scholarly journals Immunotherapy of brain metastases: breaking a “dogma”

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Anna Maria Di Giacomo ◽  
Monica Valente ◽  
Alfonso Cerase ◽  
Maria Fortunata Lofiego ◽  
Francesca Piazzini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Case Series ◽  
Daily Practice ◽  
Clinical Activity ◽  
Check Point ◽  
Wide Range ◽  
Check Point Inhibitors ◽  
Clinical Responses ◽  
The Central Nervous System

Abstract Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

scholarly journals Immune Check-Point Inhibitors and Standard Chemoradiotherapy in Definitive Head and Neck Cancer Treatment

2021 ◽  
Vol 11 (5) ◽  
pp. 393
Author(s):  
Francesca De Felice ◽  
Daniela Musio ◽  
Vincenzo Tombolini
Keyword(s):  
Clinical Trials ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Therapeutic Strategies ◽  
Check Point ◽  
Clinical Tool ◽  
Cancer Management ◽  
Check Point Inhibitors

In head and neck cancer management, there is a need for tailored approaches to optimally implement clinical outcomes. Based on the assumption that efficacy and long-term toxicity are not satisfactory for standard concurrent platinum-based chemoradiotherapy, several trials have been designed to test whether induction immunotherapy and/or concomitant immunotherapy and radiotherapy result in improved survival and toxicity outcomes. Here, we present an overview of the most recent concomitant therapeutic strategies for head and neck cancer, focusing on the knowledge available regarding check-point inhibitors. The aim is to present the characteristics of the main check-point inhibitors and to summarize the clinical trials on the combination of immune check-point inhibitors and (chemo)radiotherapy in the definitive HNC setting, in order to provide a useful clinical tool for further research.

scholarly journals Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1640 ◽  
Author(s):  
Paolo Becco ◽  
Susanna Gallo ◽  
Stefano Poletto ◽  
Mirko Pio Manlio Frascione ◽  
Luca Crotto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Target Therapy ◽  
Mapk Signaling ◽  
Janus Kinase ◽  
Clinical Activity ◽  
Tumor Resistance ◽  
Sequential Approach ◽  
Mek Inhibitors ◽  
Dismal Prognosis

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.

scholarly journals PO-1074 Radiotherapy and immuno-check point inhibitors for brain metastases. A mono-institutional analysis.

2019 ◽  
Vol 133 ◽  
pp. S597
Author(s):  
C. Di Carlo ◽  
F. Patani ◽  
D. Fasciolo ◽  
S. Di Biase ◽  
C. Rosa ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Institutional Analysis ◽  
Check Point ◽  
Check Point Inhibitors

Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 3880-3889 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Judith E. Karp
Keyword(s):  
Phase 1 ◽  
Hematologic Malignancies ◽  
Mitogen Activated Protein Kinase ◽  
Clinical Activity ◽  
Farnesyltransferase Inhibitors ◽  
New Horizons ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Clinical Responses ◽  
Low Toxicity

Abstract Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.

scholarly journals The Immunotherapy Landscape in Adrenocortical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2660
Author(s):  
Guillaume J. Pegna ◽  
Nitin Roper ◽  
Rosandra N. Kaplan ◽  
Emily Bergsland ◽  
Katja Kiseljak-Vassiliades ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Vaccine ◽  
Clinical Activity ◽  
Autologous Tumor ◽  
Early Stage Disease ◽  
Metastatic Setting ◽  
Wide Range

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.

scholarly journals Baseline and Postprocedural Health Status Outcomes in Contemporary Patients With Atrial Fibrillation Who Underwent Catheter Ablation: A Report from the Japanese Outpatient Registry

2021 ◽  
Vol 10 (18) ◽  
Author(s):  
Nobuhiro Ikemura ◽  
John A. Spertus ◽  
Takehiro Kimura ◽  
Yoshinori Katsumata ◽  
Taishi Fujisawa ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Atrial Fibrillation ◽  
Clinical Trials ◽  
Catheter Ablation ◽  
Randomized Clinical Trials ◽  
Daily Practice ◽  
Meaningful Improvement ◽  
Wide Range ◽  
Related Quality

Background Randomized clinical trials have demonstrated that catheter ablation (CA) for atrial fibrillation improves health‐related quality of life (HRQoL). In daily practice, however, CA is performed on a wide range of patients, and outcomes may vary. We aimed to examine baseline and 1‐year HRQoL outcomes of patients with atrial fibrillation after CA in daily practice. Methods and Results Using a registry‐based cohort study designed to recruit patients with atrial fibrillation newly referred to 11 hospitals, we extracted data from 1097 consecutive patients with atrial fibrillation who underwent CA between 2012 and 2019. The Atrial Fibrillation Effects on Quality of Life Overall Summary (AFEQT‐OS) was assessed at registration and 1 year after, and a 5‐point increase in AFEQT‐OS score was considered a meaningful improvement. Overall, the median age was 64 (interquartile range, 56–70) years, 836 (76.2%) were men, and 93.0% (n=1021) of the patients answered the AFEQT questionnaire. The mean AFEQT‐OS score was 74.9 (SD, 18.0) at registration and 88.8 (SD, 12.6) at 1 year after. Notably, the incidence of meaningful improvement in HRQoL after CA was 88.6% for the patients with impaired HRQoL (AFEQT‐OS score <80), which was only 40.1% in those with preserved HRQoL (AFEQT‐OS score ≥80). Female sex, left atrium diameter, and high baseline HRQoL were independently associated with nonimprovement after CA. Conclusions The improvement in HRQoL after CA was similar to that seen in clinical trials; however, one‐third of patients did not show improvement. These results underscore the importance of quantitative evaluation of patients’ HRQoL to maximize the effect of CA before its performance.

scholarly journals P3.01-79 Intracerebral Efficacy of Immune Check-Point Inhibitors in NSCLC Patients with Brain Metastases

2018 ◽  
Vol 13 (10) ◽  
pp. S897
Author(s):  
F. Ohyanagi ◽  
J. Shiihara ◽  
F. Kudo ◽  
Y. Mizushina ◽  
H. Ota ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Check Point ◽  
Check Point Inhibitors ◽  
Nsclc Patients

scholarly journals Recent Advances in Pancreatic Cancer: Novel Prognostic Biomarkers and Targeted Therapy—A Review of the Literature

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1469
Author(s):  
Konstantin Schlick ◽  
Dominik Kiem ◽  
Richard Greil
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Locally Advanced ◽  
Parp Inhibitors ◽  
Check Point ◽  
Review Of The Literature ◽  
The Past ◽  
Check Point Inhibitors ◽  
Novel Approaches

Pancreatic adenocarcinoma carries a devastating prognosis. For locally advanced and metastatic disease, several chemotherapeutic regimens are currently being used. Over the past years, novel approaches have included targeting EGFR, NTRK, PARP, K-Ras as well as stroma and fibrosis, leading to approval of NTRK and PARP inhibitors. Moreover, immune check point inhibitors and different combinational approaches involving immunotherapeutic agents are being investigated in many clinical trials. MiRNAs represent a novel tool and are thought to greatly improve management by allowing for earlier diagnosis and for more precise guidance of treatment.

scholarly journals The Efficacy of Teprotumumab for Chronic, Progressive Thyroid Eye Disease Greater Than 9 Months

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A844-A845
Author(s):  
Connie Martin Sears ◽  
Julia Y Kang ◽  
Kimberly Cockerham ◽  
Andrea L Kossler
Keyword(s):  
Clinical Trials ◽  
Smoking Status ◽  
Oral Prednisone ◽  
Visual Fields ◽  
Case Series ◽  
Thyroid Eye Disease ◽  
Muscle Size ◽  
Eye Disease ◽  
Clinical Activity ◽  
Ocular Involvement

Abstract Purpose: To evaluate the efficacy of teprotumumab for the treatment of patients with chronic, progressive Thyroid Eye Disease (TED) who do not meet the inclusion and exclusion criteria used in prior clinical trials. Methods: This is a prospective case series of patients with chronic, progressive TED, defined as ocular symptoms of more than 9 months prior to treatment initiation with teprotumumab, an insulin-like growth factor I receptor inhibitor (10 mg/kg for the first infusion then 20 mg/kg for subsequent infusions, every three weeks for a total 8 infusions). This study included patients with a Clinical Activity Score (CAS) greater than or equal to 4. Data collected included patients’ age, sex, race, baseline thyroid status, thyroid stimulating immunoglobulin, CAS, smoking status, best corrected visual acuity, intraocular pressure, Schirmer’s, pupil exam, extraocular motility, Gorman diplopia score, and exophthalmometer measurements. Pre-infusion and post-infusion external photos in all 9 gazes, orbital imaging (CT or MRI), Humphrey visual fields and optical coherence tomography were obtained when possible. Results: Ten patients with chronic TED were treated with teprotumumab either as a primary treatment or following other interventions including oral prednisone, intravenous methylprednisolone, orbital radiation, orbital decompression and/or eyelid surgery. The age range was 55 to 79, with 5 female patients and 5 male patients. Four of the patients were African American and 6 of the patients were White/Non-Hispanic. The number of years the patients had been diagnosed with Graves’ disease ranged from 4 to 33 years, with ocular involvement spanning 4 to 15 years. Patients had CT scans of the orbits to document muscle size prior to initiation, and external photos were taken at each visit. All patients improved subjectively after the first infusion and objectively by the fourth infusion. We will report the long-term follow-up after 8 infusions at ENDO2021. Discussion: Teprotumumab is a fully human monoclonal IgG1 antibody that blocks the IGF-1 receptor, disrupting the cell-to-cell signaling of the immunologic cascade and is independent of the duration or severity of TED. At this time, FDA approval for teprotumumab is for the treatment of TED without any specific restrictions. However, our teprotumumab-treated patients included those who would have been excluded in the phase 2 and 3 clinical trials due to: (1) poor thyroid control, (2) previous orbital surgery, (3) previous therapeutic interventions including steroids and radiation, (4) visual loss due to compressive optic neuropathy or exposure keratopathy and (5) chronic TED greater than 9 months. In our series, we found that teprotumumab was as effective in a wider population of chronic TED patients than included in the clinical trials.

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