The European Larynx Organ Preservation Study [MK-3475-C44].

The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70-72 Gy (EQD2/α/ß = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic's multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL. Clinical Trial Registration: clinicaltrials.gov, identifier NCT06137378.

Engineered Immunologic Niche Monitors Checkpoint Blockade Response and Probes Mechanisms of Resistance.

Antibodies to programmed cell death protein1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10-20% of PD-L1+ metastatic TNBC patients who meet criteria benefit from ICB, and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance.

NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.

Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.

BACKGROUND: The main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain. METHODS: Molecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB. RESULTS: After anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. CONCLUSIONS: In this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.

A carrier-free nanovaccine combined with cancer immunotherapy overcomes gemcitabine resistance.

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

TIGIT: Will it be the next star therapeutic target like PD-1 in hematological malignancies?

Research on the mechanism and application of checkpoint inhibitory receptors in hematologic diseases has progressed rapidly. However, in the treatment of relapserefractory (R/R) hematologic malignancies and anti-programmed cell death protein 1 (PD-1), patients who are resistant to anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are in urgent need of alternative therapeutic targets. T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) has a broad prospect as an inhibitory receptor like PD-1, but its more specific mechanism of action and application in hematologic diseases still need to be further studied. In this review, we discuss the mechanism of TIGIT pathway, combined effects with other immune checkpoints, immune-related therapy, the impact of TIGIT on hematopoietic stem cell transplantation (HSCT) and the tumor microenvironment (TME) provides a potential therapeutic target for hematologic malignancies.

Clinical Outcomes of Elective Early Discontinuation of Immunotherapy Based on Objective Response in Microsatellite Instability-High Metastatic Colorectal Cancer.

BACKGROUND: Patients with microsatellite-high (MSI-H) metastatic colorectal cancers (CRC) may experience long-lasting benefit from immune checkpoint inhibitors (ICI) upon stopping therapy. However, optimal timing and patient selection criteria for early treatment withdrawal remain undefined. In this single-center retrospective study, we characterized the clinical response and associated survival outcomes of patients who received elective early versus late treatment discontinuation. METHODS: We retrospectively analyzed patients with MSI-H metastatic CRC treated with ICI therapy from May 2015 to April 2024. Early ICI discontinuation was defined as treatment withdrawal before 2 years, and late ICI discontinuation as after 2 years. Response was assessed using Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Efficacy outcomes between early and late ICI discontinuation groups were compared using a log-rank test. RESULTS: Of 36 patients with MSI-H metastatic CRC, 12 underwent elective early ICI discontinuation and 9 experienced late ICI discontinuation. After a median follow-up of 32 months post-treatment, 91.7% (11/12) in the early discontinuation group remain off therapy without progression. PFS and OS outcomes between the early and late discontinuation groups were similarly favorable (P = .88 and P = .85, respectively), despite a 12-month difference in median duration of ICI therapy (13.3 and 25.6 months, respectively). The most common reason for elective early treatment discontinuation was clinical remission (n = 10), defined as a complete response, or a partial response with negative PET and/or ctDNA testing. CONCLUSIONS: Early ICI discontinuation guided by response criteria resulted in low rates of recurrence. Survival outcomes between early and late ICI discontinuation groups were comparable, suggesting that treatment duration can be individualized based on clinical response without compromising favorable long-term prognosis.

Steroid-Refractory Myocarditis Induced by Immune Checkpoint Inhibitor Responded to Infliximab: Report of Two Cases and Literature Review.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α.

Hypoalbuminemia and hypercalcemia are independently associated with poor treatment outcomes of anti-PD-1 immune checkpoint inhibitors in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Recent randomized phase III trials have demonstrated the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in treating patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC). However, a large proportion of such patients still have poor response. This study aimed to identify biomarkers for predicting anti-PD-1 ICI treatment outcomes . METHODS: We retrospectively analyzed 144 patients with RMHNSCC who received anti-PD-1 ICIs after progression to platinum-based chemotherapy between January 2017 and December 2022 at Kaohsiung Chang Gung Memorial Hospital. Data on clinicopathological parameters, albumin levels, calcium levels, and other pretreatment peripheral blood biomarkers, including total lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI) were collected and correlated with the treatment outcome of anti-PD-1 ICIs. RESULTS: Low tumor proportion score (TPS), low combined positive score (CPS), NLR ≥ 5, PLR ≥ 300, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly correlated with poor response of ICIs. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL, respectively (P = 0.007). The overall response rates were 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL, respectively (P < 0.001). Univariate survival analysis showed that low TPS, low CPS, NLR ≥ 5,, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly associated with worse progression-free survival (PFS) and inferior overall survival (OS). Multivariate analysis revealed that calcium ≥ 10 mg/dL and albumin < 4 g/dL were independent poor prognosticators for worse PFS and inferior OS. The two-year OS rates were 26% and 9% in patients with calcium < 10 mg/dL and ≥ 10 mg/dL, respectively (P < 0.001). The two-year OS rates were 10% and 33% in patients with albumin < 4 g/dL and ≥ 4 g/dL, respectively (P < 0.001). CONCLUSIONS: Hypercalcemia and hypoalbuminemia can potentially predict poor treatment outcomes of anti-PD-1 ICIs in patients with RMHNSCC. Blood calcium and albumin levels may be helpful in individualizing treatment strategies for patients with RMHNSCC.

Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors.

BACKGROUND: Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS: We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS: Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION: We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

Tocilizumab provides dual benefits in treating immune checkpoint inhibitor-associated arthritis and preventing relapse during ICI rechallenge: the TAPIR study.

BACKGROUND: The aim of this retrospective study was to evaluate the dual efficacy of tocilizumab (TCZ) in the treatment of ICI-related arthritis (ICI-AR) and the prevention of relapses after rechallenge. PATIENTS AND METHODS: We identified 26 patients with ICI-AR. The primary objectives were to evaluate TCZ efficacy in ICI-AR treatment and as secondary prophylaxis during ICI rechallenge in 11 of them. Patients received prednisone (CS) at 0.3 mg/kg tapered at 0.05 mg/kg weekly for six weeks. TCZ was administered at a dose of 8 mg/kg Q2w. In the subgroup receiving secondary prophylaxis (rechallenge n=11), TCZ was reintroduced with the same regimen concurrently with ICI rechallenge, and without the addition of CS. A control group of patients (rechallenge n=5) was rechallenged without TCZ. Secondary endpoints included post rechallenge evaluation of ICI duration, reintroduction of CS > 0.1 mg/kg/day, ICI-RA flares, and DCR. RESULTS: The median age of the patients was 70 years. The median follow-up from ICI initiation was 864 days. Among the 20 patients treated with TCZ for ICI-AR, all (100%) achieved an ACR70 response rate, defined as greater than 70% improvement, at 10 weeks. 81% of these patients achieved steroid-free remission after 24 weeks on TCZ. The median follow-up period was 552 days in rechallenged patients. The results demonstrated a reduction in ICI-AR relapses upon ICI rechallenge in patients receiving TCZ prophylaxis as compared to patients who did not receive prophylaxis (17% vs 40%). The requirement for CS was completely abolished with prophylaxis (0% vs 20%), and the mean duration of ICI treatment was notably extended from 113 to 206 days. The 12-month post-rechallenge outcomes showed a disease control rate (DCR) of 77%. During TCZ prophylaxis, CXCL9 remained elevated, showing no decline from their levels at the onset of ICI-AR CONCLUSIONS: In addition to treating ICI-AR, TCZ demonstrated efficacy as a secondary prophylactic agent, preventing the recurrence symptoms and lengthening ICI treatment duration after ICI rechallenge.

Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.

Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.

Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, the emergence of ICI-associated myocarditis (ICI-MC) presents a severe and potentially fatal complication with poorly understood pathophysiological mechanisms. This study aimed to identify crucial immune-related genes in ICI-MC and uncover potential therapeutic targets using bioinformatics. METHODS: Using the GSE180045 dataset, which includes three groups-Group A: ICI patients without immune adverse events, Group B: ICI patients with non-myocarditis immune adverse events, and Group C: ICI patients with myocarditis-we analyzed differentially expressed genes (DEGs) between ICI-MC samples (Group C) and non-myocarditis controls (Groups A and B). These DEGs were then cross-referenced with 1796 immune-related genes from the immPort database to identify immune-related DEGs. We conducted functional enrichment analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis), constructed a protein-protein interaction network, and identified hub genes. Validation using the GSE4172 dataset led to the identification of optimal feature genes from the overlap between hub genes and DEGs. Predictions of target MicroRNAs (miRNAs) were made, and a competing endogenous RNA (ceRNA) network was constructed. Target drugs for hub genes were predicted using the Connectivity Map database. RESULTS: We identified 58 DEGs between ICI-MC and controls, which led to the identification of 32 immune-related DEGs after intersection with 1796 immune-related genes. Functional analyses revealed enrichment in cell lysis, CD8+ T-cell receptor, natural killer cell-mediated cytotoxicity, and RAGE signaling. Notably upregulated hub genes included IL7R, PRF1, GNLY, CD3G, NKG7, GZMH, GZMB, KLRB1, KLRK1, and CD247. In the validation dataset, 407 DEGs were uncovered, resulting in the identification of 3 optimal feature genes (KLRB1, NKG7, GZMH). The predicted target miRNAs, lincRNAs, and circRNAs constituted a comprehensive ceRNA network. Among the top 10 drugs with elevated connectivity scores was acetohydroxamic acid, indicating a need for caution in ICI treatment. CONCLUSION: KG7, GZMH, and KLRB1 were identified as pivotal immune-related genes in ICI-MC. Biological enrichments included pathways involved in cell lysis, the CD8+ T-cell receptor pathway, natural killer cell-mediated cytotoxicity, RAGE signaling, and proinflammatory responses. The ceRNA network illuminated the role of critical molecules and underscored the importance of avoiding drugs such as acetohydroxamic acid in ICI treatment. Key message What is already known on this topic  Myocarditis is recognized as a serious ICI-associated toxicity, seemingly infrequent yet often fulminant and lethal. The underlying mechanisms of ICI-associated myocarditis remain not fully understood. Although the significance of T cells and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is evident, the inciting antigens, the reasons for their recognition, and the mechanisms causing cardiac cell injury are not well characterized. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems. What this study adds  Our study further validates the significance of T cells and CTLA-4 in ICI-associated myocarditis. More importantly, we identified three genes-NKG7, GZMH, and KLRB1-essential for the development of ICI-MC and proposed ceRNA networks involving these three key genes. How this study might affect research, practice or policy  The newly discovered key genes and their intricate molecular interactions offer a comprehensive perspective on the mechanisms underlying ICI-MC. Furthermore, our findings advise caution regarding the use of drugs like acetohydroxamic acid during ICI treatment. As our understanding of these regulatory networks deepens, our study provides valuable insights that could inform future therapeutic strategies for ICI-MC.

Evaluation of emergency department visits and immune-related adverse effects (irAEs) in patients treated with nivolumab.

INTRODUCTION: The development of immune checkpoint inhibitors (ICIs) represents one of the most significant advancements in cancer treatment over the past decade. Nivolumab, a widely used ICI, has been incorporated into the therapeutic regimens for various cancers. As with any drug, this drug also has side effects, including class-specific immune-related adverse effects (irAEs). Although irAEs are not rare, their diagnosis can be challenging. This study examines the emergency department (ED) visits of patients undergoing nivolumab therapy, focusing on diagnostic challenges, evaluating the management, and outcomes of irAEs in the ED setting. MATERIAL AND METHODS: A retrospective cohort study was conducted on adult patients who received nivolumab therapy for any cancer between April 1, 2018, and March 31, 2023, at a large, urban tertiary care center. In this study, we evaluated the ED visits of patients receiving nivolumab. In addition to previous studies, we evaluated irAEs in detail (percentage, recognizability, risk factors, reasons for late recognition, and outcome). Patient data were collected from electronic medical records and patient's medical files. The anamnesis, laboratory, and imaging results, ED management, and consultation notes were examined separately for each ED visit. Logistic regression models were employed to identify significant univariable predictors of ED visits and irAEs. RESULTS: A total of 199 patients were included in the study, all of whom had metastatic cancer. Of these, 154 patients (77.4%) received nivolumab therapy for non-small cell lung cancer. Most patients (71.9%, n = 143) had at least one additional comorbidity. One hundred and eleven patients (55.8%) presented to the ED. Hypertension (OR: 2.425, 95% CI: 1.226-4.795, p = 0.011) and chronic obstructive pulmonary disease (OR: 2.489, 95% CI: 1.133-5.468, p = 0.023) were identified as risk factors for ED visits. A total of 21 irAEs were diagnosed (14 in ED, 6 in the oncology clinic, and 1 in the inpatient ward). Univariate analysis found no significant association between irAE diagnosis and any specific factors. CONCLUSION: A significant proportion of the patients treated with nivolumab for advanced cancer present to ED for ICI-related adverse events, although most cases were not attributable to irAEs. Due to the vague symptomatology of irAEs, their recognition and diagnosis in the ED can be challenging. Close collaboration between ED physicians and oncologists is paramount to the management of patients with cancer in the ED.

Dissociation of LAG-3 inhibitory cluster from TCR microcluster by immune checkpoint blockade.

Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T-cell activation to elucidate the Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with T-cell receptor microcluster (TCR-MC) upon T-cell activation similar to PD-1. Lag-3 blocking antibodies (Abs) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation. Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab, which did not block MHC-II binding could still block Lag-3's inhibitory function, suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T-cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T-cell activation at TCR-MC, and the target of Lag-3 ICI is to dissociate the co-localization of Lag-3 with TCR-MC.

Advances in immunotherapy for mucosal melanoma: harnessing immune checkpoint inhibitors for improved treatment outcomes.

Mucosal melanoma (MM) poses a significant clinical challenge due to its aggressive nature and limited treatment options. In recent years, immunotherapy has emerged as a promising strategy for MM, with a particular focus on immune checkpoint inhibitors such as PD-1 and CTLA-4 inhibitors. These inhibitors have demonstrated substantial efficacy by harnessing the body's immune response against tumors. Moreover, adoptive cell transfer (ACT), anti-angiogenic therapy, and combination therapies have garnered attention for their potential in MM treatment. ACT involves modifying T cells to target melanoma cells, showing promising antitumor activity. Anti-angiogenic therapy aims to impede tumor growth by inhibiting angiogenesis, while combination therapies, including immune checkpoint inhibitors and targeted therapies, offer a multifaceted approach to overcome treatment resistance. This comprehensive review explores the advancements in immunotherapy for MM, highlighting the role of diverse therapeutic modalities in enhancing treatment outcomes and addressing the challenges posed by this aggressive malignancy.

Updates and emerging trends in the management of immune-related adverse events associated with immune checkpoint inhibitor therapy.

The rapidly expanding class of therapies targeting immune checkpoints for the treatment of various cancers now includes 8 clinically approved agents: a lymphocyte-activation gene 3 (LAG-3) inhibitor (relatlimab), a cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitor (ipilimumab), three programmed cell death protein 1 (PD-1) inhibitors (nivolumab, pembrolizumab and cemiplimab), and three programmed cell death ligand-1 (PD-L1) inhibitors (atezolizumab, durvalumab, and avelumab). Previously, we reviewed the mechanisms of immune-related adverse events (irAEs), strategies for management of irAEs, and highlighted similarities as well as differences amongst clinical guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), and European Society for Medical Oncology (ESMO). Herein, we provide an update that includes discussion of changes to these clinical guidelines since our last review, the new LAG-3 targeted agents, emerging patterns of irAEs, and new directions for improved monitoring and treatment of irAEs that could incorporate interdisciplinary pharmacist-led teams, artificial intelligence, and pharmacogenomics.

Patterns of hormonal changes in hypophysitis by immune checkpoint inhibitor.

BACKGROUND/AIMS: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events, including endocrine dysfunctions, which can have serious consequences on patient health and quality of life. The clinical course and characteristics of immune-related hypophysitis (irH) are not well established. This study aimed to analyze the clinical course and characteristics of irH. METHODS: This single-center, retrospective study analyzed data from electronic medical records of Asan Medical Center, spanning January 2017 through June 2021. It included adult patients with solid tumors who underwent thyroid and adrenal function tests, along with gonadotropin and/or growth hormone evaluations, following the initiation of ICI treatment within the same period. The study explored the clinical characteristics of ICI-treated patients with and without irH, the incidence of irH, the time to irH onset, and the associated hormonal changes. RESULTS: Twenty-one patients were included in this analysis. Clinical characteristics did not differ significantly between the irH (n = 13) and non-irH (n = 8) groups. Deficiency rates in the irH group were 23.1% for thyroid-stimulating hormone (n = 3), 76.9% for adrenocorticotropic hormone (n = 10), 61.5% for gonadotropin (n = 8), and 15.4% for growth hormone (n = 2). The overall incidence was 0.9 per person-year, with 6-month and 1-year cumulative incidences of 38.8% and 57.1%, respectively. The median time from ICI initiation to irH diagnosis was 7.7 months. Time to levothyroxine replacement was shorter in the irH group. CONCLUSION: The findings provide evidence that could facilitate the prediction of ICI-induced irH based on clinical course and characteristics.

Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment.

T cells and macrophages have the potential to collaborate to eliminate tumor cells efficiently. Macrophages can eliminate tumor cells through phagocytosis and subsequently activate T cells by presenting tumor antigens. The activated T cells, in turn, can kill tumor cells and redirect tumor-associated macrophages toward an antitumoral M1 phenotype. However, checkpoint molecules expressed on tumor cells impede the collaborative action of these immune cells. Meanwhile, monotherapy with a single immune checkpoint inhibitor (ICI) for either macrophages or T cells yields suboptimal efficacy in cancer patients. To address this challenge, here a nanoparticle capable of efficiently delivering dual ICIs to tumors for both macrophages and T cells is developed. These programmed cell death protein 1 (PD-1)-transfected macrophage membrane-derived nanoparticles (PMMNPs) can target tumors and provide signal-regulatory protein alpha and PD-1 to block CD47 and programmed cell death-ligand 1 (PD-L1), respectively, on tumor cells. PMMNPs enhance macrophage-mediated cancer cell phagocytosis and antigen presentation, promote T cell activation, and induce the reprogramming of macrophages toward an antitumoral phenotype. In syngeneic tumor-bearing mice, PMMNPs demonstrate superior therapeutic efficacy compared to nanoparticles delivering single ICIs and non-targeted delivery of anti-CD47 and anti-PD-L1 antibodies. PMMNPs capable of augmenting the antitumoral interplay between macrophages and T cells may offer a promising avenue for cancer immunotherapy.

Digitonin-Loaded Nanoscale Metal-Organic Framework for Mitochondria-Targeted Radiotherapy-Radiodynamic Therapy and Disulfidptosis.

The efficacy of radiotherapy (RT) is limited by inefficient X-ray absorption and reactive oxygen species generation, upregulation of immunosuppressive factors, and a reducing tumor microenvironment (TME). Here, the design of a mitochondria-targeted and digitonin (Dig)-loaded nanoscale metal-organic framework, Th-Ir-DBB/Dig, is reported to overcome these limitations and elicit strong antitumor effects upon low-dose X-ray irradiation. Built from Th6O4(OH)4 secondary building units (SBUs) and photosensitizing Ir(DBB)(ppy)2 2+ (Ir-DBB, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; ppy = 2-phenylpyridine) ligands, Th-Ir-DBB exhibits strong RT-radiodynamic therapy (RDT) effects via potent radiosensitization with high-Z SBUs for hydroxyl radical generation and efficient excitation of Ir-DBB ligands for singlet oxygen production. Th-Ir-DBB/Dig releases digitonin in acidic TMEs to trigger disulfidptosis of cancer cells and sensitize cancer cells to RT-RDT through glucose and glutathione depletion. The released digitonin simultaneously downregulates multiple immune checkpoints in cancer cells and T cells through cholesterol depletion. As a result, Th-Ir-DBB/dig plus X-ray irradiation induces strong antitumor immunity to effectively inhibit tumor growth in mouse models of colon and breast cancer.