Application Of Immune Checkpoint Inhibitors Research Articles

Tumor Immunology Unveiled: Advances, Challenges, and Future Prospects in Cancer Immunotherapy

Among the most important disciplines in the field of immunology, tumor immunology holds a significant place due to its focus on the interaction between tumors and the immune system. With the advancement of immunotherapy technologies in recent years, tumor immunology has emerged as one of the most exciting areas in cancer research. In this article, we will examine in detail the research progress in tumor immunology, including the mechanisms by which tumor cells evade the immune system, the application of immune checkpoint inhibitors, the development of tumor vaccines and their application in clinical practice, and how the tumor microenvironment impacts immunotherapy.

Prognostic biomarkers for immunotherapy in esophageal cancer.

Esophageal cancer (EC), a common type of malignant tumor, ranks as the sixth highest contributor to cancer-related mortality worldwide. Due to the condition that most patients with EC are diagnosed at advanced or metastatic status, the efficacy of conventional treatments including surgery, chemotherapy and radiotherapy is limited, resulting in a dismal 5-year overall survival rate. In recent years, the application of immune checkpoint inhibitors (ICIs) has presented a novel therapeutic avenue for EC patients. Both ICIs monotherapy and immunotherapy combined with chemotherapy or chemoradiotherapy (CRT) have demonstrated marked benefits for patients with advanced EC. Adjuvant or neoadjuvant therapy incorporating immunotherapy has also demonstrated promising prospects in the context of perioperative treatment. Nonetheless, due to the variable response observed among patients undergoing immunotherapy, it is of vital importance to identify predictive biomarkers for patient stratification, to facilitate identification of subgroups who may derive greater benefits from immunotherapy. In this review, we summarize validated or potential biomarkers for immunotherapy in EC in three dimensions: tumor-cell-associated biomarkers, tumor-immune microenvironment (TIME)-associated factors, and host-associated biomarkers, so as to provide a theoretical foundation to inform tailored therapy for individuals diagnosed with EC.

Predicting resistance and pseudoprogression: are minimalistic immunoediting mathematical models capable of forecasting checkpoint inhibitor treatment outcomes in lung cancer?

Background:The increased application of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 in lung cancer treatment generates clinical need to reliably predict individual patients’ treatment outcomes. Methods:To bridge the prediction gap, we examine four different mathematical models in the form of ordinary differential equations, including a novel delayed response model. We rigorously evaluate their individual and combined predictive capabilities with regard to the patients’ progressive disease (PD) status through equal weighting of model-derived outcome probabilities. Results:Fitting the complete treatment course, the novel delayed response model (R2=0.938) outperformed the simplest model (R2=0.865). The model combination was able to reliably predict patient PD outcome with an overall accuracy of 77% (sensitivity = 70%, specificity = 81%), solely through calibration with primary tumor longest diameter measurements. It autonomously identified a subset of 51% of patients where predictions with an overall accuracy of 81% (sensitivity = 81%, specificity = 81%) can be achieved. All models significantly outperformed a fully data-driven machine learning-based approach. Implications: These modeling approaches provide a dynamic baseline framework to support clinicians in treatment decisions by identifying different treatment outcome trajectories with already clinically available measurement data. Limitations and future directions:Conjoint application of the presented approach with other predictive tools and biomarkers, as well as further disease information (e.g. metastatic stage), could further enhance treatment outcome prediction. We believe the simple model formulations allow widespread adoption of the developed models to other cancer types. Similar models can easily be formulated for other treatment modalities.

Independent risk factor of drug eruption in immune checkpoint inhibitors treated liver cancer patients: high systemic immune-inflammation index

Purpose The clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of liver cancer patients. However, drug eruption associated with ICI monotherapy or combination therapy not only impacts the quality of life and treatment progress of liver cancer patients but also poses a potential threat to their lives. The study aims to investigate the risk factors of drug eruption in liver cancer patients undergoing ICIs in real-world settings. Methods We retrospectively collected data from liver cancer patients who underwent ICI therapies at the Third Affiliated Hospital of Sun Yat-sen University between 2021 and 2022. A propensity score matching (PSM) method was employed to match 31 liver cancer patients with ICI-related drug eruption (drug eruption group) to 228 liver cancer patients without immune-related adverse reactions (control group) in a 1:2 ratio, creating two groups of patients with comparable baseline characteristics. Subsequently, logistic regression analysis was then conducted to analyze the clinical risk factors associated with drug eruption caused by ICIs. Results Before PSM, there were statistically significant differences between the drug eruption group (31 cases) and the control group (228 cases) in two variables: Child-Pugh liver function classification and presence of vascular invasion (both p < 0.05). However, after PSM, no statistically significant differences were found in the clinical variables between the drug eruption group (28 cases) and the control group (52 cases). Univariate analysis revealed significantly higher levels of aspartate amino­transferase, alanine aminotransferase, glutamyl transpeptidase, and systemic immune-inflammation index (SII) and a significantly lower rate of liver cancer resection surgery before immunotherapy in liver cancer patients with drug eruption compared to the control group (p < 0.05). Multivariate analysis indicated that an elevated SII level before immunotherapy was significantly associated with the occurrence of drug eruption in liver cancer patients treated with ICIs (p < 0.05). The predictive performance of SII before immunotherapy in liver cancer patients for ICI-related drug eruption yielded an area under the receiver operator characteristic curve of 0.852, with a critical value of 749.189. Sensitivity and specificity were determined as 85.7% and 75%, respectively (p < 0.05). Conclusions Elevated systemic immune-inflammation index is identified as a risk factor for drug eruption occurrence in liver cancer patients treated with ICI therapies.

Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma.

Chinese expert consensus on the application of immune checkpoint inhibitors in liver transplantation for hepatocellular carcinoma.

Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies.

Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment. Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti-tumor immune response, which may lead to tumor progression by evading immune surveillance. Interrupting co-inhibitory signaling pathways with immune checkpoint inhibitors (ICIs) could reinvigorate the anti-tumor immune response and promote immune-mediated eradication of tumor cells. As a milestone in tumor treatment, ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies, which are in their infancy. Currently, immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies, and novel immune checkpoints, such as signal regulatory protein α (SIRPα) and tumor necrosis factor-alpha-inducible protein 8-like 2 (TIPE2), are constantly being discovered. Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies, especially when used in combination with other strategies, including oncolytic viruses (OVs), neoantigen vaccines, bispecific antibodies (bsAb), bio-nanomaterials, tumor vaccines, and cytokine-induced killer (CIK) cells. Moreover, the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune-related adverse events (irAEs). Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs. This review provided a comprehensive overview of immune checkpoints on different immune cells, the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies, including biomarkers, targets, combination of ICIs with other therapies, mechanisms of resistance to ICIs, and irAEs, which can provide novel insight into the future exploration of ICIs in tumor treatment.

Immune Checkpoint Inhibitors for Pediatric Cancers: Is It Still a Stalemate?

The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.

Characteristics of the tumor microenvironment and therapeutic progress in malignant pleural effusion

Malignant pleural effusion (MPE) can be secondary to various advanced malignant tumors. Although systemic anti tumor therapy may be effective in primary tumors, it cannot reduce the accumulation of MPE in proportion of the patients. The interaction of tumor cells, immune cells, and mesenchymal cells, as well as the abnormal proliferation of tumor-associated blood vessels, together create an immunosuppressive microenvironment for MPE, which promotes the abnormal proliferation of tumor cells and the accumulation of MPE. With the in-depth study of the tumor microenvironment, the application of local systemic anti-tumor therapy with local intrathoracic application of immune checkpoint inhibitors, immune cells, cytokines, and gene-mediated cytotoxic immunotherapy are able to alleviate the immunosuppressive tumor microenvironment and inhibit the accumulation of MPE. This article aimed to describe the tumor microenvironment in MPE and provide clues for identifying novel therapeutic targets.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology . We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a ”fifth pillar”, and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.

Comparison of the efficacy of immunotherapy at different time points during the perioperative period for stage II-III NSCLC.

e20009 Background: The application of immune checkpoint inhibitors (ICIs) in early-stage lung cancer is fraught with unresolved issues, and there are no clinical studies directly comparing the efficacy of ICIs used in neoadjuvant, adjuvant, and neoadjuvant followed by adjuvant therapy across different perioperative time points in non-small cell lung cancer (NSCLC). Consequently, the optimal timing for immunotherapy in surgically resectable NSCLC remains uncertain. Methods: This study encompassed 536 patients with stage II-III NSCLC, diagnosed and treated across multiple centers from January 2019 to December 2022. Clinical data for all patients ultimately included in the study were retrospectively collected. The primary endpoints evaluated were event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) . Secondary endpoints included pathological complete response (pCR) and major pathological response (MPR). Propensity score matching was utilized to mitigate confounding factors, comparing the efficacy of ICIs across different treatment modalities and time dimensions during the perioperative period of lung cancer. Results: The integration of neoadjuvant ICIs with chemotherapy was observed to significantly enhance pCR ( p &lt; 0.001), MPR ( p &lt; 0.001), EFS ( p = 0.002), and OS ( p &lt; 0.001) in comparison to neoadjuvant chemotherapy alone. Similarly, the combination of adjuvant ICIs with chemotherapy markedly improved DFS ( p = 0.034) and OS ( p = 0.021) relative to adjuvant chemotherapy alone. Building on these insights, we further delineated the efficacy of ICIs across distinct temporal dimensions within the perioperative interval, categorizing patients into three groups: neoadjuvant ICIs plus chemotherapy, adjuvant ICIs plus chemotherapy, and a sequential regimen of neoadjuvant followed by adjuvant ICIs plus chemotherapy. The analysis revealed no significant differences in DFS and OS among the three patient groups for stage II NSCLC. In contrast, for stage III NSCLC, both neoadjuvant ( p = 0.015) and sequential treatment approaches ( p = 0.047) demonstrated significantly improved DFS outcomes compared to the adjuvant protocol, with no substantial statistical difference noted between the neoadjuvant and sequential treatments ( p = 0.274). Furthermore, the sequential regimen outperformed the adjuvant strategy in OS ( p = 0.020). However, when comparing the neoadjuvant strategy with either the adjuvant ( p = 0.054) or sequential approaches ( p = 0.717), there were no statistically significant variances detected. Conclusions: For individuals with resectable stage III NSCLC, perioperative administration of neoadjuvant and sequential adjuvant ICIs appears to confer enhanced survival advantages. Future efforts should focus on refining treatment strategies for early-stage NSCLC, aiming to deliver enhanced survival benefits to patients.

Impact of regulatory t cells in peripheral blood on pathological complete response in patients with locally advanced gastric or gastroesophageal junction cancer undergoing neoadjuvant chemoimmunotherapy.

e16081 Background: Neoadjuvant chemotherapy has become the standard treatment for locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. With the widely clinical application of immune checkpoint inhibitors, represented by anti-PD-1 antibodies, an increasing number of patients with locally advanced G/GEJ cancer are undergoing neoadjuvant chemoimmunotherapy. However, there is currently no effective predictive marker for neoadjuvant chemoimmunotherapy in locally advanced G/GEJ cancer. We explored the role of peripheral blood regulatory T (Treg) cells in patients with locally advanced G/GEJ cancer. Methods: We retrospectively analyzed lymphocyte subpopulations before and after treatment in patients with locally advanced G/GEJ cancer who received neoadjuvant chemotherapy combined with anti-PD-1 antibodies and curative surgery. Inclusion criteria were: 1) Pathologically confirmed adenocarcinoma of the G/GEJ; 2) Clinically staged as gastric cT3-4 or N+ without distant metastasis by enhanced CT and endoscopic ultrasound examination; 3) Patients requiring neoadjuvant treatment according to gastric cancer multidisciplinary team decisions; 4) Receipt of neoadjuvant treatment with chemotherapy combined with PD-1 antibodies; 5) Completion of 3-4 cycles of treatment; 6) Underwent curative resection; 7) Lymphocyte subpopulation testing performed before the first and second cycles. Results: From July 1, 2020, to May 31, 2023, 85 patients were included. All 85 patients underwent D2 radical surgery and achieved R0 resection, with 21 patients achieving pathological complete response (pCR), resulting in a pCR rate of 24.7% (95% confidence interval (CI) 15.3-34.1%). There were no statistically significant differences in baseline characteristics between the pCR and non-pCR groups. There were no statistically significant differences in lymphocyte subpopulations between the baseline pCR and non-pCR patient groups. After one cycle of treatment (before the second cycle), there were statistically significant differences in lymphocytes, T lymphocytes, and Treg cells between the two groups. Further analysis of the absolute changes in lymphocyte subpopulations before and after one cycle of treatment revealed a greater decrease in Treg cells in the pCR group. Based on the increase or decrease in Treg cells after one cycle of treatment, the 85 patients were divided into Treg cell increase and decrease groups. The pCR rate was 11.4% (4/35, 95% CI 0.3-22.5%) in the Treg cell increase group and 34% (17/50, 95% CI 20.4-47.6%) in the Treg cell decrease group, with a statistically significant difference between the two groups ( P= 0.022). Conclusions: In locally advanced G/GEJ cancer, changes in Treg cells after one cycle of neoadjuvant treatment may serve as a predictive marker for achieving pCR.

Application of immune checkpoint inhibitors for resectable gastric/gastroesophageal cancer.

Gastric/gastroesophageal junction (G/GEJ) cancer represents a significant global health challenge. Radical surgery remains the cornerstone of treatment for resectable G/GEJ cancer. Supported by robust evidence from multiple clinical studies, therapeutic approaches, including adjuvant chemotherapy or chemoradiation, and perioperative chemotherapy, are generally recommended to reduce the risk of recurrence and enhance long-term survival outcomes post-surgery. In recent years, immune checkpoint inhibitors (ICIs) have altered the landscape of systemic treatment for advanced or metastatic G/GEJ cancer, becoming the standard first-line therapy for specific patients. Consequently, exploring the efficacy of ICIs in the adjuvant or neoadjuvant setting for resectable G/GEJ cancer is worthwhile. This review summarizes the current advances in the application of ICIs for resectable G/GEJ cancer.

Surgical management of gastric cancer in the era of immunotherapy

With the widespread application of immune checkpoint inhibitors, chemotherapy combined with immunotherapy has shown promising efficacy in the treatment of various cancers. Especially gastric cancer, this strategy is gradually expanding from first-line treatment in advanced stages to perioperative management. Compared to neoadjuvant chemotherapy alone, the combined approach not only improves pathological regression but also leads to better downstaging, which is particularly significant in gastric cancer subsets that are HER2-positive, mismatch repair deficient, PD-L1 combined positive score ≥5, or EB virus-positive. This combined treatment has made it possible to reduce the extent of gastrectomy, perform function-preserving surgeries, or even consider non-surgical strategies. Currently, exploring the optimal protocols for combining immune checkpoint inhibitors with chemotherapy, identifying potential indications for function-preserving surgery, improving surgical methods, and developing non-surgical strategies represent key issues in the surgical management of gastric cancer in the era of immunotherapy.

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice. Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality. The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs. These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

Non–small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BackgroundImmunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC.MethodsThe clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained.ResultsA total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17–29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018–2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001–1.003, p < 0.001).ConclusionsAmong patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma

BackgroundThe clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms.MethodsThe potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue.ResultsHLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors.ConclusionsHLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Effect of immune checkpoint inhibitors at different treatment time periods on prognosis of patients with extensive-stage small-cell lung cancer.

The application of immune checkpoint inhibitors (ICIs) in treating patients with extensive-stage small-cell lung cancer (ES-SCLC) has brought us new hope, but the real-world outcome is relatively lacking. Our aim was to investigate the clinical use, efficacy, and survival benefit of ICIs in ES-SCLC from real-world data analysis. A retrospective analysis of ES-SCLC patients was conducted between 2012 and 2022. Progression-free survival (PFS) and overall survival (OS) were assessed between groups to evaluate the value of ICIs at different lines of treatment. PFS1 was defined as the duration from initial therapy to disease progression or death. PFS2 was defined as the duration from the first disease progression to the second disease progression or death. One hundred and eighty patients with ES-SCLC were included. We performed landmark analysis, which showed that compared to the second-line and subsequent-lines ICIs-combined therapy group (2SL-ICIs) and non-ICIs group, the first-line ICIs-combined therapy group (1L-ICIs) prolonged OS and PFS1. There was a trend toward prolonged OS in the 2SL-ICIs group than in the non-ICIs group, but the significance threshold was not met (median OS 11.94months vs. 11.10months, P = 0.14). A longer PFS2 was present in the 2SL-ICIs group than in the non-ICIs group (median PFS2 4.13months vs. 2.60months, P < 0.001). First-line ICIs plus chemotherapy should be applied in clinical practice. If patients did not use ICIs plus chemotherapy in first-line therapy, the use of ICIs in the second line or subsequent lines of treatment could prolong PFS2.

Progress of lymphocyte activation gene 3 and programmed cell death protein 1 antibodies for cancer treatment: A review.

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5years, ranging from 34 to 72. The median follow-up time was 12.3months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.

Abstract 7527: Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients

Abstract Background: The application of immune checkpoint inhibitors (ICIs) as adjuvant therapy post-lung cancer surgery is expected to confer significant benefits. However, the risk factors for severe immune-related adverse events (irAEs) remain incompletely understood, and managing irAEs may require long-term steroid use. The identification of biomarkers for irAEs in patients with surgically resected lung cancer is an urgent need. Methods: We analyzed 43 lung cancer patients who received ICI treatment for recurrence postoperatively. Macrodissection of lung cancer lesions was performed on FFPE specimens from resected lungs, from which total RNA was extracted. We conducted gene expression analysis of 770 immune-related genes using the PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle, WA, USA). The relationship between gene expression changes and irAEs or the efficacy of ICI treatment was examined. For validation, immunostaining of proteins strongly associated with irAEs was performed to determine their expression status in tissue specimens. Results: Among the 43 patients (30 males, 13 females, median age 68), 28 had adenocarcinoma, and 15 had squamous cell carcinoma. PD-L1 positivity was observed in 36 patients. The treatment regimens included pembrolizumab monotherapy for 18 patients and combination immunotherapy for 25 patients, with 25 patients responding to treatment and 7 developing irAEs. There was a marked difference in gene expression between adenocarcinoma and squamous cell carcinoma, with a notably higher number of tumor-infiltrating lymphocytes (TILs) in adenocarcinoma. An increase in TILs was observed in cases with irAEs across both cancer types. Additionally, an increased CD8/Treg ratio and CD8/exhausted T cell ratio were noted in adenocarcinomas with irAEs. A strong correlation between IRF5 gene expression and the occurrence of irAEs in adenocarcinoma was also confirmed by immunohistochemistry. Conclusion: We have identified tumor immune microenvironments correlated with the onset of irAEs following ICI treatment in patients with postoperative recurrence of lung cancer. This discovery could contribute to perioperative treatment strategies and improve our understanding of tumor immune mechanisms. Citation Format: Yujin Kudo, Jun Matsubayashi, Satoshi Takahashi, Masaru Hagiwara, Masatoshi Kakihana, Toshitaka Nagao, Tatsuo Ohira, Norihiko Ikeda. Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7527.