Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors.

Background: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study.

Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer.

Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB.

Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy.

Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC.

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.

Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.

Outcomes With Postrecurrence Systemic Therapy Following Adjuvant Checkpoint Inhibitor Treatment for Resected Melanoma in CheckMate 238.

Purpose: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy.

Patients And Methods: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

Effects of Active Chronic Cigarette-Smoke Exposure on Circulating Fibrocytes.

Purpose: This study aimed to evaluate the hypothesis that active smoking impacts upon mediators and abundance of circulating fibrocyte cells in smoking-related disease characterised by fibrosis.

Methods: Flow cytometry and enzyme-linked immunosorbent assays were used to investigate blood from five patient groups: healthy never-smokers, healthy current smokers, stable chronic obstructive pulmonary disease (COPD) active smokers, idiopathic pulmonary fibrosis (IPF) never-smokers, and IPF active smokers.

Results: A significant inverse dose-response relationship was observed in healthy smokers among cumulative smoking burden (pack-years) and fibrocyte abundance (p = 0.

Identifying MAGE-A4-positive tumors for TCR T cell therapies in HLA-A∗02-eligible patients.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients.

Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma.

Background: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.

Patients And Methods: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+.

Nodal Metastases in Stage 3 Head and Neck Melanoma: Patterns of Metastases and Patterns of Failure.

Objective: Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre-operative CT as a nodal drainage assessment tool.

Methods: Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care.

Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.

Adoptive cell therapy with autologous, ex vivo-expanded, tumor-infiltrating lymphocytes (TILs) is being investigated for treatment of solid tumors and has shown robust responses in clinical trials. Based on the encouraging efficacy, tolerable safety profile, and advancements in a central manufacturing process, lifileucel is now the first US Food and Drug Administration (FDA)-approved TIL cell therapy product. To this end, treatment management and delivery practice guidance is needed to ensure successful integration of this modality into clinical care.

The Role of Adjuvant Radiotherapy for the Treatment of Resected High-Risk Stage III Cutaneous Melanoma in the Era of Modern Systemic Therapies.

Modern adjuvant systemic therapies (STs) have revolutionized the management of stage III melanoma. Currently, the role of adjuvant radiotherapy (RT) remains unclear. In this single-center retrospective study, patients with clinically detectable stage III melanoma with high-risk features for lymph node basin (LNB) recurrence and whose tumors were fully resected with complete lymphadenectomy (CLD) between 2010 and 2019 were assessed.

Management of comorbidities in difficult and severe asthma.

Difficult-to-treat and severe asthma are challenging clinical entities. In the face of suboptimal asthma control, the temptation for clinicians is to reflexively escalate asthma-directed therapy, including increasing exposure to corticosteroids and commencement of costly but potent biologic therapies. However, asthma control is objectively and subjectively assessed based on measurable parameters (such as exacerbations or variability in pulmonary physiology), symptoms and patient histories.

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

Background: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.

Methods: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT).

Background: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb).

Methods: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI.

Immune Checkpoint Inhibitors in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience from a Canadian Comprehensive Cancer Centre.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022.

Dupilumab as a treatment for cutaneous immune-related adverse events induced by immune checkpoint inhibitors: A case series and review of the literature.

Immune checkpoint inhibitors have revolutionized cancer treatment. They can induce cutaneous immune-related adverse events. One patient with immune-related eczema and two with immune-related bullous pemphigoid were successfully treated with dupilumab.

Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CT ) in idiopathic pulmonary fibrosis.

Background And Objective: There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers.

Study Design And Methods: IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach.

Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.

Purpose: Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma.

Toxicity and outcomes of melanoma brain metastases treated with stereotactic radiosurgery: the risk of subsequent symptomatic intralesional hemorrhage exceeds that of radiation necrosis.

Purpose: We aimed to assess the outcomes and patterns of toxicity in patients with melanoma brain metastases (MBM) treated with stereotactic radiosurgery (SRS) with or without immunotherapy (IO).

Methods: From a prospective registry, we reviewed MBM patients treated with single fraction Gamma Knife SRS between 2008 and 2021 at our center. We recorded all systemic therapies (chemotherapy, targeted therapy, or immunotherapy) administered before, during, or after SRS.

Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy.

Cutaneous melanoma (CM) patients respond better to immune checkpoint inhibitors (ICI) than mucosal and uveal melanoma patients (MM/UM). Aiming to explore these differences and understand the distinct response to ICI, we evaluated the serum metabolome of advanced CM, MM, and UM patients. Levels of 115 metabolites were analyzed in samples collected before ICI, using a targeted metabolomics platform.