Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

Efficacy of immune checkpoint inhibitors differs in various status of carcinoma: a study based on 29 cohorts with 3255 participants.

BACKGROUND: Pre-clinical data have revealed that viral infection, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Human Papilloma virus (HPV), may lead to the development of "hot" or "immune-sensitive" tumors, which may impact the efficacy of immune checkpoint inhibitor (ICIs). Therefore, This study aimed to investigate the impact of viral status on the efficacy of ICIs. METHODS: Electronic databases were searched to identify relevant trials. The primary endpoints were overall survival (OS) and progression-free survival (PFS) measured by hazard ratio (HR). Stratified analyses were accomplished based on viral types, treatment regimens, and patient locations. RESULTS: A total of 3255 participants were recruited, including 252 cases of gastric cancer, 156 cases of nasopharyngeal carcinoma, 1603 cases of hepatocellular carcinoma, and 1244 cases of head and neck squamous cell carcinoma. Pooled results demonstrated a significant association between viral infection and favorable outcomes in patients receiving ICIs, including improved OS [HR = 0.67, 95%CI (0.57-0.79), P < 0.0001], increased ORR [OR = 1.43, 95%CI (1.14-1.80), P = 0.0018], and a trend toward enhanced PFS [HR = 0.75, 95%CI (0.56-1.00), P = 0.05]. In subgroup analyses, patients treated with ICIs who were exposed to HBV/HCV or HPV infection exhibited an evidently superior OS without heterogeneity, compared to those without infection. CONCLUSIONS: This study indicated that the presence of viral infection was evidently associated with improved outcomes in cancer patients undergoing ICIs, particularly in cases of HBV/HCV and HPV infections.

γδ T cells and the PD-1/PD-L1 axis: a love-hate relationship in the tumor microenvironment.

Gamma delta (γδ) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of γδ T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of αß T cells. However, γδ T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on γδ T cells. This understanding can serve as a therapeutic foundation for improving γδ T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.

Acute kidney injury in cancer patients receiving anti-vascular endothelial growth factor monoclonal antibody vs. immune checkpoint inhibitors: a retrospective real-world study.

BACKGROUND: Anti-vascular endothelial growth factor monoclonal antibody (anti-VEGF) or immune checkpoint inhibitors (ICIs) combined with chemotherapy are commonly administered to cancer patients. Although cancer patients receiving anti-VEGF or ICIs have been reported to experience an increased risk of acute kidney injury (AKI), comparative studies on the AKI incidence have not been evaluated. METHODS: Cancer patients receiving anti-VEGF or ICIs were retrospectively selected from the hospital information system of the First Affiliated Hospital of Wenzhou Medical University between Jan, 2020 and Dec, 2022 and were divided into two groups according to the treatment regimen: anti-VEGF group and ICIs group. The baseline characteristics were propensity-score matched. The primary outcome was sustained AKI. A comparison of cumulative incidence of sustained AKI was performed by Kaplan-Meier curves and log-rank test. Risks for outcomes were assessed using Cox proportional regression. RESULTS: A total of 1581 cancer patients receiving anti-VEGF (n = 696) or ICIs (n = 885) were included in the primary analysis. The ICIs group had a higher cumulative incidence of sustained AKI within one year than the anti-VEGF group (26.8% vs. 17.8%, P < 0.001). Among 1392 propensity score matched patients, ICIs therapy (n = 696) was associated with an increased risk of sustained AKI events in the entire population (HR 2.0; 95%CI 1.3 to 2.5; P = 0.001) and especially in those with genitourinary cancer (HR 4.2; 95%CI 1.3 to 13.2; P = 0.015). Baseline serum albumin level (> 35 g/l) was an important risk factor for a lower incidence of sustained AKI in the anti-VEGF group (HR 0.5; 95%CI 0.3 to 0.9; P = 0.027) and the ICIs group (HR 0.3; 95%CI 0.2 to 0.5; P < 0.001). CONCLUSIONS: Among cancer patients in this real-world study, treatment with ICIs increased incidence of sustained AKI in one year. Baseline serum albumin level was an important risk factor for sustained AKI. The risk factors for sustained AKI differed between the anti-VEGF group and the ICIs group. TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov (NCT06119347) on 11/06/2023.

Neuromyelitis optica associated with the use of Atezolizumab in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are a pharmacological group increasingly used in Oncology and Hematology. These treatments can lead to autoimmune complications, with neurological conditions, especially central nervous system (CNS) involvement, being rare. We describe a case of seropositive neuromyelitis optica in a patient with locally advanced lung adenocarcinoma treated with Atezolizumab.

Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

Survival analysis of comprehensive treatment in Chinese patients with metastatic melanoma: A retrospective analysis.

BACKGROUND: Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is limited, mainly due to different pathological subtypes. The patients in western countries are mainly skin melanoma (about 90%), while the acral and mucosal types are dominant in China, accounting for 41.8% and 22.6% respectively. Acral and mucosal melanoma have lower response rates to immunotherapy and chemotherapy. OBJECTIVE: Whether immune checkpoint inhibitors can improve the survival of Chinese patients with malignant melanoma, therefore, we conducted a retrospective analysis. METHODS: We analyzed 53 patients with metastatic melanoma treated in our hospital to evaluate the efficacy and safety of PD-1 mAb in Chinese patients with metastatic melanoma, and performed univariate and multivariate analyses of prognostic factors that may affect overall survival (OS). RESULTS: In a study of 125 patients with advanced malignant melanoma, 53 patients participated, with a median follow-up of 16 months. Among these, 69.8% died, and 30.2% remained on treatment. Median progression-free survival (PFS) was 6 months, and median OS was 19 months. Patients treated with immune checkpoint inhibitors had improved outcomes, with a median PFS of 7 months and a median OS of 24 months. Patients with bone metastasis and aberrant Lactate dehydrogenase (LDH) post-treatment had worse prognoses, while immunotherapy was a protective factor. Subgroup analysis showed the benefits of immunotherapy across various patient characteristics. No unexpected toxicities were observed. CONCLUSION: The study highlights the efficacy of immune checkpoint inhibitors, particularly PD-1 mAb, in improving survival outcomes for Chinese patients with metastatic melanoma.

Impact of immune checkpoint inhibitors (ICIs) therapy on interferon-γ release assay (IGRA) and diagnostic value in non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Tuberculosis (TB), a highly contagious respiratory disease, presents a significant global health threat, with a notable increase in incidence reported by the WHO in 2022. Particularly, the interplay between TB and non-small cell lung cancer (NSCLC) gains attention, especially considering the rising use of immune checkpoint inhibitors (ICIs) in cancer treatment. This interplay may influence TB diagnostics and reactivation, warranting a closer examination. METHODS: A retrospective analysis was conducted on clinical data of NSCLC patients with positive T-SPOT results before undergoing anti-tumor treatment at Zhongshan Hospital (Xiamen), Fudan University, from January 1, 2021 to December 31, 2022. We assessed the incidence of tuberculosis reactivation and treatment outcomes among these patients. Moreover, we compared the differences in tuberculosis activity between the ICIs and non-ICIs treatment groups. Additionally, we observed the changes in T-SPOT spot count before and after immunotherapy, analyzing their association with tuberculosis activity and prognosis. RESULTS: A total of 40 NSCLC patients with positive T-SPOT results before treatment were included in the study, with 26 patients in the ICIs treatment group and 14 patients in the non-ICIs treatment group. The study found no significant differences between the two groups in terms of gender, age, stage, histological type, performance status, driver gene expression, and distant metastasis. With a median follow-up time of 10.0 (6.0-14.5) months, three cases (11.5%) in the ICIs treatment group developed tuberculosis activity, diagnosed at 2, 3, and 12 months after ICIs treatment initiation. Conversely, no tuberculosis activity was observed in the non-ICIs treatment group, and the difference between the two groups was not significant (P = 0.186). Among the 32 patients who received ICIs treatment, spot count dynamics were diverse: four cases (12.5%) showed an increase, 12 cases (37.5%) had no change, and 16 cases (50.0%) had a decrease. During the follow-up, the progression rate (PD) was 50.0%, 75.0%, and 62.5% in the three groups, respectively (P = 0.527). Similarly, the mortality rate was 0%, 25.0%, and 25.0%, respectively (P = 0.106). Interestingly, among the patients with decreased spot counts, three cases (18.75%) were diagnosed with active pulmonary tuberculosis. CONCLUSIONS: For NSCLC patients with a positive T-SPOT response undergoing ICIs treatment, our study observed indications of active tuberculosis. The varied T-SPOT spot count changes post-ICIs treatment suggest a complex interaction, potentially linking T-SPOT spot count reduction to tuberculosis reactivation risk. These preliminary findings underscore the importance of further research to more accurately assess T-SPOT's diagnostic utility in this context.

Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment.

An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment.

As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.

Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

A retrospective real-world study: the efficacy of immune-related combination therapies in advanced non-small cell lung cancer after resistance to EGFR-TKIs.

BACKGROUND: Whether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear. METHODS: We evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments. RESULTS: The ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan-Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis. CONCLUSIONS: This study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy.

Efficacy of immune checkpoint inhibitor monotherapy or combined with other small molecule-targeted agents in ovarian cancer.

Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer.

Myocarditis is a rare immune-related adverse events (irAEs) with high mortality rates, with few reports on its clinical characteristics and prognostic impact. This study designed to explore the associations between cardiac parameters and outcomes of myocarditis in advanced non-small cell lung cancer (NSCLC) who treated with immune checkpoint inhibitor (ICI). Fourteen patients diagnosed with ICI-associated myocarditis by clinicians were admitted to the study analysis. By Cox univariate and multivariate survival analyses, potential risk factors for the development of severe myocarditis were identified. Survival analysis was also performed to explore the prognosis of patients with myocarditis. Among patients with myocarditis, higher B-type natriuretic peptide (BNP) levels (P = 0.04) and conduction block (P = 0.03) were associated with progression to severe myocarditis. In addition, high lactate dehydrogenase (LHD) levels (P = .04) and myocarditis onset within 2 months (P = 0.02) were prognostic factors of severe myocarditis. The median progression-free survival (PFS) time and median overall survival (OS) time for all patients were 5.9 months and 18.5 months, respectively. However, there were no statistical differences between mild and severe cohorts in terms of PFS and OS (PFS: 4.5 vs. 8.5 months, P = 0.17; OS: 21.3 vs. 18.5months, P = 0.36). And we found that the earlier occurrence of myocarditis, worse PFS prognosis (4.5 months vs. 10.5 months, P = 0.008), while no difference in OS (18.5 months vs. 21.3 months, P = 0.35). Compared to mild myocarditis, severe myocarditis presented with higher BNP levels and cardiac conduction abnormalities. In addition, patients with mild and early myocarditis tended to have better survival rates.

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria.

PURPOSE: To investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). METHODS: Sixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients' overall survival (OS). RESULTS: Median patient follow up [95% CI] was 61.5 months [45.3 - 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS. CONCLUSION: In patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information.

Network meta-analysis of first-line immune checkpoint inhibitor therapy in advanced non-squamous non-small cell lung cancer patients with PD-L1 expression ≥ 50.

INTRODUCTION: The optimal first-line immunotherapy regimen for advanced non-squamous non-small cell lung cancer (NS-NSCLC) patients with programmed cell death ligand 1 (PD-L1) expression ≥ 50% remains unclear. Our aim is to determine the most effective treatment regimen through a network meta-analysis (NMA) comparing these treatments. METHODS: A systematic search was performed in PubMed, Cochrane Library, Web of Science, and Embase databases, and a Bayesian network meta-analysis was conducted. To ensure transparency, the study was registered in the International Prospective Register of Systematic Reviews (CRD42022349712). RESULTS: The analysis included 11 randomized controlled trials (RCTs) with 2037 patients and 12 immunotherapy combinations. ICI-ICI, ICI alone, and chemotherapy-ICI showed significant advantages over chemotherapy in terms of overall survival (OS) and progression-free survival (PFS). Pembrolizumab plus chemotherapy showed the best OS results compared to chemotherapy. Tislelizumab plus chemotherapy and sintilimab plus chemotherapy provided the best PFS results. CONCLUSIONS: For NS-NSCLC patients with PD-L1 ≥ 50%, pembrolizumab plus chemotherapy, tislelizumab plus chemotherapy, and sintilimab plus chemotherapy are recommended as good treatment options based on the results of this Network meta-analysis (NMA).

Radiation combined with immune checkpoint inhibitors for unresectable locally advanced non-small cell lung cancer: synergistic mechanisms, current state, challenges, and orientations.

Until the advent of immune checkpoint inhibitors (ICIs), definitive radiotherapy (RT) concurrently with chemotherapy was recommended for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC). The trimodality paradigm with consolidation ICIs following definitive concurrent chemoradiotherapy has been the standard of care since the PACIFIC trial. Preclinical evidence has demonstrated the role of RT in the cancer-immune cycle and the synergistic effect of RT combined with ICIs (iRT). However, RT exerts a double-edged effect on immunity and the combination strategy still could be optimized in many areas. In the context of LA-NSCLC, optimized RT modality, choice, timing, and duration of ICIs, care for oncogenic addicted tumors, patient selection, and novel combination strategies require further investigation. Targeting these blind spots, novel approaches are being investigated to cross the borders of PACIFIC. We discussed the development history of iRT and summarized the updated rationale for the synergistic effect. We then summarized the available research data on the efficacy and toxicity of iRT in LA-NSCLC for cross-trial comparisons to eliminate barriers. Progression during and after ICIs consolidation therapy has been regarded as a distinct resistance scenario from primary or secondary resistance to ICIs, the subsequent management of which has also been discussed. Finally, based on unmet needs, we probed into the challenges, strategies, and auspicious orientations to optimize iRT in LA-NSCLC. In this review, we focus on the underlying mechanisms and recent advances of iRT with an emphasis on future challenges and directions that warrant further investigation. Taken together, iRT is a proven and potential strategy in LA-NSCLC, with multiple promising approaches to further improve the efficacy. Video Abstract.

Traditional Treatment Approaches and Role of Immunotherapy in Lung Malignancy and Mesothelioma.

There is no denying that many revolutions took place in the fight against cancer during the last decades. However, cancers have always managed to find new ways to challenge humankinds. Variable genomic epidemiology, socio-economic differences and limitations of widespread screening are the major concerns in cancer diagnosis and early treatment. A multidisciplinary approach is essentially to manage a cancer patient efficiently. Thoracic malignancies including lung cancers and pleural mesothelioma are accountable for little more than 11.6% of the global cancer burden [4]. Mesothelioma is one of the rare cancers, but concern is the incidences are increasing globally. However, the good news is first-line chemotherapy with the combination of immune checkpoints inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and mesothelioma has showed promising respond and improved overall survival (OS) in pivotal clinical trials [10]. ICIs are commonly referred as immunotherapy are antigens on the cancer cells, and inhibitors are the antibodies produce by the T cell defence system. By inhibiting immune checkpoints, the cancer cells become visible to be identified as abnormal cells and attack by the body's defence system [17]. The programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) inhibitors are commonly used immune checkpoint blockers for anti-cancer treatment. PD-1/PD-L1 are proteins produced by immune cells and mimic by cancer cells that are implicated in inhibiting T cell response to regulate our immune system, which results tumour cells escaping the defence mechanism to achieve immune surveillance. Therefore, inhibiting immune checkpoints as well as monoclonal antibodies can lead to effective apoptosis of tumour cells [17]. Mesothelioma is an industrial disease caused by significant asbestos exposure. It is the cancer of the mesothelial tissue which presents in the lining of the mediastinum of pleura, pericardium and peritoneum, most commonly affected sites are pleura of the lung or chest wall lining [9] as route of asbestos exposure is inhalation. Calretinin is a calcium binding protein, typically over exposed in malignant mesotheliomas and the most useful marker even while initial changes take place [5]. On the other hand, Wilm's tumour 1 (WT-1) gene expression on the tumour cells can be related to prognosis as it can elicit immune response, thereby inhibit cell apoptosis. A systematic review and meta-analysis study conducted by Qi et al. has suggested that expression of WT-1 in a solid tumour is fatal however, it gives the tumour cell a feature of immune sensitivity which then acts positively towards the treatment with immunotherapy. Clinical significance of WT-1 oncogene in treatment is still hugely debatable and needs further attention [21]. Recently, Japan has reinstated Nivolumab in patients with chemo-refractory mesothelioma. According to NCCN guidelines, the salvage therapies include Pembrolizumab in PD-L1 positive patients and Nivolumab alone or with Ipilimumab in cancers irrespective of PD-L1 expression [9]. The checkpoint blockers have taken over the biomarker-based research and demonstrated impressive treatment options in immune sensitive and asbestos-related cancers. It can be expected that in near future the immune checkpoint inhibitors will be considered as approved first-line cancer treatment universally.

Predictors of thyroid adverse events during cancer immunotherapy: a real-life experience at a single center.

BACKGROUND: Thyroid dysfunction is among the most common immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) therapy. Data regarding potential predictors of the development of thyroid irAEs are still limited and sometimes conflicting. PATIENTS AND METHODS: We assessed potential risk factors and clinical outcomes associated with the onset of thyroid irAEs in a cohort of patients with different types of cancer treated with ICIs at a single center. Clinical and biochemical data, including thyroid function tests and autoantibodies at baseline and during treatment, were collected, and the onset of thyroid irAEs was recorded. Patients with thyroid dysfunction and/or under levothyroxine therapy before starting ICI were excluded. RESULTS: 110 patients (80 M, 30 F, aged 32-85 years; 56.4% non-small-cell lung cancer, 87% treated with anti-PD-1) with complete information were included in the study. Among them, 32 (29%) developed thyroid irAEs during ICIs therapy. Primary hypothyroidism was the most common irAEs, occurring in 31 patients (28.18% of the whole cohort), including 14 patients who experienced a transient thyrotoxicosis. About 60% of irAEs occurred within the first 8 weeks of therapy. At multivariate analysis, anti-thyroid autoantibodies positivity at baseline (OR 18.471, p = 0.022), a pre-existing (autoimmune and non-autoimmune) thyroid disorder (OR 16.307, p < 0.001), and a family history of thyroid diseases (OR = 9.287, p = 0.002) were independent predictors of the development of thyroid irAEs. CONCLUSION: Our data confirm the high frequency of thyroid dysfunctions (mostly hypothyroidism) during ICIs, and provide data on valuable predictors of thyroid toxicities that may help clinicians in identifying patients at risk for developing irAEs.