Kidney Renal Clear Cell Carcinoma (KIRC) is a prevalent urinary malignancies worldwide. Glycosylation is a key post-translational modification that is essential in cancer progression. However, its relationship with prognosis, tumour microenvironment (TME), and treatment response in KIRC remains unclear.

Expression profiles and clinical data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering, Cox regression, and LASSO regression analyses were conducted to develop an optimal glycogene-related signature. The prognostic relevance of this molecular signature was rigorously analyzed, along with its connections to tumour microenvironment (TME), tumour mutation burden, immune checkpoint activity, cancer-immunity cycle regulation, immunomodulatory gene expression patterns, and therapeutic response profiles. Validation was performed using real-world clinical specimens, quantitative PCR (qPCR), and immunohistochemistry (IHC), supported by cohort analyses from the Human Protein Atlas (HPA) database.

A glycogene-associated prognostic scoring system was established to categorize patients into risk-stratified subgroups. Patients in the high-risk cohort exhibited significantly poorer survival outcomes (p < 0.001). By incorporating clinicopathological variables into this framework, we established a predictive nomogram demonstrating strong calibration and a concordance index (C-index) of 0.78. The high-risk subgroup displayed elevated immune infiltration scores (p < 0.001), upregulated expression of immune checkpoint-related genes (p < 0.05), and an increased frequency of somatic mutations (p = 0.043). The risk score positively correlated with cancer-immunity cycle activation and immunotherapy-related signals. The high-risk groups also showed associations with T cell exhaustion, immune-activating genes, chemokines, and receptors. Drug sensitivity analysis revealed that low-risk patients were more sensitive to sorafenib, pazopanib, and erlotinib, whereas high-risk individuals responded better to temsirolimus (p < 0.01). qPCR and IHC analyses consistently revealed distinct expression patterns of MX2 and other key genes across the risk groups, further corroborated by the HPA findings.

This glycogene-based signature provides a robust tool for predicting prognosis, TME characteristics, and therapeutic responses in KIRC, offering potential clinical utility in patient management.

Over the last decade, the increasing global prevalence of melanoma has sparked growing interest in immunotherapies, which show significant potential against this form of skin cancer. This research aims to offer a framework to guide future studies and inspire new research directions. In this study, we used the Web of Science Core Collection to collect papers on immunotherapy and melanoma published between 2014 and 2024. With Excel and visualization tools like VOSviewer, COOC 13.2, Citespace, and Bibliometrix (R-Tool of R-Studio), we analyzed the data to spot trends and new focuses in the research. Our findings indicate a substantial surge in research activity concerning immunotherapy and melanoma between 2014 and 2024. The USA and China emerged as leading contributors, engaging in extensive and close collaborative efforts with European counterparts. Furthermore, seven of the top 10 research institutions are located in the USA, with the MD Anderson Cancer Center in Texas being the most productive. In addition, the Journal of Cancer Immunotherapy is the journal with the most articles published in the field. Professor Georgina V. Long from the Melanoma Institute at the University of Sydney was one of the most productive scholars. Keyword analysis shows that immune checkpoint inhibitors, tumor microenvironment and targeted therapies are key areas of interest for the research community. This paper uses bibliometric analysis to outline research trends and key points in immunotherapy and melanoma from 2014 to 2024, which helps understand the current research and guides future research directions.

Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage (p < 0.001) and previous exposure to immune checkpoint inhibitors (p = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival (p = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival (p = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.

In-transit (IT) melanoma represents a distinct, heterogeneous pattern of disease that arises as superficial tumors along the track between the primary site and the draining regional lymph node basin. Many therapies have been explored for treatment of this disease with the goal of maximizing delivery of the therapeutic agent to the tumor while minimizing systemic toxicities. These include regional chemotherapies, intralesional injections, checkpoint inhibitors, immunomodulators, and vaccines in various combinations or as monotherapy. Here, we review the general managemnt of patients with ITmelanoma, the range of currently available treatment options, and recommendations for specific therapies for individual patients.

Tumor-infiltrating lymphocytes (TILs) often have upregulated expression of immune checkpoint receptors, such as programmed cell death 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3). Patients treated with antibodies targeting PD-1 or its ligand (PD-L1) can develop resistance or relapse, with LAG-3 upregulation on T cells being one possible mechanism. FS118 is a tetravalent, bispecific antibody comprising a full-length IgG 1 anti-PD-L1 antibody with bivalent LAG-3-binding capability in the fragment crystallizable region. Here we demonstrate how the structure of FS118 is important for its function. We generated variants of FS118 and tested their ability to mediate LAG-3 shedding using staphylococcal enterotoxin B assays, antigen recall assays, and soluble LAG-3 ELISAs. Mediated by metalloproteases ADAM10 and ADAM17, FS118 induced shedding of LAG-3 from the surface of both CD4 + and CD8 + T cells. We also determined the effect of surrogate antibodies on immune cell LAG-3 expression and proliferation in syngeneic mouse models. In vivo , the bivalent LAG-3 binding sites of a mouse surrogate of FS118 and their location in the fragment crystallizable region were important for eliciting maximal reduction in LAG-3 levels on the surface of TILs, as variants with a single LAG-3 binding site in the fragment crystallizable region, or with reversed orientation of the LAG-3 and PD-L1 binding sites, were less efficient at inducing shedding. We also show that PD-L1, not PD-1, binding drives the LAG-3 reduction on TILs. We hypothesize that the LAG-3 bivalency in the fragment crystallizable region of FS118 allows LAG-3 clustering, which optimizes cleavage by ADAM10/ADAM17 and thus shedding.

Immune checkpoint inhibitors and targeted therapies (BRAF/MEK inhibitors) have transformed the care of patients with stage IV melanoma, now with 5-year overall survival rates around 50%. Surgeons should be acquainted with these drugs, the multidisciplinary considerations of their use, and the unique immune-related adverse events (irAEs) they can cause. In this review, we discuss systemic therapies for cutaneous melanoma, including the biology of immune checkpoint inhibition, treatment indications, and toxicities. We also explain how these irAEs and other toxicities can impact surgical planning and perioperative management.

Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.

Lymphocyte activation gene-3 (LAG-3) has emerged as a critical immune checkpoint receptor primarily modulating T-cell responses through distinct immune regulatory mechanisms. Recent advances have elucidated LAG-3's complex receptor-ligand interactions, structure-function relationships, and unique signaling pathways. LAG-3 antagonistic antibodies, such as relatlimab approved for melanoma, have shown promising efficacy with favorable toxicity profiles, though only in combinational therapies. While LAG-3's role in oncology continues to expand, it is also gaining recognition as a potential therapeutic target for other disorders. This review highlights recent progress in understanding LAG-3's molecular features, ligand regulation, signaling, and immune modulation mechanisms. Additionally, it explores emerging questions in oncology and the exciting potential of therapies targeting the LAG-3 pathway in autoimmune disease. A deeper understanding of LAG-3's confounding biology and disease relevance would drive the development of novel immunotherapies across broader clinical indications.

Understanding the dynamics of the tumor-immune ecosystem is crucial for advancing neoadjuvant strategies in cancer treatment. This study investigated alterations in the tumor-immune microenvironment related to the response to preoperative combination therapy with paclitaxel, carboplatin, and cetuximab in patients with advanced head and neck squamous cell carcinoma. Thirty patients underwent combination therapy. Biopsy or surgical specimens were obtained before and after treatment. Single-cell-based, 14-marker multiplex immunohistochemistry and image cytometry were employed to assess changes in immune cell densities and profiles. Three distinct immune profiles were identified: hypo-, lymphoid-, and myeloid-inflamed. Significant decreases in tumor volume and increases in CD45+ cells and programmed cell death ligand 1 (PD-L1) scores were observed in the hypo- and lymphoid-inflamed groups, whereas the myeloid-inflamed group showed minimal changes. After treatment, increased calreticulin expression in tumor cells, together with increased lymphoid cell lineages, was observed in non-recurrent cases. The myeloid-inflamed group exhibited higher expression of hypoxia inducible factor 1α and zinc finger E-box-binding homeobox 2, suggesting the presence of a hypoxic and metastasis-promoting environment. Spatial analysis revealed that responders had a high infiltration of T cells within tumor cell nests, whereas non-responders had fewer T cells, with β-catenin expression in cancer cells. Upregulated lymphocyte activation gene 3 in the myeloid-inflammation group, and PD-L1 dynamics suggest potential targets for further therapy. These findings highlight the need for targeted neoadjuvant strategies based on immune profiling.

Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions.

Melanoma treatment comprised a few treatment choices with insufficient efficacy before the emergence of molecularly targeted medication and immune checkpoint inhibitors, which dramatically improved patient outcomes. B-Rapidly Accelerated Fibrosarcoma (BRAF) and Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitors significantly improved survival in BRAF-mutant melanoma and immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agents, established new standards of care. Challenges remain, however, including the existence of resistance mechanisms and the reduced efficacy of immune-based therapies in Asian populations, particularly for acral and mucosal subtypes. This review highlights historical and current therapeutic advancements, discusses regional considerations, and explores emerging strategies aiming at globally optimizing melanoma management.

In phase 2/3 randomized RELATIVITY-047, nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), a clinically meaningful but not statistically significant improvement in overall survival (OS), and a numerically higher objective response rate (ORR) versus nivolumab alone in patients with previously untreated advanced melanoma.

Descriptive 4-year updated analyses in patients treated with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination versus nivolumab 480 mg intravenously every 4 weeks are presented. Primary endpoint was PFS by blinded independent central review (BICR). Other endpoints included melanoma-specific survival (MSS).

At 45.3 months' minimum follow-up, nivolumab plus relatlimab versus nivolumab PFS improvement was maintained: 4-year PFS rates were 30.6 % (95 % CI, 25.4-35.9) versus 23.6 % (95 % CI, 18.9-28.5); OS was numerically better with 4-year OS rates of 52.0 % (95 % CI, 46.6-57.1) versus 42.8 % (95 % CI, 37.5-47.9); and ORR difference was maintained at 43.9 % (95 % CI, 38.7-49.3) versus 33.4 % (95 % CI, 28.6-38.6), respectively. 4-year MSS rates were 59.7 % (95 % CI, 54.1-64.8) for nivolumab plus relatlimab and 49.6 % (95 % CI, 44.0-54.9) for nivolumab. Efficacy across the majority of prespecified subgroups favored the combination. No new or unexpected safety signals were identified.

With 4 years of follow-up, nivolumab plus relatlimab demonstrated durable improvement in outcomes versus nivolumab monotherapy for patients with previously untreated advanced melanoma. The durable benefit observed comes at a lower toxicity cost compared with other immuno-oncology combinations.

ClinicalTrials.gov Identifier: NCT03470922.

Combination immune checkpoint inhibitor therapy (ICI) with ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) + nivolumab (anti-PD-1) in untreated, metastatic melanoma has achieved a ten-year melanoma-specific survival of 52%. However, approximately 40%-55% of patients with metastatic melanoma have primary resistance and do not initially respond to anti-PD-1, and an additional 25% of patients develop secondary resistance, exhibiting an initial response followed by disease progression. In PD-1-refractory melanoma, treatment options are limited. Addition of ipilimumab, relatlimab (anti-LAG3), or lenvatinib (VEGFR TKI) has minimal to modest efficacy. Switching to targeted BRAF/MEK inhibition improves survival for BRAF-mutant disease. MEK and KIT inhibitors have limited activity in NRAS- and KIT-mutant metastatic melanoma, respectively. Recently, personalized, autologous tumor-infiltrating lymphocyte therapy has become a US Food and Drug Administration-approved second-line option; lifileucel demonstrates durable response (approximately 30%) in heavily pretreated, metastatic melanoma. Emerging therapeutics that show promising clinical benefit in ongoing clinical trials include novel engineered oncolytic viral and human leukocyte antigen (HLA)-restricted immune-mediated T-cell therapies. As a therapy which is limited to patients who are HLA-A*02:01, T-cell receptor (TCR) engineered T cells (TCR-T) iterates on personalized adoptive cell transfer, and immune mobilizing monoclonal TCRs against cancer are CD3 bispecifics that bind glycoprotein 100 (tebentafusp, approved for metastatic uveal melanoma) or PRAME to activate T cells. Finally, in patients at high risk for immune-related adverse events (irAEs), ICI should still be considered. ICI may be given with modified immunosuppression in patients with autoimmune disease or previous organ transplantation. Cumulative data support safe administration in older patients and in ICI rechallenge for patients with previous irAE.

Current first-line treatment for patients with metastatic melanoma with BRAFV600E or BRAFV600K mutations includes immunotherapy with immune checkpoint inhibitors and targeted therapy; however, the optimal sequencing of these treatments is unclear. We aimed to investigate the use of a targeted-therapy induction regimen before treatment with immune checkpoint inhibitors.

This open-label, randomised, controlled, phase 2 trial (EBIN) was conducted at 37 centres in eight European countries. Eligible patients were 18 years or older and had previously untreated, unresectable, stage III or IV melanoma with BRAFV600E or BRAFV600K mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to one of two groups. Those in the induction group received targeted therapy (oral encorafenib 450 mg once a day plus oral binimetinib 45 mg twice a day for 12 weeks) followed by immune checkpoint inhibitors (intravenous nivolumab 3 mg/kg plus intravenous ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by intravenous nivolumab 480 mg once every 4 weeks until unacceptable toxicity, disease progression, or 2 years of treatment). Patients in the control group received immune checkpoint inhibitors as above without any induction targeted therapy. Randomisation was conducted using a minimisation technique and was stratified by centre and a variable defined using stage and lactate dehydrogenase activity. The primary outcome was progression-free survival in the intention-to-treat population. Safety was assessed in all patients who initiated the protocol treatment. In this Article we report the primary analysis. The study is registered with ClinicalTrials.gov, NCT03235245, and is ongoing.

Between Nov 12, 2018, and July 11, 2022, 271 patients were randomly assigned: 136 to the induction group and 135 to the control group. 103 (38%) patients were female, 168 (62%) were male, and the median age was 55 years (IQR 43-66). The median follow-up time was 21 months (IQR 13-33). There was no evidence of a longer progression-free survival in the induction group than in the control group (hazard ratio 0·87, 90% CI 0·67-1·12; p=0·36). The median progression-free survival was 9 months (95% CI 7-13) in the induction group and 9 months (5-14) in the control group. Grade 3-5 treatment-related adverse events occurred in 57 (42%) of 136 patients who started treatment in the induction group and in 42 (32%) of 131 patients who started treatment in the control group. The most common grade 3-4 treatment-related adverse event was hepatitis (17 [13%] of 136 patients in the induction group and nine [7%] of 131 patients in the control group). Serious treatment-related adverse events occurred in 45 (33%) of 136 patients in the induction group and 33 (25%) of 131 patients in the control group. There were three treatment-related deaths: two from cardiac events (heart failure and arrhythmia) in the induction group and one from meningitis in the control group.

The targeted-therapy induction regimen did not improve progression-free survival compared with first-line treatment with immune checkpoint inhibitors in unselected patients with advanced melanoma with BRAFV600E or BRAFV600K mutations.

Bristol Myers Squibb and Pierre Fabre.

EMB-02 is a symmetric bispecific antibody targeting programmed cell death protein-1 and lymphocyte-activation gene 3 simultaneously. Here, we present the first-in-human study results of EMB-02 in patients with advanced solid tumors.

Patients were treated with intravenous infusions of EMB-02 at doses of 6-900 mg. The primary objective was to evaluate the safety and tolerability and to determine the maximum tolerated dose and/or recommended phase II dose(s). Secondary objectives included characterizing the pharmacokinetic (PK) profile, assessing preliminary antitumor activity and the immunogenicity.

A total of 47 patients were enrolled. All grade and grade 3/4 treatment-emergent and treatment related adverse events occurred in 97.9%, 48.9%, 68.1% and 12.8% patients, respectively. The objective response rate (ORR) was 6.4% and clinical benefit rate at 24 weeks (CBR-24) was 25.5% in overall population. The CBR-24 was 33.3% in checkpoint inhibitor (CPI)-naïve patients, and 15% in CPI-treated. No clear relationship was observed between the efficacy and PD-L1, LAG-3, or MHC II expression level. Doses 360 mg or higher resulted in sustained saturation of PD-1 receptors on circulating CD3 + T cells.

EMB-02 demonstrated a favorable safety profile and early efficacy signals in multiple solid tumors, warranting further development. (NCT04618393).

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the importance of implementing ATB stewardship recommendations in routine oncology practice. Microbiota-centered interventions are now being explored to treat gut dysbiosis and optimize ICI responses. Early-phase clinical trials evaluating fecal microbiota transplantation (FMT) from ICI responders or healthy donors have shown that this approach is safe and provided preliminary data on potential efficacy to overcome both primary and secondary resistance to ICI in melanoma, non-small cell lung cancer, and renal cell carcinoma. More targeted interventions including live bacterial products including Clostridium butyricum and Akkermansia massiliensis represent novel microbiome-based adjunct therapies. Likewise, dietary interventions, such as high-fiber diets, have shown promise in enhancing ICI activity. In this ASCO Educational Book, we summarize the current state-of-the-evidence of the clinical relevance of the intestinal microbiota in cancer immunotherapy and provide a practical guide for ATB stewardship.

Responses to immune checkpoint inhibitors (ICIs) differ significantly between uveal melanoma (UM) and cutaneous melanoma (CM) patients. We investigated the immune profile of metastatic UM(mUM) patients and identified markers that are predictive of improved survival. Metastatic liver samples from 189 UM patients and 48 CM patients were analyzed at genomic and transcriptional levels, and survival analysis was performed on a subgroup of 76 ICI-treated mUM patients. UM liver metastases seem to preserve the genomic and immune characteristics of primary UM (pUM), with a low prevalence of ICI markers and high mutation rates of GNA11, GNAQ, BAP1, and SF3B. Compared with mCM, UM liver metastasis showed lower infiltration of several immune cells, but a greater proportion of M2 macrophages. Compared with UM liver metastases, CM liver metastases showed higher expression of G2M checkpoint and EF2 target genes. Among the mUM and mCM samples, expression of G2M and E2F pathway genes was highest in tumors with high TMB values and T-cell inflamed scores. A longer median overall survival (OS) was observed in mUM patients with higher expression of LAG3, HLA class I, or HLA class II; which may represent a small proportion of immune hot tumors. Expression patterns of G2M checkpoint and E2F targets suggest a possible contribution to immunotherapy response.

This study aimed to evaluate the predictive value of MHC class II (MHC-II) expression by melanoma cells in a large cohort of metastatic cutaneous melanoma patients treated with immune checkpoint inhibitors (ICIs). We conducted a single-center, retrospective study involving stage IV cutaneous melanoma patients who received ICI as first-line therapy. MHC-II expression in melanoma cells was quantified using dual-color anti-SOX10 and anti-MHC-II immunohistochemistry on tumor samples from 95 patients. The primary endpoint was event-free survival (EFS), with secondary endpoints including 1-year EFS, 1-year overall survival (OS), disease control rate (DCR), and the correlation between MHC-II expression and clinico-biological characteristics. The cohort had a median age of 67 years (range, 33-90), with a male-to-female ratio of 50 : 45. Thirty-three percent of patients received the ipilimumab-nivolumab combination. The median follow-up was 16.8 months. Disease progression occurred in 58 patients (61%), with a median time to progression of 4.8 months. Forty-six patients (48.4%) experienced an event within the first year, and 52 patients (54.7%) died during follow-up. MHC-II positivity was observed in ≥10% of melanoma cells in 6.3% of patients. MHC-II expression was significantly associated with 1-year EFS ( P  = 0.037) and DCR ( P  = 0.032), but not with EFS or 1-year OS. Age, phototype, and brain metastases were correlated with MHC-II expression status. Our findings suggest that MHC-II expression by melanoma cells may serve as a favorable predictive biomarker for survival in metastatic cutaneous melanoma patients treated with ICIs.

Although effective treatment options for malignant melanoma already exist, currently available adjuvant and neoadjuvant therapies are not always sufficient to prevent relapse or ensure a long-term treatment response. Many patients develop resistance or show inadequate responses to existing therapies. Therefore, there is an urgent need for new and more effective therapeutic approaches in the adjuvant and neoadjuvant settings to sustainably improve patient prognosis.

This study provides an overview of current developments in melanoma treatment, with a particular focus on the adjuvant and neoadjuvant application of novel immunotherapies.

A literature search and discussion of relevant recent studies was carried out.

Adjuvant mRNA-based adjuvant treatment combined with pembrolizumab demonstrated a significantly improved relapse-free survival compared to pembrolizumab monotherapy (79% vs. 62%). The value of adjuvant LAG‑3 antibodies in combination with PD‑1 blockers remains inconclusive. A neoadjuvant intralesional treatment with daromun after complete removal of tumor tissue reduced the risk of recurrence by 41% and led to a significant extension in relapse-free survival (16.7 months vs. 6.8 months). Tebentafusp improved overall survival in metastatic uveal melanoma and is currently being investigated in the adjuvant and neoadjuvant setting.

The mRNA-based treatment combined with checkpoint inhibitors have the potential to induce long-term immune responses. The efficacy of LAG-3 inhibitors in the adjuvant setting is currently under evaluation in clinical studies. The immunocytokine treatment with daromun shows promising results in the neoadjuvant setting by stimulating both local and systemic immune responses. Future studies should focus on identifying optimal combinations of treatment to improve the long-term prognosis of patients.

Cellular therapy has been an evolving therapeutic approach in advanced melanoma over the past 40 y. The first tumor infiltrating lymphocyte (TIL) therapy, lifileucil, was Food and Drug Administration-approved in 2024 for patients with metastatic melanoma who have previously been treated with an anti-PD-1 therapy and BRAF inhibitor (BRAF V600 mutant disease). Further clinical development of TIL therapy will hopefully lead to safer and more effective strategies. Cellular therapy in melanoma has also expanded beyond TIL therapy with anti-tumor activity demonstrated for TCR-transduced T-cell products and T-cell engager bi-specific agents that target melanoma antigens.

Renal cell carcinoma (RCC), exhibiting remarkable heterogeneity, can be highly infiltrated by regulatory T cells (Tregs). However, the relationship between Treg and the heterogeneity of RCC remains to be explored.

We acquired single-cell RNA-seq profiles and 537 bulk RNA-seq profiles of TCGA-KIRC cohort. Through clustering, monocle2 pseudotime and prognostic analyses, we identified Treg states-related prognostic genes (TSRPGs), then constructing the RCC Treg states-related prognostic classification (RCC-TSC). We also explored its prognostic significance and multi-omics landmarks. Additionally, we utilized correlation analysis to establish regulatory networks, and predicted candidate inhibitors. More importantly, in Xinhua cohort of 370 patients with kidney neoplasm, we used immunohistochemical (IHC) staining for classification, then employing statistical analyses including Chi-square tests and multivariate Cox proportional hazards regression analysis to explore its clinical relevance.

We defined 44 TSRPGs in four different monocle states, and identified high immune infiltration RCC (HIRC, LAG3+, Mki67+) as the highly exhausted subtype with the worst prognosis in RCC-TSC (p < 0.001). BATF-LAG3-immune cells axis might be its underlying metastasis-related mechanism. Immunotherapy and inhibitors including sunitinib potentially conferred best therapeutic effects for HIRC. Furthermore, we successfully validated HIRC subtype as an independent prognostic factor within the Xinhua cohort (OS, HR = 16.68, 95% CI = 1.88-148.1, p = 0.011; PFS, HR = 4.43, 95% CI = 1.55-12.6, p = 0.005).

Through integrated bioinformatics analysis and a large-sample retrospective clinical study, we successfully established RCC-TSC and a diagnostic kit, which could stratify RCC patients with different prognosis and to guide personalized treatment.

Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA).

Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts.

Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively.

Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

In the last decade, the management of melanoma and Merkel cell carcinoma has changed dramatically following the results of landmark clinical trials in surgical and medical management. This review will provide a brief background for the clinical surgical oncologist as to how certain trials are conducted and designated by regulatory bodies. Additionally, we will herein review the landscape of ongoing multicenter interventional trials for cutaneous melanoma and Merkel cell carcinoma.

Neoadjuvant therapy for advance-stage melanoma has had increasing momentum over the past decade owing to several landmark clinical trials. Neoadjuvant therapy has now been shown to confer multiple advantages over adjuvant therapy, including more robust antitumor immunity, improved prognostication, and ability to personalize surgical and medical therapy based on therapeutic response. Neoadjuvant therapy has led to a major shift in clinical and surgical practice for melanoma, and future trials will give further insight into improving patient outcomes.

Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.

Melanoma has important burden in older populations due to high incidence and aggressive biology. The emergence of immunotherapy with immune checkpoint inhibitors and targeted therapy (BRAF/MEK inhibitors) significantly improved melanoma prognosis. Currently, the body of knowledge on the efficacy and tolerability of these treatments in geriatric patients is primarily based on the results outside of clinical trials since the majority of clinical studies do not include older patients. We present a comprehensive narrative review of published data regarding efficacy and safety of therapeutic modalities using immune checkpoint inhibitors in patients age 65-75 years and >75 years: the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor (ipilimumab), the anti-programmed death-ligand 1 (PD-1) inhibitors (nivolumab and pembrolizumab), and the lymphocyte activation gene-3 (LAG-3) inhibitor (relatlimab). We carefully address difficulties in multi-disciplinary clinical decision-making in care of older melanoma patients. Although many older patients may not be offered immunotherapy, the available evidence indicates that immunotherapy is equally beneficial in the older patients and does not have higher incidence of adverse events in this group of patients compared to younger population.

Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.

Esophageal squamous carcinoma (ESCC) is a common malignant tumor of the gastrointestinal tract with high morbidity and mortality rates. Lymphocyte activation gene-3 (LAG3), an important suppressive immune checkpoint in tumor immunity, exhibits a wobbling effect in the prediction of ESCC efficacy.

Tumor bite paraffin-embedded specimens from 84 patients diagnosed with ESCC, all of whom received radical concurrent chemoradiotherapy (CCRT) at our institution, were screened. For each tissue, we delineated the partitions and analyzed the spatial distribution of the tumor in an in situ immune microenvironment. The density and regional characteristics of immune factor-positive cells, together with the dynamics of various cells based on treatment regimens, were considered important factors influencing the prognostic significance of cancer.

Compared with baseline tissues, the density of CD4 + and CD8 + T cells in the tumor microenvironment of the on-treatment tissues decreased, but the expression of IFN-γ in CD4 + and CD8 + T cells increased. The density of LAG3 positive cells was correlated significantly with the density of CD4 + and CD8 + T cells in both baseline and on-treatment tissues. The density of LAG3 + T cells and the rate of LAG3 positivity in activated CD4 + and CD8 + T cells were associated with elevated Ki67 expression. There was a significant correlation between high LAG3 expression and active CD4 + and CD8 + T cells in tumor cells. Elevated densities and tighter spatial relationships of both CD4 + and CD8 + T cells were associated with longer overall survival with ESCC.

Concurrent chemoradiotherapy without combined immunotherapy inhibited tumor-infiltrating T cells to a certain extent, and elevated immune checkpoint LAG3 was closely associated with immune activation in the ESCC tumor microenvironment.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enabling the immune system to effectively target and destroy cancer cells. While ICIs offer significant survival benefits across various malignancies, their use is associated with a unique profile of immune-related adverse events, including potentially fatal cardiovascular toxicities. Recent studies have highlighted various cardiac complications associated with ICIs, such as myocarditis, arrhythmias, heart failure, pericarditis, atherosclerosis, and hypertension. These complications arise from mechanisms involving T-cell activation and cytokine release. Patient-related factors such as pre-existing cardiovascular disease, diabetes mellitus, age, gender, and genetic predisposition, along with treatment-related factors like specific ICI regimens, contribute to these toxicities. To manage these complications effectively, comprehensive cardiovascular risk assessment and monitoring before, during, and after ICI therapy are crucial. Adhering to guidelines from the European Society of Cardiology (ESC) and other international organizations allows for early recognition of cardiovascular toxicities and tailored interventions. This review emphasizes the importance of cardioprotective measures, regular monitoring, and multidisciplinary collaboration between oncologists and cardiologists to mitigate cardiovascular risk and optimize patient outcomes. Ongoing research is essential to better understand the mechanisms of ICI-induced cardiovascular toxicities and to develop effective management strategies for affected patients. As we continue to expand the use of ICIs in oncology, balancing oncologic efficacy with cardiovascular safety remains critical.

The National Comprehensive Cancer Network guidelines list combination immunotherapy as the preferred first-line (1L) treatment for unresectable or metastatic melanoma over BRAF and MEK inhibitor (BRAFi/MEKi) therapy, regardless of BRAF mutation status. However, the economic impact of 1L treatment with nivolumab plus relatlimab (NIVO + RELA) vs BRAFi/MEKi therapies for BRAF-mutated advanced melanoma has not been assessed.

To compare the health care costs, cost per progression-free life-year (PFLY), and cost per life-year (LY) of NIVO + RELA vs dabrafenib plus trametinib (DAB + TRAM), encorafenib plus binimetinib (ENCO + BINI), and vemurafenib plus cobimetinib (VEM + COBI) as 1L treatment for BRAF-mutated, unresectable or metastatic melanoma.

A cost-per-outcome model compared the economic value of NIVO + RELA vs each BRAFi/MEKi therapy. Clinical inputs were derived from previous matching-adjusted indirect comparisons using individual patient data from the BRAF-mutant subgroup of RELATIVITY-047 and published data pooled from COMBI-d, COMBI-v, COLUMBUS, and coBRIM. LYs, PFLYs per investigator, and treatment duration were estimated using the restricted mean survival time. Health care costs (2024 US dollars), including drug acquisition and administration costs, disease management costs over the preprogression and postprogression periods, and adverse event management costs, were calculated over 5 years. Several scenario analyses were performed, including adding subsequent treatment costs.

Over 5 years, NIVO + RELA was associated with improved PFLYs and LYs compared with DAB + TRAM (mean PFLY: 1.94 vs 1.82 years, mean LY: 3.41 vs 2.77 years), ENCO + BINI (1.87 vs 1.78 years and 3.40 vs 2.91 years, respectively), and VEM + COBI (2.12 vs 1.80 years and 3.39 vs 2.63 years). The estimated total costs over 5 years were lower for NIVO + RELA vs DAB + TRAM ($300,479 vs $519,770), ENCO + BINI ($343,996 vs $572,556), and VEM + COBI ($296,361 vs $317,851). Main cost drivers were drug acquisition and administration costs. NIVO + RELA had lower costs per PFLY and per LY than DAB + TRAM ($155,107 vs $285,617 and $88,203 vs $187,699, respectively); ENCO + BINI ($183,628 vs $322,113 and $101,151 vs $196,924); and VEM + COBI ($139,688 vs $176,645 and $87,315 vs $121,086). The sensitivity analyses' results supported the base-case results.

NIVO + RELA showed improved LYs and PFLYs at lower cost than all 3 BRAFi/MEKi comparators over 5 years. These results support the economic value of NIVO + RELA for patients with previously untreated, BRAF-mutated, unresectable or metastatic melanoma.

The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival (PFS) and numerically, although not statistically, superior overall survival (OS) for ipilimumab + nivolumab (I + N).

The objective of this study was to compare the efficacy and safety of N with I + N as first-line treatment for metastatic melanoma in a real-world setting.

Patients were prospectively included in the French MelBase cohort from 2013 to 2022. Eligible patients were those in first-line treatment for stage IIIc or IV melanoma, undergoing immunotherapy with N or I + N. The primary endpoint was OS at 36 months. The secondary endpoints included PFS at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the inverse probability of treatment weighting (IPTW) method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, lactate dehydrogenase levels and BRAF mutation status).

Patients were treated with N (n = 406) or I + N (n = 416). OS at 36 months was higher in the I + N group at 57.1% [95% confidence interval (CI) 50.7-64.2] than in the N group [46.6% (95% CI 41.6-52.1)]; hazard ratio (HR) 1.4 (95% CI 1.1-1.8). PFS at 36 months was significantly improved in the I + N group (42.3%) compared with the N group (21.9%), with a HR of 1.6 (95% CI 1.4-1.9). The objective response rate (ORR) was similar for the two groups (44%). The overall incidence of side-effects was comparable (82% vs. 84%), and severe toxicity (grade ≥ 3) was more frequent, although not significantly so, in the I + N arm vs. the N arm (41% vs. 29%).

Our results are consistent with those from the Checkmate 067 study, except for the ORR and the incidence of toxicities, which proved to be lower in our analysis.

In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.

PD-(L)1-based immune checkpoint inhibitor therapies have profoundly impacted the treatment of many solid malignancies. Although the addition of CTLA-4 checkpoint inhibitors can enhance anticancer activity, it also significantly increases the rate of immune-related adverse events. Therefore, there has been much interest in identifying additional immune checkpoints to improve the outcomes seen with PD-1-based therapy while minimizing additional side effects. One such target, lymphocyte-activation gene 3 (LAG-3), has long been recognized as an important inhibitor of T-cell function via modulation of the T-cell receptor pathway. Several drugs targeting LAG-3 have been developed, including most prominently the monoclonal antibody relatlimab. To date, the most significant demonstration of efficacy in targeting LAG-3 has been the use of relatlimab with the PD-1 inhibitor nivolumab in the treatment of advanced melanoma. The combination of nivolumab plus relatlimab is more efficacious compared to PD-1 inhibition alone, as has been previously seen with the combination of CTLA-4 inhibitor ipilimumab with nivolumab. However, nivolumab plus relatlimab offers a potentially more favorable toxicity profile. Here, the authors review the mechanism of the LAG-3 pathway and its rationale as a target for anticancer therapy as well as currently available data regarding the use of LAG-3 agents in treating melanoma and other solid tumors. Other investigational agents that target LAG-3 via novel mechanisms are also reviewed.

IntroductionThe combination nivolumab-relatlimab has demonstrated therapeutic benefits for patients with metastatic melanoma. However, its adverse effects can affect various organs, including the eye.Case reportWe present the case of an 80-year-old man who developed complete color blindness after the 2nd dose of nivolumab-relatlimab for advanced cutaneous melanoma. He also had significant blurry vision. Fundoscopy identified bilateral serous macular detachment. Ocular coherence tomography confirmed serous infiltration within the macula. After a thorough investigation, causality assessment linked this retinal effect to nivolumab-relatlimab (probable relationship via Naranjo criteria).Management and outcomeThe patient was treated with corticosteroids, intravenous immunoglobulin (IVIG), rituximab, and plasmapheresis, with improvement in blurry vision. However, he continued to experience persistent absence of color perception ("black and white vision") at a follow-up visit six months later.Discussion/conclusionFurther studies are necessary to understand the exact pathophysiology of this process. We hypothesize that it involves direct toxicity to the photoreceptors or retinal ganglion cells, leading to irreversible color vision loss. Effective strategies for preventing this significant, life-changing toxic effect of nivolumab-relatlimab should be sought.

Immune checkpoint inhibitors (ICIs) have led to enduring responses in subsets of patients with cancer. However, these responses carry the risk of immune-related adverse events (irAEs), which can diminish the overall benefit of ICI treatment. While associations between irAE development and overall survival have been increasingly documented, there is a need for further understanding of these connections in large prospective real-world cohorts.

The Resistance Drivers for Immuno-Oncology Patients Interrogated by Harmonized Molecular Datasets (RADIOHEAD) study, a pan-tumor, prospective cohort of 1,070 individuals undergoing standard of care first-line ICI treatment, aims to identify factors driving irAEs and clinical response. Clinical data and longitudinal blood samples were collected prospectively at multiple time points from 49 community-based oncology clinics across the USA. Structured, harmonized clinical data underwent unbiased statistical analysis to uncover predictors of real-world overall survival (rwOS) and risk factors for irAEs.

Across 1,070 participants' treatment courses, RADIOHEAD accumulated over 4,500 clinical data points. Patients experiencing any irAE (25.4%, n=272) exhibited significantly improved rwOS in the pan-tumor cohort (n=1,028, HR=0.41, 95% CI=(0.31, 0.55)). This association persisted when adjusting for age and metastatic disease in multivariate time-dependent Cox proportional hazard analysis, and was consistent across major tumor subtypes, including lung cancer and melanoma. Skin and endocrine irAEs of any grade were strongly associated with improved rwOS (Cox proportional hazard analysis, skin, p=2.03e-05; endocrine, p=0.0006). In this real-world cohort, the irAE rate appeared lower than those reported in clinical trials. Patients receiving corticosteroids prior to initiation of ICI treatment had significantly worse survival outcomes than non-users (HR 1.37, p=0.0054), with a stronger association with systemic steroid use (HR 1.75, p=0.0022). The risk of irAE was increased by exposure to combination immunotherapy relative to monotherapy (OR 4.17, p=2.8e-7), zoster vaccine (OR 2.4, p=5.2e-05), and decreased by prior chemotherapy (OR 1.69, p=0.0005).

The RADIOHEAD cohort is a well-powered, real-world cohort that clearly demonstrates the association between irAE development with improved response and baseline steroid use with worse response to ICI treatment after adjustment for survival bias.