Etirinotecan Pegol (NKTR-102) in Patients With Active Brain Metastases From Lung or Breast Cancer.

Background: Brain metastases are common in patients with lung and breast cancer and are associated with poor outcomes. While there is some intracranial activity with systemic therapies, most chemotherapies are minimally effective. Etirinotecan pegol (EP) is a PEGylated chemotherapy with favorable pharmacokinetics over irinotecan.

Severe infections in pediatric MS and related disorders patients on B-cell depleting therapies compared to sphingosine-1-receptor modulators.

Background: There is limited data on infection risk in pediatric onset multiple sclerosis and related disorders (MSARD).

Objectives: Analyze rate of severe infections in pediatric MSARD patients on B-cell depleting therapies (BCT) compared to fingolimod.

Methods: This was a retrospective chart review of pediatric MSARD patients from the Harvard Multiple Sclerosis Patient Database and the MGH Pediatric Multiple Sclerosis Center database treated with BCT or fingolimod.

The price of delay: Insurance-related treatment delays in patients with gynecologic cancer receiving immunotherapy.

Objective: To assess factors impacting insurance-related treatment delay in patients with gynecologic cancer receiving immunotherapy (IO).

Methods: A retrospective single-institution cohort study was performed in patients with gynecologic cancers receiving IO between 2017 and 2023. Treatment delays were defined as ≥14 days to treatment and severe delays were defined as ≥28 days to treatment.

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF metastatic colorectal cancer.

The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAF metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAF colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAF mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29-71) and median progression-free survival of 7.4 months (95% CI, 5.

A First-in-Human Study of ATM Inhibitor Lartesertib as Monotherapy in Patients with Advanced Solid Tumors.

Purpose: This first-in-human Phase 1, open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of the highly potent and selective oral ataxia‑telangiectasia mutated (ATM) kinase inhibitor lartesertib.

Patients And Methods: Patients with advanced solid tumors received oral doses of lartesertib for a dose range of 100-400 mg once daily (QD). Dose-escalation was based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model.

T cell receptor repertoire in cell-free DNA as a proxy for tumor infiltrates in patients treated with pembrolizumab.

Profiling tumor and systemic T cell receptor (TCR) repertoires can identify features associated with the clinical benefit of patients with cancer on immune checkpoint blockade therapy. This study reports on the diversity and specificity analysis of TCR sequences from 58 tumor, 306 peripheral blood mononuclear cell (PBMC), and 73 cell-free DNA (cfDNA) samples from 81 patients with solid tumors treated with pembrolizumab. This analysis reveals that head and neck carcinomas have significantly lower PBMC diversity and shorter persistence of pembrolizumab-induced diversification compared to other cancers.

How can we increase the value of clinical trials with immunotherapy?

In the 40 years since the initial studies with interleukin-2 led to the Society for Immunotherapy of Cancer's creation, immunotherapy has become a crucial pillar of cancer therapy that is extending and improving countless lives worldwide. Checkpoint inhibitor immunotherapy has become a standard of care treatment for over 20 distinct types of cancer, and other immunotherapy approaches such as novel engineered cytokines, T-cell engagers, oncolytic viruses, personalized cancer vaccines and various cellular therapies are in active development and have already or may eventually receive regulatory approval. This commentary examines what we have learned during this remarkable four-decade drug development journey and how we can best leverage that knowledge to efficiently develop, license and apply future immunotherapy approaches.

Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in NOTCH1 or NOTCH2, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from NOTCH1/2-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in NOTCH2-inactivated SCLCs.

Exploring TROP2 expression in oropharyngeal squamous cell carcinoma: Association with prognosis and tumor immune microenvironment composition.

Oropharyngeal squamous cell carcinoma (OPSCC) presents prognostic and therapeutic challenges. Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein involved in oncogenic signaling pathways and has been explored as a therapeutic target in many solid tumors. This study aims to evaluate the prevalence and prognostic significance of TROP2 expression in OPSCC and explore its association with the tumor immune microenvironment composition.

Ivosidenib for IDH1-Mutant Intrahepatic Cholangiocarcinoma: Insights From a Multicenter Real-World Study.

Background & Aims: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options and a poor prognosis. While first-line combination therapies have improved outcomes, second-line treatment remains challenging. Ivosidenib, an IDH1 inhibitor, has shown promise in treating IDH1 mutant CCA, but real-world data is limited.

Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Background: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.

B-cell antigen presentation in central nervous system autoimmunity.

The role of B cells in central nervous system (CNS) autoimmunity was initially highlighted by successful clinical trials of anti-CD20 monoclonal antibodies in multiple sclerosis (MS). Research in MS as well as in aquaporin 4 (AQP4)-IgG neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) has expanded our appreciation of the contribution of B cells in multiple CNS autoimmune diseases. B cells have multiple functions in the initiation and propagation of CNS autoimmunity that extend beyond autoantibody production, including bidirectional interactions with T cells via B-cell antigen presentation.

Adverse event profiles and management of cisplatin-based chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a systematic review.

Background: Patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) are treated with curative intent. Treatment guidelines recommend tumor resection, followed by adjuvant radiotherapy or chemoradiotherapy in patients with high risk of disease recurrence, or definitive chemoradiotherapy in patients who do not undergo surgery. When indicated, concurrent cisplatin provides benefit over radiotherapy alone but is highly toxic.

Stratifying risk in oligoprogressive EGFR-mutated non-small cell lung cancer (NSCLC): The role of liquid biopsy.

Background: EGFR-TKIs have markedly enhanced outcomes for non-small cell lung cancer (NSCLC) patients, but resistance development is virtually inevitable. In the context of oligoprogressive disease (OPD), local treatments can target resistant clones while EGFR-TKIs maintain systemic control, potentially extending the duration of therapy. However, identifying patients who benefit from this combined approach remains unclear.

Multiparametric cellular and spatial organization in cancer tissue lesions with a streamlined pipeline.

Multiplex immunostaining analysis remains fragmented, underperforming and labour intensive despite tissue proteomic methodologies achieving ever-increasing marker complexity. Here we propose an open-source, user-guided automated pipeline that streamlines start-to-finish, single-cell resolution analysis of whole-slide tissue, named multiplex-imaging analysis, registration, quantification and overlaying (MARQO). MARQO integrates elastic image registration, iterative nuclear segmentation, unsupervised clustering with mini-batch k-means and user-guided cell classification through a graphical interface.

Choroid Plexus Enlargement in Multiple Sclerosis Correlates with Cortical and Phase Rim lesions on 7-T MRI and Predicts Progression Independent of Relapse Activity.

Background And Purpose: In multiple sclerosis (MS), the choroid plexus is thought to promote and sustain the disease immunopathological inflammatory process. However, its association with cortical pathology and disease progression is still uncertain. We aim to characterize choroid plexus enlargement and evolution in MS, its relationship with imaging markers of compartmentalized inflammation and clinical outcome.

Paramagnetic rim lesions are associated with choroid plexus inflammation and expansion over 5 years in people with multiple sclerosis.

Background: Chronic active white matter inflammation is linked with multiple sclerosis (MS) clinical severity and is likely integral in MS progression. It has also been associated with choroid plexus (CP) inflammation in vivo, pointing to a potential pathophysiological link between the two phenomena. However, how these aspects of the disease co-evolve over time remains poorly understood nor has their relationship been specifically assessed in people with progressive MS (pwPMS).

Identification of cellular factors associated with inflammation and neurodegeneration in multiple sclerosis.

Background: Serum biomarkers as neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) enabled early identification of multiple sclerosis (MS) patients at risk of relapse-associated worsening (RAW) or progression independent of relapses (PIRA). However, the immunological mechanisms underlying these clinical phenotypes remain unclear.

Methods: We conducted a cross-sectional study including 117 MS patients and 84 healthy controls (HC).

Treatment recommendations for the systemic pharmacological treatment of systemic sclerosis digital ulcers: Results from the World Scleroderma Foundation Ad Hoc Committee.

Introduction: Digital ulcers are an important disease manifestation of systemic sclerosis and are associated with significant morbidity. As such, there is an urgent need for the development of evidence-based recommendations to guide clinicians in the treatment of digital ulcers.

Methods: A steering committee of international experts was established.

Evaluating the role of anti-EBV antibodies as biomarkers for the evolution of multiple sclerosis: A longitudinal study.

Background: Epstein-Barr virus seropositivity has been strongly associated with the onset of multiple sclerosis (MS); however, the utility of measuring EBV-antibodies as biomarkers for MS progression remains uncertain.

Objectives: To determine if baseline anti-EBV antibody titer levels are associated with mid-term evolution of MS.

Methods: A total of 237 participants (187 MS patients and 50 healthy controls, HC) were tested for anti-EBNA1 and anti-VCA IgG levels, whose relative concentrations were categorized into lower and highest quartiles.

Real-world Efficacy of Sodium Hypochlorite Body Wash in Managing Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin condition characterized by nodules, abscesses, and tunnels that may develop in various parts of the body, particularly in the axillary, gluteal, and inguinal regions. Treatment for HS varies based on clinical presentation and disease progression and encompasses antibiotics, hormonal therapy, biologics, topical treatments, and surgical procedures. Despite the array of available treatment options, patients typically require multiple treatment modalities to alleviate symptoms, which can include antimicrobial cleansers and washes, though there is limited evidence regarding their effectiveness in managing HS.

A phase 1B trial of vocimagene amiretrorepvec in patients with advanced solid tumors: Safety, tumor homing, and immune modulatory effects.

Vocimagene amiretrorepvec (Toca 511) is a replicating retroviral vector (RRV) encoding cytosine deaminase that converts 5-fluorocytosine (5-FC) into 5-fluorouracil in the tumor microenvironment. This study investigated the safety and immunomodulatory effects of systemically administered Toca 511 and Toca FC in advanced cancer patients. Eligible subjects received three daily intravenous (i.