Evaluation of the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, particularly when diagnosed at an unresectable stage. Traditional treatments for advanced HCC have limited efficacy, prompting the exploration of combination therapies. This systematic review and meta-analysis evaluate the effectiveness and safety of combining PD-1/PD-L1 inhibitors with anti-angiogenic agents in patients with unresectable HCC. Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, including studies up to June 2024. Randomized controlled trials (RCTs) comparing combination therapy (PD-1/PD-L1 inhibitors with anti-angiogenic agents) to monotherapy or standard treatments in unresectable HCC patients were included. Data were synthesized using random-effects models, with pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs). Results: Five Phase III RCTs involving 1515 patients were included. Combination therapy significantly improved OS (HR: 0.71, 95% CI: 0.60-0.85) and PFS (HR: 0.64, 95% CI: 0.53-0.77) compared to monotherapy or standard treatments. The pooled OR for ORR was 1.27 (95% CI: 1.57-2.11), indicating a higher response rate with combination therapy. However, the risk of AEs was also higher in the combination therapy group (RR: 1.04, 95% CI: 1.02-1.06). Subgroup analyses revealed consistent benefits across different types of PD-1/PD-L1 inhibitors and anti-angiogenic agents, with no significant publication bias detected. Conclusions: The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents offers significant benefits in improving OS and PFS in patients with unresectable HCC, although it is associated with an increased risk of adverse events.

Predictive value of near-term prediction models for severe immune-related adverse events in malignant tumor PD-1 inhibitor therapy.

Immune-related adverse events (irAEs) impact outcomes, with most research focusing on early prediction (baseline data), rather than near-term prediction (one cycle before the occurrence of irAEs and the current cycle). We aimed to explore the near-term predictive value of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), absolute eosinophil count (AEC) for severe irAEs induced by PD-1 inhibitors. Data were collected from tumor patients treated with PD-1 inhibitors. NLR, PLR, and AEC data were obtained from both the previous and the current cycles of irAEs occurrence. A predictive model was developed using elastic net logistic regression Cutoff values were determined using Youden's Index. The predicted results were compared with actual data using Bayesian survival analysis. A total of 138 patients were included, of whom 47 experienced grade 1-2 irAEs and 18 experienced grade 3-5 irAEs. The predictive model identified optimal α and λ through 10-fold cross-validation. The Shapiro-Wilk test, Kruskal-Wallis test and logistic regression showed that only current cycle data were meaningful. The NLR was statistically significant in predicting irAEs in the previous cycle. Both NLR and AEC were significant predictors of irAEs in the current cycle. The model achieved an area under the ROC curve (AUC) of 0.783, with a sensitivity of 77.8% and a specificity of 80.8%. A probability ≥ 0.1345 predicted severe irAEs. The model comprising NLR, AEC, and sex may predict the irAEs classification in the current cycle, offering a near-term predictive advantage over baseline models and potentially extending the duration of immunotherapy for patients.

Efficacy of PD-1 or PD-L1 inhibitors for the therapy of cervical cancer with varying PD-L1 expression levels: a single-arm meta-analysis.

Objective: To assess the effectiveness and tolerability of both PD-1 and PD-L1 inhibitors in advanced cervical cancer (CC), focusing on varying PD-L1 levels. Methods: A comprehensive exploration was carried out on EMBASE, PubMed, Cochrane Library databases as well as Web of Science up to May 25, 2024, for studies involving advanced CC patients receiving PD-1/PD-L1 inhibitors. Inclusion criteria were studies reporting objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), as well as median overall survival (OS). Data extraction and quality assessment were performed by two reviewers using the JBI Case Series Critical Appraisal Checklist, followed by a meta-analysis via STATA/MP 16.0. Results: Five eligible studies comprising 223 patients were chosen. ORR and DCR were 42% (95% CI: 17%-66%, P = 0.00) and 70% (95% CI: 22%-117%, P = 0.00), respectively, in the PD-L1 positive patients and were 36% (95% CI: 17%-54%, P = 0.00) and 47% (95% CI: 30%-63%, P = 0.00), respectively, in patients with PD-L1 negativity. For patients exhibiting PD-L1 positivity, median PFS and median OS were 3.98 months (95% CI: 0.80-7.16, P = 0.01) and 11.26 months (95% CI: 3.01-12.58, P = 0.00), respectively. Conclusion: With PD-1/PD-L1 inhibitors, PD-L1 positive CC patients demonstrate superior ORR, DCR, median PFS, and median OS, underscoring PD-L1 as one biomarker for immunotherapy response.

Hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib plus PD-1 inhibitors in hepatocellular carcinoma patients with tumor thrombosis in the inferior vena cava and/or right atrium.

RATIONALE AND OBJECTIVES: Hepatocellular carcinoma (HCC) with invasion into the inferior vena cava (IVC) or the right atrium (RA) presents significant therapeutic challenges due to its rapid progression and limited available treatments. MATERIALS AND METHODS: This retrospective study evaluated the effectiveness of hepatic arterial infusion chemotherapy alongside lenvatinib and PD-1 inhibitors (HAIC-Len-PD1) compared to treatment with only lenvatinib and PD-1 inhibitors (Len-PD1). A total of 115 patients with HCC and IVC or RA invasion were included. We analyzed groups for median overall survival (OS) and progression-free survival (PFS) through the Kaplan-Meier method, along with tumor response rates, disease control rates, and adverse event frequencies. RESULTS: The HAIC-Len-PD1 treatment showed a marked improvement in median OS (22.2 vs. 14.4 months; P = 0.007) and median PFS (13.8 vs. 5.1 months; P = 0.001) over the Len-PD1 regimen. There was also a higher overall response rate (68.7% vs. 37.5%; P < 0.05) and disease control rate (92.5% vs. 75%; P < 0.05) observed in the HAIC-Len-PD1 group. A subgroup analysis demonstrated consistent survival benefits across diverse patient demographics. Although the incidence of adverse events was higher in the HAIC-Len-PD1 group, these were generally manageable and well-tolerated. CONCLUSION: The combined regimen of HAIC, lenvatinib, and PD-1 inhibitors may improve survival and tumor management in HCC patients with IVC or RA invasion, suggesting a potential therapeutic option for this critically at-risk group. Further research in the form of randomized controlled trials are needed to verify these findings for advanced-stage HCC with vascular compromise.

Efficacy and safety of PD-1 inhibitors plus anti-angiogenesis tyrosine kinase inhibitors with or without transarterial chemo(embolization) for unresectable hepatocellular carcinoma: a meta-analysis.

Background: The triple combination of programmed cell death protein-1 (PD-1) inhibitors plus anti-angiogenesis tyrosine kinase inhibitors (TKIs) with or without transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) enhance the effect of treatment for unresectable hepatocellular carcinoma (uHCC). The present study compared the efficacy and safety of PD-1 plus TKI with or without transarterial chemo(embolization) for uHCC. Methods: The meta-analysis was conducted using data acquired from PubMed, EMBASE, the Cochrane Library, Ovid, Web of Science, and Clinical Trials.gov from the inception date to December 2023. All clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CIs) were used to measure the pooled effect. In addition, subgroup analysis was conducted to determine the specific patient population that benefited. Results: The OS (HR = 0.47; 95% CI: 0.39-0.56, P <  0.05), PFS (HR = 0.52; 95% CI: 0.45-0.60, P < 0.05), and ORR (RR = 1.94; 95% CI: 1.60-2.35, P < 0.05) were significantly better in TACE/HAIC+TKI+PD-1(TACE/HAIC TP) group than TKI+PD-1(TP) group. The incidence of AEs was acceptable. Conclusion: The triple therapy of TACE/HAIC TP had better efficacy for uHCC than TP, with acceptable security. Systematic review registration: PROSPERO, identifier CRD42023475953.

Higher tumor mutational burden and PD-L1 expression correlate with shorter survival in hematologic malignancies.

Background: The prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies. Objectives: This study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies. Design: This real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018). Methods: TMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records. Results: In 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04). Conclusion: TMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies. Trial registration: ClinicalTrials.gov NCT02478931.

Adjuvant Therapy for High-Risk Stage II Melanoma: Current Paradigms in Management and Future Directions.

Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma.

Clinical Significance of Thyroid Autoantibodies in Differential Diagnosis and Predicting the Course of Programmed Cell Death Protein-1 Inhibitor-Induced Thyroid Dysfunction.

OBJECTIVE: Thyroid immune-related thyrotoxicosis is one of the most common adverse effects in patients treated with programmed cell death protein-1 (PD-1) inhibitors. We investigated the significance of levels of serum anti-thyroglobulin antibodies (TgAbs), anti-thyroid peroxidase antibodies (TPOAbs), and thyroid-stimulating hormone receptor antibodies (TRAbs) in the identification of anti-PD-1-induced thyroid thyrotoxicosis. METHODS: We divided 161 patients with thyroid dysfunction who received PD-1 inhibitors at our hospital between January 2022 and June 2024 into 3 groups: primary hypothyroidism group, primary hyperthyroidism group, and destructive thyroiditis group. The characteristics of the 3 groups were determined, and the positivity rates of serum TgAbs, TPOAbs, and TRAbs were assessed. An additional 42 patients diagnosed with Hashimoto's thyroiditis were selected as the control group for PD-1 inhibition-induced destructive thyroiditis. Age, sex, and time of transition from thyrotoxicosis to hypothyroidism in the 2 groups were compared. RESULTS: In the primary hypothyroidism group, only 1 case was TPOAbs-positive (1/1%). In the destructive thyroiditis group, the positivity rate for TPOAbs or TgAbs was 92.9%, and TPOAbs and TgAbs were negative in the primary hyperthyroidism group. TRAbs were undetectable in all 3 groups. There were statistically significant differences in age, sex, and time from thyrotoxicosis to hypothyroidism in the PD-1 induced destructive thyroiditis and Hashimoto's thyroiditis groups. CONCLUSIONS: In patients with thyrotoxicosis caused by PD-1 inhibitors, serum TgAb, and TPOAb levels can be used to distinguish between primary hyperthyroidism and destructive thyroiditis. This study provides insights into novel treatment targets and effective management strategies for PD-1-induced thyrotoxicosis.

Efficacy, safety, and prognostic modeling in neoadjuvant immunotherapy for esophageal squamous cell carcinoma.

OBJECTIVE: To evaluate the safety and efficacy of neoadjuvant immunotherapy in patients with esophageal squamous cell carcinoma (ESCC) and construct a prognostic model. METHODS: Clinical data were retrospectively collected from patients with locally advanced ESCC who received neoadjuvant immunotherapy and chemotherapy. The primary endpoints were major pathologic remission rate and disease-free survival, and secondary endpoints were treatment-related adverse events and perioperative complications. Correlates affecting pathological response were analyzed using univariate and multivariate logistic regression, survival-related variables were screened by Boruta and least absolute shrinkage and selection operator Cox regression analysis. A nomogram was constructed and utilized to test the predictive efficacy of the treatment with receiver operating characteristic curve and decision curve analysis. RESULTS: A total of 181 patients were enrolled, of whom 119 (66 %) patients received 3-4 cycles of treatment. Treatment-related adverse events occurred in 65.2 % of the patients, with 13.3 % experiencing severe complications. Major pathological remission rate was achieved in 68 (37.6 %) patients, with no significant difference between the treatment cycle groups (P=0.925). The nomogram included pathologic TNM stage, lymphovascular invasion, post-treatment and post-surgery albumin levels, and post-treatment systemic immune-inflammation index. One-year disease-free survival area under the curve was 0.86 (95 %CI, 0.75-0.97) in the derivation cohort and 0.75 (95 %CI, 0.50-0.99) in the validation cohort, with good calibration performance. CONCLUSIONS: Pathological staging combined with albumin level and systemic immune-inflammation index could be a superior predictor of survival prognosis in ESCC patients receiving neoadjuvant immunotherapy. The findings of this study yield new evidence regarding the efficacy and safety of neoadjuvant immunotherapy in ESCC and provide a tool for identifying patients at risk of recurrence.

Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy (CAP 04): a single-arm phase II trial.

BACKGROUND: The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer. METHODS: This single-arm Simon's two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle. RESULTS: Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred. CONCLUSIONS: Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors. TRIAL REGISTRATION: This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.

Chronic Use of Abemaciclib Leading to Breathlessness and Demise: A Case Report.

Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal disease that can occur at any duration of treatment. Patients may present with vague respiratory symptoms such as progressive cough, dyspnea, and decreased activity tolerance. Among checkpoint inhibitors, CIP is higher in programmed death 1 (PD-1) inhibitors. An 82-year-old Latina woman with estrogen receptor (ER)-positive human epidermal growth factor receptor (HER)-2-negative lobular carcinoma of the right breast had been treated by partial mastectomy followed by adjuvant hormonal treatment and radiation in 2014. Then CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) was followed by letrozole and abemaciclib, PD-1, therapy in 2022. In 2023, the patient presented with a dry cough and worsening dyspnea with a new oxygen requirement. She was admitted to the hospital with a diagnosis of multifocal pneumonia and sepsis. She unfortunately developed rapidly higher oxygen requirements and acute respiratory distress syndrome (ARDS) and was ultimately presumed to have CIP. She was intubated on hospital day 6 and extubated on day 12 with no plans for reintubation and do-not-resuscitate status. She subsequently had demise after a period of respiratory arrest. CIP is rare but associated with fatal outcomes, especially with the development of ARDS. It is important, along the course of cancer treatment and goals of care discussion, to educate patients and their families on possible side effects of chemotherapy and involve specialists early with the goal of lowering mortality rates. Most patients do not survive this unfortunate progression of disease.

A Patient With Hepatocellular Carcinoma and Lung Metastasis Successfully Underwent Curative Surgery Following the Downstaging Treatment: A Case Report.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Hepatic resection constitutes the major curative treatment option, but a significant proportion of patients are not surgical candidates on initial evaluation. Along with the development of novel therapeutic strategies including targeted therapies and immunotherapies, a few HCCs can achieve tumor downstaging and be curatively resected. A 52-year-old man was diagnosed with HCC with portal vein invasion and extensive pulmonary and lymph node metastasis. Transarterial chemoembolization (TACE) in conjunction with donafenib and sintilimab was given. Primary tumors in the liver largely shrank with almost complete elimination of the lung metastases following treatment. The patient subsequently underwent curative surgery for HCC, and the pathological examination revealed complete necrosis of the tumor. Targeted immunotherapy was continued after surgery and no disease progression was found on the latest follow-up. Advanced HCC with distant metastasis might have an excellent response to combination therapy of TACE with tyrosine kinase-targeted inhibitors and PD-1 blocker, and achieve opportunity for curative surgery. This efficacy may be associated with the remodeling of immune microenvironment and angiogenesis. HCC is extremely heterogeneous, and the response to therapeutics varies among patients. There is a lack of useful biomarkers to predict therapeutic efficacy, which needs further studies.

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].

Efficacy and safety of PD-1 Monoclonal antibodies in the treatment of esophageal squamous cell carcinoma: Systematic review and meta Regression.

Background: Esophageal Squamous Cell Carcinoma (ESCC) contributes to the global burden of disease. Conventional treatments such as surgical resection and chemotherapy offer limited long-term survival rates. Recently, immunotherapies targeting PD-1 have shown promise in other cancers, but their efficacy in ESCC remains unclear. Methods: The 31 studies eligible for this study included a total of 10,681 patients who were subjected to immunotherapy, either alone or in combination with traditional chemotherapy. A comprehensive search was conducted on September 1, 2023, across databases including CENTRAL, PubMed, MEDLINE, Web of Science, Embase, and Scopus. Results: For OSR, results indicate a significantly improved survival at different time points (6, 12, and 24 months), with an odds ratio of 0.636 (95 % CI 0.595-0.680; Z = -13.292; p < 0.00001). In terms of PFS, PD-1 inhibitors demonstrated improvements at different time points; pooled odds ratio was 0.568 (95 % CI 0.511-0.633; Z = -10.357; p < 0.00001). Regarding ORR, the pooled analysis showed an overall odds ratio of 1.724 (95 % CI 1.554-1.913; Z = 10.289; p < 0.00001), indicating improved treatment response. DCR did not suggest a significant advantage for PD-1 inhibitors over chemotherapy, with an odds ratio of 0.904 (95 % CI 0.784-1.043; Z = -1.381; p = 0.167). Conclusions: There is compelling evidence reinforcing the efficacy and safety of PD-1 inhibitors, as monotherapy or in combination with chemotherapy, for the treatment of ESCC. PD-1 inhibitors demonstrate a significant advantage in terms of OSR, PFS, and ORR.

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.

Which Is More Suitable for First-Line Treatment of Extensive-Stage Small Cell Lung Cancer, PD-L1 Inhibitors Versus PD-1 Inhibitors? A Systematic Review and Network Meta-Analysis.

BACKGROUND: In this network meta-analysis (NMA), the efficiency and safety of PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy were compared in the first-line therapy of patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: We searched research databases, conference abstracts, and trial registries and subsequently chose relevant studies and extracted dates. The NMA was conducted to estimate the efficiency and safety of the PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy on overall survival (OS), progression-free survival (PFS), overall remission rate (ORR), and adverse events (AEs). Studies were assessed for quality. Subgroup analyses were used to evaluate study heterogeneity. RESULTS: We included six randomized trials with a total of 3163 patients. Direct comparisons showed that patients who received either PD-1 inhibitors + chemotherapy (HR: 0.71, 95% CI: 0.57-0.87) or PD-L1 inhibitors + chemotherapy (HR: 0.74, 0.61-0.89) demonstrated significantly longer OS than those who received placebo + chemotherapy. The results of the NMA showed that no significant differences in OS (HR 0.96 95% CI: 0.72-1.3), PFS (HR 0.83, 95% CI: 0.51-1.4), and ORR (OR 1.3 95% CI: 0.66-2.5) were observed for PD-1 inhibitors + chemotherapy compared with PD-L1 inhibitors + chemotherapy, but the Bayesian ranking revealed that patients receiving PD-1 inhibitors + chemotherapy tended to have longer OS, PFS benefit, and better treatment response than patients receiving PD-L1 inhibitors + chemotherapy. In terms of safety, no significant difference was observed in their safety profiles. CONCLUSION: In comparison to placebo + chemotherapy, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy significantly improved survival for ES-SCLC. According to the available data, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy had equivalent efficacy and safety; however, the level of evidence of this type of comparison is limited.

[Comparison of Short-term Efficacy of Neoadjuvant Immunotherapy Combined with Chemotherapy and Surgery Alone for Locally Advanced Resectable 
Non-small Cell Lung Cancer].

BACKGROUND: Lung cancer is the cancer with the highest incidence and mortality rates in China, and non-small cell lung cancer (NSCLC) accounts for 80%-85% of all malignant lung tumors. Currently, surgical treatment remains the primary treatment modality for lung cancer. In recent years, the effectiveness of immune checkpoint inhibitors for NSCLC has become a consensus, and neoadjuvant immunochemotherapy (nICT) has shown promising efficacy and safety in early to intermediate stage NSCLC. However, there are fewer studies related to nICT for locally advanced NSCLC. This study aims to evaluate the efficacy and safety of nICT therapy in locally advanced resectable NSCLC. METHODS: 85 confirmed resectable stage IIIA and IIIB patients treated in the Department of Thoracic Surgery, Second Hospital of Lanzhou University, from January 2021 to April 2024, were divided into the nICT group (n=32) and the surgery alone group (n=53). Clinical baseline data, perioperative indicators, postoperative complications, imaging response rate, pathological response rate, incidence of adverse events, and quality of life were compared between the two groups. RESULTS: There were no statistically significant differences in clinical baseline data between the two groups (P>0.05). Incidence of choosing thoracotomy was higher in the nICT group than in the surgery alone group (P=0.002). There were no significant differences in surgical time, intraoperative blood loss, number of dissected lymph nodes, duration of chest tube placement, postoperative hospital stay, and R0 resection rate between the two groups (P>0.05). The overall incidence of postoperative complications was 31.25% in the nICT group and 22.64% in the surgery alone group, with no statistically significant difference (P=0.380). In the nICT group, the objective response rate (ORR) was 84.38%, with 5 cases of complete response (CR)(15.63%), 22 cases of partial response (PR)(68.75%), 15 cases of pathological response rate (pCR)(46.88%), and 11 cases of major pathological reaponse (MPR) (34.38%). During nICT treatment, 12 cases (37.50%) experienced grade 3 treatment-related adverse events, no death induced by adverse events or immune related adverse events. Moreover, the symptoms of the patients were improved after nICT treatment. CONCLUSIONS: Neoadjuvant immunochemotherapy shows promising efficacy in locally advanced resectable NSCLC, with manageable treatment-related adverse events. It is a safe and feasible neoadjuvant treatment modality for locally advanced resectable NSCLC.

Exploring prognostic factors for survival in patients with advanced pancreatic cancer undergoing PD-1 inhibitor immunotherapy.

Immunotherapy, led by programmed cell death protein-1 (PD-1) inhibitors, has emerged as a prominent antitumor therapy, yet prognostic challenges persist in pancreatic cancer (PC). This retrospective, single-center study evaluated prognostic factors in advanced PC patients treated with PD-1 inhibitors at the PLA General Hospital's Oncology Department from 2015-2022. With ethics approval by the Ethics Committee of the General Hospital of the People's Liberation Army (S2021-228-03), we analyzed 126 patients using Kaplan-Meier and Cox models. p < .05 was considered a statistically significant difference. Median overall survival (mOS) and progression-free survival (mPFS) were 12.1 and 4.6 months, respectively. Significant mOS predictors were surgery history (44.2 months vs. 10 months, *p = .022), absence of liver metastases (44.2 months vs. 6.4 months, *p = .034), and baseline CA19-9 ≤ 216.15 U/ml (18.5 months vs. 9.2 months, *p = .049). For mPFS, histologic differentiation (5.5 months vs. 3.2 months, *p = .022) and first-line PD-1 inhibitor use (5.1 months vs. 1.5 months, ***p = .001) were key. Subgroup analyses highlighted early progression in low histologic differentiation and earlier death without surgery. History of surgery, absence of liver metastases, baseline CA19-9 level, and histologic intermediate/high differentiation may predict PD-1 inhibitor efficacy in advanced PC, pending validation in prospective trials.

Impact of PD-1/PD-L1 inhibitors on survival in stage III non-small-cell lung cancer: A systematic review.

Background: Lung cancer is the leading cause of cancer-related death, and non-small-cell lung cancer (NSCLC) is the predominant subtype. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are widely used to treat stage IV NSCLC. This study systematically reviewed the literature to clarify the impact of PD-1/PD-L1 inhibitor treatment on the survival of patients with stage III NSCLC. Methods: Randomized phase III clinical trials of PD-1/PD-L1 inhibitors administered to patients with stage III NSCLC that were written in English and published between November 2012 and November 2022 were eligible for review. The sources of information were the MEDLINE database (last consulted on December 26, 2022), ScienceDirect website (last consulted on December 26, 2022), and CENTRAL register (last consulted on December 27, 2022). The outcomes of interest were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and event-free survival (EFS). Risk of bias assessments were performed according to the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The findings have been assessed for certainty according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Results: Fourteen eligible studies and 2788 participants were included in the review. The key characteristics used to group the participants were disease histology, percentage of PD-L1 expression in cancer cells, and timeline of therapy. OS and PFS were improved (risk ratio [RR]: 0.85; 95% confidence interval [CI]: 0.75-0.96 and RR: 0.75; 95% CI: 0.70-0.86, respectively) based on the use of PD-L1 inhibitors after chemoradiation and OS was improved using first-line PD-1 inhibitors plus chemotherapy in non-squamous NSCLC (RR: 0.40; 95% CI: 0.17-0.95), with the GRADE results indicating moderate quality of evidence. Conclusion: This review highlights the OS and PFS benefits of PD-L1 inhibitors in stage III NSCLC when used after chemoradiation and OS benefits of first-line PD-1 inhibitors added to chemotherapy in non-squamous stage III disease.