Efficacy and safety of PD-1 monoclonal antibody combined with interferon-alpha 1b and anlotinib hydrochloride as the second-line therapy in patients with unresectable advanced melanoma: A retrospective study.

BACKGROUND: Immune-checkpoint inhibitors are now used more commonly in combination than monotherapy as the first-line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first-line immune therapy. METHODS: We reviewed the clinical profiles of patients diagnosed with stage IIIC-IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti-PD-1 mono antibody plus interferon(IFN)-alpha 1b and anlotinib hydrochloride as the second-line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T-cells using mIHC staining in available tumor samples. RESULTS: Fifty-five patients were included in this study. The median follow-up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression-free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor-infiltrating T cells in patients without objective response. CONCLUSION: PD-1 monoclonal antibody plus interferon-alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second-line therapy.

The Microbiota in Cancer: A Secondary Player or a Protagonist?

The intestinal microbiota and the human body are in a permanent interaction. There is a symbiotic relationship in which the microbiota plays a vitally important role in the performance of numerous functions, including digestion, metabolism, the development of lymphoid tissue, defensive functions, and other processes. It is a true metabolic organ essential for life and has potential involvement in various pathological states, including cancer and pathologies other than those of a digestive nature. A growing topic of great interest for its implications is the relationship between the microbiota and cancer. Dysbiosis plays a role in oncogenesis, tumor progression, and even the response to cancer treatment. The effect of the microbiota on tumor development goes beyond a local effect having a systemic effect. Another aspect of great interest regarding the intestinal microbiota is its relationship with drugs, modifying their activity. There is increasing evidence that the microbiota influences the therapeutic activity and side effects of antineoplastic drugs and also modulates the response of several tumors to antineoplastic therapy through immunological circuits. These data suggest the manipulation of the microbiota as a possible adjuvant to improve oncological treatment. Is it possible to manipulate the microbiota for therapeutic purposes?

A two-stage ensemble learning based prediction and grading model for PD-1/PD-L1 inhibitor-related cardiac adverse events: A multicenter retrospective study.

BACKGROUND: Immune-related cardiac adverse events (ircAEs) caused by programmed cell death protein-1 (PD-1) and programmed death-ligand-1 (PD-L1) inhibitors can lead to fulminant and even fatal consequences. This study aims to develop a prediction and grading model for ircAEs, enabling graded management of patients. METHODS: This study utilized medical record systems from two medical institutions to develop a prediction and grading model for ircAEs using ten machine learning algorithms and two variable screening methods. The model was developed based on a two-stage ensemble learning framework. In the first stage, the ircAEs and non-ircAEs cases were classified. In the second stage, ircAEs cases were grouped into grades 1-2 and 3-5. The experiments were evaluated using five-fold cross-validation. The model's prediction performance was assessed using accuracy, precision, recall, F1 value, Brier score, receiver operating characteristic curve area (AUC), and area under the precision-recall curve (AUPR). RESULTS: 615 patients were included in the study. 147 experienced ircAEs, and 44 experienced grade 3-5 ircAEs. The soft voting classifier trained using the variables screened by feature importance ranking performed better than other classifiers in both stages. The average AUC for the first and second stages is 84.18 % and 85.13 %, respectively. In the first stage, the three most important variables are N-terminal B-type natriuretic peptide (NT-proBNP), interleukin-2 (IL-2), and C-reactive protein (CRP). In the second stage, the patient's age, NT-proBNP, and left ventricular ejection fraction (LVEF) are the three most critical variables. CONCLUSIONS: The prediction and grading model of ircAEs based on two-stage ensemble learning established in this study has good performance and potential clinical application.

Inflammatory markers as prognostic markers in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Various inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein-to-albumin ratio (CAR), have been linked to the effectiveness of immunotherapy in multiple types of malignancies. We investigated how these inflammatory markers affect the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) receiving immunotherapy. Methods: The databases PubMed, Embase, and Cochrane were systematically searched up until March 26, 2024, to identify relevant literature. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted from the eligible studies. Data analysis was conducted using Review Manager and STATA 17.0 software to assess the impact of each indicator on prognosis. Subgroup analysis was performed to explore potential sources of heterogeneity in the data. Results: The analysis included sixteen studies with 1316 patients. A higher baseline NLR was significantly associated with poorer overall survival (OS) (pooled HR: 1.55, 95%CI: 1.14-2.11, P=0.006) and progression-free survival (PFS) (pooled HR: 1.59, 95% CI: 1.21-2.10, P<0.05). Furthermore, a high NLR after immunotherapy was strongly correlated with poor OS (pooled HR: 5.43, 95% CI: 3.63-8.12, P<0.01). Additionally, higher baseline C-reactive CAR was significantly associated with worse OS (pooled HR: 2.58, 95% CI: 1.96-3.40, P<0.01). Conclusion: The inflammatory markers NLR and CAR serve as effective prognostic biomarkers for immunotherapy in patients with HNSCC. However, the practical application of clinical detection requires further validation through large-scale prospective studies to confirm these findings and explore the underlying mechanisms.

Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

A Phase 3 Study of Pembrolizumab versus Placebo for Previously Treated Patients from Asia with Hepatocellular Carcinoma: Health-Related Quality of Life Analysis from KEYNOTE-394.

Introduction: KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods: HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results: The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, -8.4; 95% CI: -11.7 to -5.1) versus pembrolizumab (-4.0; 95% CI: -6.4 to -1.6; difference vs. placebo: 4.4; 95% CI: 0.5-8.4; nominal p = 0.0142). Similarly, a greater decline in the EQ-5D-3L visual analog scale score was observed with placebo (-6.9; 95% CI: -9.4 to -4.5) versus pembrolizumab (-2.7; 95% CI: -4.5 to -1.0; difference vs. placebo: 4.2; 95% CI: 1.2-7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58-1.25; nominal p = 0.1993). Conclusion: Patients receiving placebo showed a greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma.

The development of anti-PD-1 antibody-induced spinal cord injury in bone marrow transplant C57BL/6 Rag1-/- mouse model.

Aims: This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI). Methods: Bone marrow transplant Rag1-/- mice were used to establish SCI model. Results: Anti-PD-1 results in SCI via CD8+ T-cells activation, while excessive activation of CD8+ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8+ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8+ T-cells activation induced neurotoxicity via upregulation perforin, GrB and FasL and inhibiting PI-9. Additionally, neuroserpin suppressed CD8+ T-cells activation via perforin/GrB/PI-9/FasL pathways. Conclusion: These results may provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1.

What is this article about? In the process of treating cancer, immune checkpoint inhibitors such as anti-programmed death 1 (anti-PD-1) therapy, as a form of immunotherapy, have developed rapidly and changed the way to manage cancers significantly. However, some cancer patients who receive immune checkpoint blockade treatment suffer from severe adverse effects including spinal cord injury (SCI). This article for the first time constructed a bone marrow transplant mouse model to explore the toxicity mechanism of anti-PD-1 therapy-caused SCI.What were the results? We found that anti-PD-1 therapy can induce the activation of immune cells, while immune cell activation further promotes self-destruction of nerve cells by regulating cell death pathways.What do the results of the study mean? The mechanism of anti-PD-1 therapy-caused SCI is to activate of immune cells through regulating cell death pathways, thereby inducing self-destruction of nerve cells. These findings provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1 therapy.

Intranasal Multiepitope PD-L1-siRNA-Based Nanovaccine: The Next-Gen COVID-19 Immunotherapy.

The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are nanotechnology-based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next-generation multiepitope nanovaccines co-deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD-L1 expression. As a case study, we focused on SARS-CoV-2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular- and humoral-specific responses against SARS-CoV-2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS-CoV-2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology-based vaccines, it is shown that the lyophilized nanovaccine is stable for long-term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats.

T-cell immunosuppression in sepsis is augmented by sciatic denervation-induced skeletal muscle atrophy.

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid-derived suppressor cells (MDSC), and T-cells in peritoneal and spleen were analysed using flow cytometry. DN-induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T-lymphocyte-associated antigen (CTLA)-4+ CD4+ T-cells, programmed death (PD)-1+ CD8+ T-cells, regulatory T-cells, and the CTLA-4+ regulatory T-cells was statistically significantly higher in DN-CLP mice than in sham-CLP mice. Skeletal muscle atrophy before sepsis triggers excessive T cell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy.

Successful treatment of PD1-inhibitor induced psoriasiform dermatitis using IL-17 blockade without compromising immunotherapy efficacy.

INTRODUCTION: Pembrolizumab is a monoclonal PD-1 inhibitor used in the treatment of lung cancer in addition to several other malignancies. Psoriasiform dermatitis is a well-documented adverse effect. CASE REPORT: We present a 68 year-old-male with a 50-year smoking history and a 30-year remote history of plaque psoriasis, limited to the knees and elbows, who presented with metastatic non-small cell lung cancer. He was started on a chemotherapy regimen of carboplatin, paclitaxel, and pembrolizumab. One month later, he presented to dermatology with diffuse erythematous scaly papules coalescing into plaques on 80% of body surface area (BSA). MANAGEMENT & OUTCOME: Pembrolizumab treatment was paused. The patient was prescribed triamcinolone 0.1% twice daily, but still had significant BSA at one-month and was started on an Il-17 inhibitor, ixekizumab, clearing the psoriasiform dermatitis. He was rechallenged with pembrolizumab every 3 weeks and repeat PET/CT demonstrated excellent tumor response. DISCUSSION: This case prompted a literature review to further characterize the use of IL-17 inhibitors for psoriasiform dermatitis in the setting of ICI therapy. All six cases demonstrated improvement of psoriasiform dermatitis, with two cases showing partial response and four cases showing complete resolution. In three of the six cases, the patients exhibited clinical response to the primary malignancy after rechallenging with ICI, while remaining on an IL-17 inhibitor. Our case, in conjunction with the other reported cases, seems to suggest that IL-17 blockade can maintain a fine balance in this challenging clinical scenario by treating psoriasiform dermatitis without compromising the efficacy of immunotherapy.

Three-Year Analysis of Adjuvant Therapy in Postoperative Melanoma including Acral and Mucosal Subtypes.

BACKGROUND: Adjuvant therapy has improved the clinical prognosis for postoperative melanoma patients. However, the long-term efficacy of this therapy on the melanoma acral and mucosal subtypes has not been fully evaluated in previous trials. This study assessed the 3-year recurrence-free survival and overall survival of patients with melanoma, including the acral and mucosal subtypes, treated with anti-PD-1 antibody (Ab) or with the combination of the BRAF and MEK inhibitors dabrafenib and trametinib. METHODS: We retrospectively analyzed both the 3-year time to relapse (TTR) and overall survival (OS) of 120 patients treated with anti-PD-1 antibody (Ab), or with the combination of dabrafenib and trametinib. RESULTS: The overall median TTR was 18.4 months, with a range of 0.69 to 36 months. The 3-year TTR of the acral and mucosal types was 28.1% and 38.5%, respectively. Baseline tumor thickness (TT) and acral type were associated with the TTR in subgroup analysis. Moreover, we classified 104 acral and non-acral cutaneous patients into the anti-PD-1 Abs or dabrafenib plus trametinib combined therapies cohort in multiple analyses. The acral subtype and TT were detected as important prognostic factors. In the 3-year OS, only tumor ulceration was associated with the OS in both univariate and multiple analyses. There was no significant difference in baseline or treatment-related factors of the mucosal type (p > 0.05). CONCLUSION: This study suggests that adjuvant therapy is more effective with non-acral cutaneous melanoma than either the acral or mucosal types at the 3-year TTR endpoint.

Anti-tumor effect of innovative tumor treatment device OM-100 through enhancing anti-PD-1 immunotherapy in glioblastoma growth.

Glioblastoma (GBM) is associated with a median survival rate of less than 15 months, necessitating innovative treatment approaches. This study investigates the safety and efficacy of the low-frequency magnetic field (LFMF) OM-100 instrument in GBM therapy. In vitro experiments utilized normal astrocyte and GBM cell lines, determining that OM-100 at 100 kHz for 72 h selectively targeted GBM cells without harming normal cells. Subsequent analyses revealed OM-100's impact on cell viability, apoptosis, migration, invasion, reactive oxide species levels, and PD-L1 expression. In vivo studies on mice with U87-induced GBM demonstrated OM-100's synergy with anti-PD-1 therapy, leading to significant tumor volume reduction and increased apoptosis. Notably, OM-100 exhibited safety in healthy mice. Overall, OM-100 could enhance anti-PD-1 immunotherapy effectiveness probably by directly inhibiting tumor proliferation and migration as well as promoting PD-L1 expression, offering a promising therapeutic strategy for GBM treatment.

Immune checkpoint inhibitors targeting PD-1/PD-L1 in the treatment of human lymphomas.

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of malignancies arising from B cells, T cells, and natural killer (NK) cells at various stages of differentiation. Conversely, classical Hodgkin lymphomas (cHLs) primarily feature Reed-Sternberg cells (RSCs) amid a background of reactive immune cells. Immunomodulatory pathways, notably the PD-1/PD-L1 axis, play pivotal roles in tumor immune evasion across both NHLs and cHLs. Elevated expression of PD-1 and PD-L1 is observed in a spectrum of lymphomas, influencing prognosis and treatment response. Therapeutically, immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized lymphoma management, particularly in relapsed/refractory cases. Nivolumab and pembrolizumab, among others, have demonstrated efficacy in various B-cell lymphomas, with promising outcomes in cHL. Combination strategies incorporating ICIs with conventional chemotherapy or targeted agents show enhanced efficacy and are being explored extensively. In this review we discuss the most important features of the tumor microenvironment of NHLs and cHLs, address the therapeutic approaches with ICIs and try to outline future perspectives.

PD-1 inhibitors in advanced esophageal squamous cell carcinoma: a survival analysis of reconstructed patient-level data.

Background: Recently, a sum of trials of programmed cell death-1 (PD-1) inhibitors combined with chemotherapy have shown excellent efficacy compared to chemotherapy alone in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no head-to-head comparison and consensus on which immunotherapy regimen results in better survival outcomes. This study aimed to evaluate the survival efficacy of various PD-1 inhibitor-based therapies in the first-line treatments for patients with advanced ESCC. Methods: Data collected prior to 31 July 2023 were searched in the PubMed, Cochrane Library, Embase, Medline, and Web of Science databases. Overall survival (OS) and progression-free survival curves were pooled using the MetaSurv package. Survival data were compared by reconstructed individual patient data. Results: A total of 4,162 patients and seven randomized controlled trials were included. After synthesizing, PD-1 inhibitors prolonged median OS from 11.3 months (95% CI (confidence interval) 10.7-11.7) to 15.6 months (95% CI 14.7-16.3). Based on reconstructed patient-level data, the toripalimab, tislelizumab, and sintilimab group achieved the longest OS, whereas the sintilimab and tislelizumab group had the lowest risk of recurrence than other treatments. In patients with a combined positive score of ≥10, sintilimab had better OS efficacy than pembrolizumab (HR: 0.71, 95% CI: 0.52-0.96). In terms of tumor proportion score of ≥1%, camrelizumab, nivolumab, and toripalimab showed proximate survival benefits in both OS and progression-free survival. Conclusion: PD-1 inhibitor combined with chemotherapy significantly improved the survival time of patients with advanced ESCC. Toripalimab, tislelizumab, and sintilimab plus chemotherapy showed the best OS benefit. Longer progression-free benefits might be generated from adding tislelizumab and sintilimab to chemotherapy. Sintilimab was strongly recommended for patients with high programmed cell death-ligand 1 abundance. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42024501086].

Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying Peptide-Drug Conjugate.

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvß3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies.

Monocyte/Macrophage-Mediated Transport of Dual-Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein-1 Inhibitor Against Microsatellite-Stable Colorectal Cancer.

Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.

Case report: Lichenoid eruption under immunotherapy with MK-4830 and pembrolizumab in a breast cancer patient.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet they can induce immune-related adverse events (irAEs), including cutaneous toxicities such as lichenoid eruptions. Pembrolizumab, a PD-1 inhibitor, is known for its association with lichen-planus-like reactions, while the side effect profile of combining immunotherapy with MK-4830, a novel fully human IgG4 monoclonal antibody that targets ILT-4, remains limited. Case report: We present a case of a 47-year-old female with metastatic breast cancer who developed a grade 2 Common Terminology Criteria for Adverse Events (CTCAE) lichenoid reaction after 9 months of MK-4830 and pembrolizumab use. Confluent, erythematous papules with Wickham's striae appeared predominantly on the extremities. Initial therapy with high-potency topical corticosteroids proved insufficient, however prednisone 40 mg daily resulted in satisfactory remission of lichen-planus-like reaction, permitting continued immunotherapy without dosage adjustment. Conclusion: This case highlights the novel occurrence of lichenoid eruption induced by MK-4830 and pembrolizumab in breast cancer treatment. The patient was successfully treated with oral prednisone, which controlled the skin symptoms without interrupting ICI therapy. We emphasize that early diagnosis and treatment of low-grade lichenoid eruption can prevent the cessation of ICIs, thereby combining the benefits of managing irAEs and avoiding cancer progression, leading to a better long-term prognosis.

Pretreatment pulmonary tumor necrosis is a promising prognostic imaging biomarker for first-line anti-PD-1/PD-L1 therapy in advanced lung squamous cell carcinoma: a multi-institutional, propensity score-matching cohort analysis.

Background: Tumor necrosis (TN) is a common feature in lung squamous cell carcinoma (LSCC), which could provide useful predictive and prognostic information. Objectives: This study aimed to investigate the effect of pretreatment pulmonary TN (PTN) on the prognosis of first-line anti-programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitor in advanced LSCC. Design: We conducted a retrospective study to analyze the association between the presence of PTN and clinical outcomes in advanced LSCC patients treated with anti-PD-1/PD-L1 inhibitors. Methods: Data from 240 eligible patients were collected from 27 hospitals across China between 2016 and 2020. The presence of PTN was assessed using contrast-enhanced chest computed tomography (CT) imaging at baseline. We utilized the Cox proportional-hazards regression model to analyze the association between PTN and clinical outcomes. In addition, to account for potential confounding factors and ensure comparability between groups, we employed propensity score-matching (PSM) analysis. Results: In the overall patient cohort, the presence of PTN was 39.6%. The median follow-up duration was 20.3 months. The positive PTN group exhibited a notably inferior median progression-free survival (PFS; 6.5 months vs 8.6 months, p = 0.012) compared to the negative PTN group. Within the Cox proportional-hazards regression model, PTN emerged as an independent predictor of unfavorable PFS (hazard ratio (HR) = 1.354, 95% confidence interval (CI): 1.002-1.830, p = 0.049). After PSM, the median PFS for the positive PTN group (6.5 months vs 8.0 months, p = 0.027) remained worse than that of the negative PTN group. Multivariate analyses also further underscored that the presence of PTN independently posed a risk for shorter PFS (HR = 1.494, 95% CI: 1.056-2.112, p = 0.023). However, no statistically significant difference in overall survival was observed between the two groups. Conclusion: Our study suggests that the presence of PTN on baseline contrast-enhanced chest CT is a potential negative prognostic imaging biomarker for the outcome of anti-PD-1/PD-L1 inhibitor therapy in advanced LSCC. Further studies are warranted to validate these findings and explore the underlying mechanisms.

Predicting anti-PD-1/PD-L1 inhibitor treatment outcomes: pulmonary tumor necrosis in lung squamous cell carcinoma Our study focused on lung squamous cell carcinoma (LSCC) patients receiving first-line anti-PD-1/PD-L1 therapy. We explored the impact of a feature called pretreatment pulmonary tumor necrosis (PTN) on their prognosis. PTN was identified in 39.6% of patients using baseline chest CT scans. Results revealed that patients with PTN had a shorter time without disease progression (median PFS of 6.5 months compared to 8.6 months) and a higher risk of unfavorable outcomes. This suggests that PTN may serve as a negative prognostic imaging marker for anti-PD-1/PD-L1 therapy in advanced LSCC. Further research is needed to confirm and understand these findings better.

Case report: A sustained survival benefit of third-line immunotherapy for refractory thymic carcinoma.

Thymic carcinoma (TC) is an uncommon type of thymic epithelial tumors. Patients with relapsed or refractory TCs have a poor prognosis. Immune checkpoint inhibitor monotherapy can be applied as a second-line treatment for such cases. This study reported a TC patient who did not respond to conventional chemotherapy and radiotherapy but achieved prolonged partial remission lasting 17 months following the third-line treatment with anti-programmed cell death-1 inhibitor sintilimab. This patient did not experience any serious side effects associated with sintilimab treatment. The above results demonstrated that sintilimab could be a feasible therapeutic option for refractory TC patients.