labeled, off-label, and/or combined with investigational immune checkpoint inhibitors or other treatment modalities) from 2018 to 2020. We used the following key words: clinical trials, phase 1, Phase 2; and the following filters: cancer, humans; and selected the checkpoint inhibitors that had been approved by the FDA by March 2021, i.e., "pembrolizumab", "nivolumab", "atezolizumab", "durvalumab", "cemiplimab", "avelumab", and "ipilimumab. Clinical trials with their checkpoint inhibitors as in their labeled indications, off-label use or their combinations with investigational immune checkpoint inhibitors or other treatment modalities were included. Studies describing supportive care or locoregional treatments; cellular, viral, or vaccine therapy; studies in the adjuvant or neoadjuvant setting; and pediatric studies were excluded. Overall, 173 articles reporting on relevant studies were identified. Using these articles, we compiled a data file of study-specific covariates for each study. We recorded the immunotherapeutic agent, tumor type and biomarker, and clinical outcomes (objective response rate and median values [point estimate] and confidence intervals for progression-free survival and overall survival. Using these data, we carried out meta-analyses for the three outcomes and meta-regression on study-specific covariates. The same data could be used for any alternative implementation of meta-analysis and meta-regression, using more structured inference models reflecting different levels of dependence based on the available study-specific covariates.
RESUMO
PURPOSE: OBI-999 is a novel antibody-drug conjugate comprising the Globo H-targeting antibody (OBI-888) linked to the cytotoxic payload monomethyl auristatin E. OBI-999 demonstrated excellent dose-dependent tumor growth inhibition in breast, gastric, and pancreatic cancer xenograft models as well as a lung cancer patient-derived xenograft model. We conducted a phase I study of OBI-999 monotherapy in patients with advanced cancer (ClinicalTrials.gov identifier: NCT04084366). PATIENTS AND METHODS: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg every 21 days as part of a 3 + 3 trial design. Primary end points were the incidence of dose-limiting toxicities and adverse events and determination of the maximum tolerated dose (MTD)/recommended phase II dose. RESULTS: Fifteen adult patients were treated. OBI-999 was well tolerated up to 1.2 mg/kg, the maximum tolerated dose. The most common treatment-emergent adverse events were neutropenia and anemia. OBI-999 exhibited nonlinear pharmacokinetics at all doses, with lower clearance at higher doses. The three patients treated at the 1.6 mg/kg dose level developed grade 4 neutropenia during cycles 1 and 2. Five (33.3%) patients had stable disease (SD) including one patient with adenoid cystic carcinoma of the oropharynx with SD for 13 cycles and one patient with gastroesophageal junction adenocarcinoma with SD for eight cycles. OBI-999 was well tolerated; however, dose-dependent, noncumulative neutropenia was dose-limiting. CONCLUSION: The recommended phase II dose was determined to be 1.2 mg/kg once every 3 weeks. A phase II cohort-expansion study is now enrolling patients with pancreatic, colorectal, and other cancers expressing high levels of Globo H.
Assuntos
Adenocarcinoma , Antineoplásicos , Imunoconjugados , Neutropenia , Adulto , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Antineoplásicos/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológicoRESUMO
Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão/métodos , Oncologia , Drogas em Investigação/uso terapêutico , BiomarcadoresRESUMO
Advances in molecular technologies and targeted therapeutics have accelerated the implementation of precision oncology, resulting in improved clinical outcomes in selected patients. The use of next-generation sequencing and assessments of immune and other biomarkers helps optimize patient treatment selection. In this review, selected precision oncology trials including the IMPACT, SHIVA, IMPACT2, NCI-MPACT, TAPUR, DRUP, and NCI-MATCH studies are summarized, and their challenges and opportunities are discussed. Brief summaries of the new ComboMATCH, MyeloMATCH, and iMATCH studies, which follow the example of NCI-MATCH, are also included. Despite the progress made, precision oncology is inaccessible to many patients with cancer. Some patients' tumors may not respond to these treatments, owing to the complexity of carcinogenesis, the use of ineffective therapies, or unknown mechanisms of tumor resistance to treatment. The implementation of artificial intelligence, machine learning, and bioinformatic analyses of complex multi-omic data may improve the accuracy of tumor characterization, and if used strategically with caution, may accelerate the implementation of precision medicine. Clinical trials in precision oncology continue to evolve, improving outcomes and expediting the identification of curative strategies for patients with cancer. Despite the existing challenges, significant progress has been made in the past twenty years, demonstrating the benefit of precision oncology in many patients with advanced cancer.
RESUMO
IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose IL2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n = 6; Grade 2, n = 4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in posttreatment tumor tissue. Individual T-cell receptors (TCR) contained in T-cell products exhibited broad variation in TCR avidity, with the majority being low avidity. High-avidity TCRs were identified in some patients' products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs. See related Spotlight by Uslu and June, p. 865.
Assuntos
Imunoterapia Adotiva , Neoplasias , Adulto , Feminino , Humanos , Masculino , Linfócitos T CD8-Positivos , Estudos de Viabilidade , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Neoplasias/etiologia , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
Assuntos
Neoplasias , Medicina de Precisão , Inteligência Artificial , Ensaios Clínicos como Assunto , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão/métodos , ProteômicaRESUMO
BACKGROUND: Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. METHODS: (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. RESULTS: (1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10-8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. CONCLUSIONS: Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.
RESUMO
Background: BBI608 is an investigational reactive oxygen species generator that affects several molecular pathways. We investigated BBI608 combined with immune checkpoint inhibitors in patients with advanced cancers. Methods: BBI608 (orally twice daily) was combined with ipilimumab (3 mg/kg IV every 3 weeks); pembrolizumab (2 mg/kg IV every 3 weeks); or nivolumab (3 mg/kg IV every 4 weeks). We assessed the safety, antitumor activity and the pharmacokinetic profile of BBI combined with immunotherapy. Results: From 1/2017 to 3/2017, 12 patients were treated (median age, 54 years; range, 31-78; 6 men). Treatment was overall well tolerated. No dose-limiting toxicity was observed. The most common adverse events were diarrhea (5 patients: grade (G)1-2, n = 3; G3, n = 2) and nausea (4 patients, all G1). Prolonged disease stabilization was noted in five patients treated with BBI608/nivolumab lasting for 12.1, 10.1, 8.0, 7.7 and 7.4 months. The median progression-free survival was 2.73 months. The median overall survival was 7.56 months. Four patients had prolonged overall survival (53.0, 48.7, 51.9 and 48.2 months). Conclusions: Checkpoint inhibitors combined with BBI608 were well tolerated. Several patients had prolonged disease stabilization and overall survival. Prospective studies to elucidate the mechanisms of response and resistance to BBI608 are warranted.
RESUMO
We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient's/physician's choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.
RESUMO
BACKGROUND: Patients with advanced and/or metastatic solid tumors have limited treatment options. Mutations that serve as biomarkers of carcinogenesis can be found in cell-free DNA of patients' plasma. Analysis of circulating tumor DNA (ctDNA) was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is not technically feasible or it is associated with high risk for complications. The role of ctDNA in precision oncology is promising but its clinical significance across tumor types remains to be validated. We report a case series of three heavily pretreated patients with advanced solid tumors who received matched targeted therapy based on ctDNA analysis and/or tumor molecular profiling. CASE PRESENTATION: Three patients with advanced, metastatic cancer and the following characteristics are presented: a 71-year-old woman with ovarian cancer and BRCA2 mutation identified in ctDNA and tumor tissue was treated with a PARP inhibitor and achieved partial response by RECIST (Response Evaluation Criteria in Solid Tumors) for 22.6+ months; a 40-year-old woman with adenoid cystic carcinoma of the parotid gland was treated with a MEK/RAF pathway inhibitor on the basis of RAF1 amplification on ctDNA analysis and had stable disease for 20.2 months; and a 56-year-old woman with breast cancer and a BRCA1 mutation identified by ctDNA analysis was treated with a PARP inhibitor and achieved stable disease for 9.1 months. All three patients are alive at the time of this report. CONCLUSIONS: These results suggest that ctDNA analysis can contribute to selection of targeted therapy in patients with advanced, metastatic cancer. Prospective clinical trials to evaluate and optimize ctDNA biomarkers, as well as the integration of novel and/or alternative targeted therapies, are warranted to fully assess the role of ctDNA analysis in cancer therapy. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02152254). Registered May 28, 2014. https://www.clinicaltrials.gov/ct2/show/NCT02152254. MD Anderson protocol # PA12-1161 (approval ID IRB1 FWA00000121) and # PA11-0377 (approval ID IRB4 FWA00005015).
RESUMO
The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyperprogression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. US Food and Drug Administration-approved molecular biomarkers of immunotherapy response include mismatch repair deficiency and/or microsatelliteinstability and tumor mutational burden of at least 10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (eg, ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome, those potentially associated with resistance include ß2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers to optimize the implementation of precision immunotherapy in patient care.
Assuntos
Inibidores de Checkpoint Imunológico , Fator 2 Relacionado a NF-E2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Estudos Prospectivos , Imunoterapia , Genômica , Biomarcadores Tumorais/genética , DNA Helicases , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismoRESUMO
T-cell receptor (TCR)-based adoptive therapy employs genetically modified lymphocytes that are directed against specific tumor markers. This therapeutic modality requires a structured and integrated process that involves patient screening (e.g., for HLA-A*02:01 and specific tumor targets), leukapheresis, generation of transduced TCR product, lymphodepletion, and infusion of the TCR-based adoptive therapy. In this review, we summarize the current technology and early clinical development of TCR-based therapy in patients with solid tumors. The challenges of TCR-based therapy include those associated with TCR product manufacturing, patient selection, and preparation with lymphodepletion. Overcoming these challenges, and those posed by the immunosuppressive microenvironment, as well as developing next-generation strategies is essential to improving the efficacy and safety of TCR-based therapies. Optimization of technology to generate TCR product, treatment administration, and patient monitoring for adverse events is needed. The implementation of novel TCR strategies will require expansion of the TCR approach to patients with HLA haplotypes beyond HLA-A*02:01 and the discovery of novel tumor markers that are expressed in more patients and tumor types. Ongoing clinical trials will determine the ultimate role of TCR-based therapy in patients with solid tumors.
Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Animais , Humanos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Microambiente TumoralRESUMO
PURPOSE: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor. PATIENTS AND METHODS: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018). RESULTS: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC50 = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, n = 2; rectal adenocarcinoma, n = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively. CONCLUSIONS: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Neoplasias , Animais , Antineoplásicos/efeitos adversos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Camundongos , Neoplasias/tratamento farmacológicoRESUMO
Claims are made for the validity of some self-report pain scales for 3- and 4-year-old children, but little is known about their ability to use such tools. This systematic review identified self-report pain intensity measures used with 3- and/or 4- year-old participants (3-4yo) and considered their reliability and validity within this age span. The search protocol identified research articles that included 3-4yo, reported use of any pain scale, and included self-reported pain intensity ratings. A total of 1,590 articles were screened and 617 articles met inclusion criteria. Of the included studies, 98% aggregated self-report data for 3-4yo with data for older children, leading to overestimates of the reliability and validity of self-report in the younger age group. In the 14 studies that provided nonaggregated data for 3-4yo, there was no evidence for 3-year-old and weak evidence for 4-year-old children being able to use published self-report pain intensity tools in a valid or reliable way. Preschool-age children have been reported to do better with fewer than the 6 response options offered on published faces scales. Simplified tools are being developed for young children; however, more research is needed before these are adopted. PERSPECTIVE: Some self-report pain scales have been promoted for use with 3- and 4-year-old children, but this is on the basis of studies that aggregated data for younger and older children, resulting in overestimates of reliability and validity for the preschool-age children. Scales with fewer response options show promise, at least for 4-year-old children.