Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer.

CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.

Office-based flexible sigmoidoscopy allows rapid assessment and management of suspected immune checkpoint inhibitor-related colitis.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently complicated by immune-related adverse events, including immunotherapy-related colitis (irColitis). Early and accurate diagnosis, including endoscopy, is essential for appropriate management, yet the real-world feasibility and clinical impact of early endoscopic evaluation remain unclear.

Methods: We conducted a retrospective analysis of patients who underwent office-based, unsedated flexible sigmoidoscopy between February 2019 and April 2022 as part of the RAPID-GI program at Memorial Sloan Kettering Cancer Center.

Scalable topic modelling decodes spatial tissue architecture for large-scale multiplexed imaging analysis.

Recent progress in multiplexed tissue imaging is deepening our understanding of tumor microenvironments related to treatment response and disease progression. However, analyzing whole-slide images with millions of cells remains computationally challenging, and few methods provide a principled approach for integrative analysis across images. Here, we introduce SpatialTopic, a spatial topic model designed to decode high-level spatial tissue architecture from multiplexed images.

Long-Term Survival and Biomarker Analysis Evaluating Neoadjuvant Plus Adjuvant Relatlimab (anti-LAG3) and Nivolumab (anti-PD1) in Patients With Resectable Melanoma.

Immune checkpoint blockade (ICB) has revolutionized outcomes for patients with melanoma across multiple disease settings. In patients with advanced, unresectable disease, the ICB combination of nivolumab (anti-PD1) and relatlimab (anti-LAG-3) has demonstrated improved clinical outcomes compared with nivolumab monotherapy. There exists an unmet need to identify biomarkers that predict response to this combination regimen and rational therapeutic strategies to overcome resistance.

Programmed death ligand-1 PET imaging in patients with melanoma: a pilot study.

Programmed death ligand-1 (PD-L1) is an inducible protein heterogeneously expressed in melanoma. Assessment of PD-L1 expression is challenging and standard immunohistochemistry (IHC) requires biopsies and cannot capture heterogeneity of expression. Noninvasive imaging methods provide evaluation of expression across lesions in the body.

Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma.

Response to immune checkpoint inhibitors (ICIs) in metastatic melanoma (MM) varies among patients, and current baseline biomarkers predicting treatment outcomes are limited. As mitochondrial (MT) metabolism has emerged as an important regulator of host immune function, we explored the association of host MT genetics (MT haplogroups) with ICI efficacy in 1,225 ICI-treated patients with MM from the clinical trial CheckMate-067 and the International Germline Immuno-Oncology Melanoma Consortium. We discovered and validated significant associations of MT haplogroup T (HG-T) with resistance to anti-programmed cell death protein-1-based ICI (both single-agent and combination) and have shown that HG-T is independent from established tumor predictors.

Natural Language Processing of Radiology Reports to Assess Survival in Patients with Advanced Melanoma.

: To use natural language processing (NLP) to extract large-scale data from the CT radiology reports of patients with advanced melanoma treated with immunotherapy and to determine whether liver metastases affect survival. : Patient criteria (M1 disease subclassified into M1a, M1b, or M1c) as well as alternative criteria (M1 with advanced melanoma, imaged with CT chest, abdomen, and pelvis from July 2014-March 2019) were included retrospectively. NLP was used to identify metastases from CT reports, and then patients were classified according to American Joint Committee on Cancer (AJCC) staging disease subclassified into M1L+ or M1L-, indicating whether liver metastases were present or not).

Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors.

Importance: While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma.

Objective: To characterize SLRs among patients treated with ICI for advanced solid tumors.

Management and Outcomes of Clostridioides difficile Infection in Patients on Immune Checkpoint Inhibitors.

Background: Data on the severity, management, and outcomes of Clostridioides difficile infection (CDI) in patients presenting with diarrhea while receiving immune checkpoint inhibitors (ICIs) are limited. This study aimed to evaluate the course of CDI in this population and the overlapping diagnosis of immune-related enterocolitis (irEC).

Methods: This retrospective cohort included ICI-treated patients who presented with diarrhea and underwent CDI stool nucleic acid amplification PCR testing at Memorial Sloan Kettering Cancer Center between July 2015 and July 2021.

Top advances of the year: Neoadjuvant immunotherapy in melanoma.

Overall, much progress was made in 2024 in the realm of neoadjuvant immunotherapy including the firm establishment of neoadjuvant immunotherapy as superior to only adjuvant immunotherapy for patients with resectable stage III melanoma with the NADINA trial results. However, unanswered questions remain regarding the optimal neoadjuvant immunotherapy regimen, long-term outcomes after modifying adjuvant approaches based on pathologic response, and if additional measurements of anti-tumor efficacy, in addition to pathologic response, can further help tailor adjuvant therapy decisions.

Quantitatively defined stromal B cell aggregates are associated with response to checkpoint inhibitors in unresectable melanoma.

Multiplex immunofluorescence (mIF) is a promising tool for immunotherapy biomarker discovery in melanoma and other solid tumors. mIF captures detailed phenotypic information of immune cells in the tumor microenvironment, as well as spatial data that can reveal biologically relevant interactions among cell types. Given the complexity of mIF data, the development of automated analysis pipelines is crucial for advancing biomarker discovery.

Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling.

Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher costs limit its wide adoption.

Longitudinal Genomic Analysis to Fine-tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients with BRAFV600-Mutant Metastatic Melanoma.

Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma.

Patients And Methods: Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment-naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II).

IL13Rα2-Targeting Antibodies for Immuno-PET in Solid Malignancies.

Interleukin-13 receptor α-2 (IL13Rα2) is a cell surface receptor frequently expressed in solid malignancies, such as glioblastoma and melanoma, with limited expression in healthy tissue, rendering it an ideal target for noninvasive and specific tumor delineation. In this study, we report the development of 5 novel IL13Rα2-targeted human monoclonal antibodies (mAbs) KLG-1-5; in subsequent in vitro and in vivo studies after radiolabeling with Zr, we evaluate their performance to identify a lead candidate. Five novel human anti-IL13Rα2 mAbs KLG-1-5 were developed and in vitro binding properties and target specificity assessed.

Artificial Intelligence for Drug Discovery: An Update and Future Prospects.

Artificial intelligence (AI) has become a pivotal tool for medical image analysis, significantly enhancing drug discovery through improved diagnostics, staging, prognostication, and response assessment. At a high level, AI-driven image analysis enables the quantification and synthesis of previously qualitative imaging characteristics, facilitating the identification of novel disease-specific biomarkers, patient risk stratification, prognostication, and adverse event prediction. In addition, AI can assist in response assessment by capturing changes in imaging "phenotype" over time, allowing for optimized treatment plans based on real-time analysis.

Randomized clinical trial of a digital integrative medicine intervention among patients undergoing active cancer treatment.

Exercise and mindfulness-based interventions have growing evidence for managing fatigue and comorbid symptoms; however, packaging them in a cohesive digital way for patients undergoing cancer treatment has not been evaluated. We conducted a randomized controlled trial to assess the impact of a 12 week digital integrative medicine program, Integrative Medicine at Home (IM@Home), versus enhanced usual care on fatigue severity (primary outcome), comorbid symptoms and acute healthcare utilization (secondary outcomes), in 200 patients with solid tumors experiencing fatigue during treatment. Fatigue severity decreased more in IM@Home than in the control (1.

Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis.

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort.

Fertility outcomes post immune checkpoint inhibitor exposure.

Harrold et al. evaluate the fertility impact of checkpoint inhibitor blockade (ICB), demonstrating that unlike in utero exposure, post-exposure conception appears to result in uncomplicated pregnancies and healthy progeny. They demonstrate contemporaneous monitoring of temporal female hormonal fluctuations before, on, and post ICB exposure and prior to successful embryo implantation.

Intratumoral vidutolimod in combination with PD-1 blockade in locoregionally advanced melanoma.

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.

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.

Spatial Immunophenotyping from Whole-Slide Multiplexed Tissue Imaging Using Convolutional Neural Networks.

The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images.