The effects of immune checkpoint inhibitors vs. chemotherapy combined with brain radiotherapy in non-small cell lung cancer patients with brain metastases.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent form of cancer, often leading to brain metastases (BM) and a significant decline in patient prognosis. Whether immune checkpoint inhibitors (ICIs) combined with brain radiotherapy is superior to conventional chemotherapy combined with brain radiotherapy in those patients remains to be explored. MATERIALS AND METHODS: Our study enrolled 161 NSCLC patients with BM who underwent either ICIs combined with brain radiotherapy or chemotherapy combined with brain radiotherapy. End points included overall survival (OS), progression-free survival (PFS), intracranial PFS (IPFS), and extracranial PFS (EPFS). Univariate and multivariate Cox regressions were employed to identify prognostic risk variables. RESULTS: Patients receiving ICIs combined with brain radiotherapy exhibited significantly longer OS compared to those receiving chemotherapy combined with brain radiotherapy (34.80 months vs. 17.17 months, P = 0.005). In the Cox regression analysis, chemotherapy combined with brain radiotherapy (HR, 1.82; 95% CI, 1.09-3.05; P = 0.023), smoking (HR, 1.75; 95% CI, 1.02-2.99; P = 0.043) and squamous cell carcinoma (HR, 2.59; 95% CI, 1.31-5.13; P = 0.006) were associated with a worse prognosis. After propensity score matching (PSM), this finding remained consistent with before PSM (43.73 months vs. 17.17 months, P = 0.018). Squamous cell carcinoma (HR, 2.46; 95% CI, 1.15-5.26; P = 0.021) and CT + RT (HR, 2.11; 95% CI, 1.15-3.88; P = 0.016) were associated with a less favorable prognosis. CONCLUSION: The study suggests that the combination of ICIs and brain radiotherapy provides superior OS for NSCLC patients with BM, compared to the chemotherapy combined with brain radiotherapy.

The administration of immune checkpoint inhibitors via an elastomeric pump versus conventional intravenous infusion: an economic perspective.

BACKGROUND: Recent studies have underscored the potential of innovative administration methods to mitigate the capacity burden on healthcare systems, without compromising the quality of care. This study assessed and compared the resource utilization and associated costs of two distinct administration modes of immune checkpoint inhibitors: the innovative elastomeric pump and conventional intravenous infusion. This comparison can inform sustainable healthcare practices and healthcare decision-making to optimize treatment efficiency in an era of escalating healthcare demands. METHODS: In this micro-costing study, data on resource use and time allocation for drug preparation and administration were collected using an observational, non-interventional study design. Data were registered at the oncology daycare unit and hospital pharmacy. Cost categories included drug acquisition, disposable materials, healthcare professional time for drug administration, drug preparation, and patient time spent at the oncology day care unit. RESULTS: Drug administration through the elastomeric pump resulted in substantially lower healthcare costs when compared to conventional infusion, particularly due to reduced labor and chair time. The elastomeric pump reduced the total chair time by 78% and nurse time by 55%. Total average costs (excluding drug costs) were €103,47 and €77.99 for conventional infusion and the elastomeric pump, respectively, showcasing potential savings of €25.48 (P < 0.001) per administration. CONCLUSIONS: This study demonstrated that the elastomeric pump not only offers substantial cost savings but also enhances the treatment capacity of the oncology day care unit. These findings support the adoption of the elastomeric pump in clinical settings as a cost-saving and efficient alternative to conventional infusion. TRIAL REGISTRATION: This study has been registered in the National Trial Register (NTR), with the reference number NTR NL9473. Registration date: 05-05-2021.

Fc-optimized checkpoint antibodies for cancer immunotherapy.

The development of checkpoint antibodies for cancer therapy has been guided by the principle of blocking T cell inhibitory signals. Recognition of the role of the Fc domain in therapeutic activities, through the depletion of immunosuppressive populations and myeloid cell activation, prompts a shift toward the development of optimized Fc-engineered checkpoint antibodies.

Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study.

Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies.

Immune checkpoint inhibitors-related thyroid dysfunction: influencing factor analysis, prediction model development, and management strategy proposal.

BACKGROUND: With the extensive utilization of immune checkpoint inhibitors (ICIs) across various cancers, ICIs-related thyroid dysfunction (ICI-TD) has become a growing concern in clinical practice. This study aimed to devise an individualized management strategy for ICI-TD to enhance the early identification and proactive management in cancer patients. METHODS: We designed and conducted a three-phase study. Initially, we analyzed the influencing factors through a systematic review and meta-analysis, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Moreover, the study protocol was registered with PROSPERO (CRD42019131133). Subsequently, prediction models for ICI-TD were developed utilizing 11 algorithms based on the real-world cohort data from July 20, 2018 (the approval date of the first ICIs, Pembrolizumab in China), to October 31, 2022. Considering discrimination, calibration, and clinical utility, we selected the model with the best performance for web calculator development. Finally, individualized management strategies for ICI-TD were proposed by combining evidence-based analysis with practical considerations. RESULTS: The systematic review encompassed 21 observational studies involving 4,145 patients, revealing associations between ICI-TD and factors such as female gender, age, receipt of Pembrolizumab (versus other ICIs), and baseline levels of thyroid-stimulating hormone, free thyroxine, and antithyroid antibodies. In the prediction model development phase, 621 participants were enrolled, with 36 patients developing ICI-TD. The model based on the LightGBM algorithm demonstrated superior performance, leading to the development of a web calculator. Based on these findings and existing guidelines, individualized monitoring and treatment pathways for pharmacists were devised. CONCLUSION: This study offers comprehensive insights into managing ICI-TD, potentially enhancing tailored cancer immunotherapy management.

Transarterial chemoembolization combined with molecular targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma beyond the up-to-seven criteria: a propensity score-matching analysis.

PURPOSE: Not all patients benefit from transarterial chemoembolization (TACE) due to the heterogeneity of the tumour burden in intermediate-stage hepatocellular carcinoma (HCC). To compare the outcomes of transarterial chemoembolization (TACE) combined with molecular-targeted agents plus immune checkpoint inhibitors (TACE-MTAs-ICIs) with those of TACE for patients with unresectable hepatocellular carcinoma (uHCC) that were beyond the up-to-seven criteria. PATIENTS AND METHODS: Between January 2019 and July 2022, 130 patients diagnosed with uHCC beyond the up-to-seven criteria were retrospectively identified, including 47 patients who received TACE-MTAs-ICIs and 83 patients who received TACE alone. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included tumour response and adverse events (AEs). RESULTS: There were 43 matched patients. The median OS and PFS times in the TACE-MTAs-ICIs group were significantly longer than those in the TACE group (OS: 27.2 vs. 15.9 months, p = 0.007; PFS: 15.4 months vs. 4.8 months, p < 0.001). The objective response rate (ORR) in the TACE-MTAs-ICIs group was higher than that in the TACE group (65.1% vs. 37.2%, p = 0.010). Reversible AEs (grade 3 or 4) occurred differently in TACE-MTAs-ICIs and TACE groups (83.7% vs. 51.2%, p = 0.001). Univariate and multivariate analyses revealed that TACE-MTAs-ICIs treatment was an independent favourable prognostic factor for both PFS and OS (p < 0.001). CONCLUSION: For uHCC patients beyond the up-to-seven criteria, TACE-MTAs-ICIs provided superior ORR and OS. Early combined TACE and systemic treatment should shift for patients who are beyond these criteria.

The ORR and median OS reached 65.1% and 27.2 months, respectively, in the treatment model of TACE-MTAs-ICIs for patients with unresectable HCC that were beyond the up-to-seven criteria.TACE-TKI-ICI yielded a synergistic effect on these patients and was an independent favourable prognostic factor for PFS and OS.

Immune checkpoint inhibitors for patients with metastatic triple-negative inflammatory breast cancer (INCORPORATE): An international cohort study.

BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive clinical presentation of breast cancer, recapitulating a specific biology with more immune-vulnerability than non-IBC. Patients with metastatic, triple-negative IBC (mTN-IBC) receive immune checkpoint inhibitors (ICIs) and chemotherapy, similarly to patients with triple-negative non-IBC. However, the benefit derived from ICI incorporation in this rare type of breast cancer is unknown. METHODS: We conducted a multicenter, international, retrospective, cohort study to evaluate the activity of ICIs in patients with metastatic, triple-negative, primary IBC, who received ICIs plus first line chemotherapy from January 2015 to April 2023. A sample size of 42 patients allowed to detect an increase in 6-months real-world progression-free survival (rwPFS) rate from 40 % with only chemotherapy to 60 % with ICI and chemotherapy. RESULTS: 41 patients from eight international IBC referral centers were included (61 % with primary, de novo mTN-IBC, 61 % with visceral disease). All received ICIs plus first line chemotherapy and 24 % underwent breast surgery and/or locoregional radiotherapy. After a median follow-up of 19.3 months, the 6-months rwPFS rate was 30 % (95 % Confidence Interval [CI], 17-45 %), the median rwPFS was 3.3 months (95 % CI: 2.2-5.4), the median overall survival was 15.7 months (95 % CI: 6.8-16.3). CONCLUSIONS: This one-sample analysis showed a poor outcome of patients with mTN-IBC, despite the treatment with ICI, in contrast with the expected benefit based on preclinical evidence of immune-vulnerability of IBC. These results suggest the need to further investigate the role of immunotherapy in this aggressive and rare type of breast cancer presentation.

Unraveling the Impact of Sarcopenia-Induced Lymphopenia on Treatment Response and Prognosis in Patients with Stage III Non-Small Cell Lung Cancer: Insights for Optimizing Chemoradiation and Immune Checkpoint Inhibitor.

PURPOSE: Sarcopenia is a poor prognostic factor in non-small cell lung cancer (NSCLC). However, its prognostic significance in patients with NSCLC receiving immune checkpoint inhibitors (ICIs) and its relationship with lymphopenia remain unclear. We aimed to investigate the prognostic role of sarcopenia and its effect on lymphocyte recovery in patients with stage III NSCLC treated with concurrent chemoradiotherapy (CCRT) followed by ICI. MATERIALS AND METHODS: We retrospectively evaluated 151 patients with stage III NSCLC who received definitive CCRT followed by maintenance ICI between January 2016 and June 2022. Sarcopenia was evaluated by measuring the skeletal muscle area at the L3 vertebra level using computed tomography scans. Lymphocyte level changes were assessed based on measurements taken before and during CCRT and at 1, 2, 3, 6, and 12 months post-CCRT completion. RESULTS: Even after adjusting for baseline absolute lymphocyte count through propensity score-matching, patients with pre-radiotherapy (RT) sarcopenia (n=86) exhibited poor lymphocyte recovery and a significantly high incidence of grade ≥3 lymphopenia during CCRT. Pre-RT sarcopenia and grade ≥3 lymphopenia during CCRT emerged as prognostic factors for overall survival and progression-free survival, respectively. Concurrent chemotherapy dose adjustments, objective response after CCRT, and discontinuation of maintenance ICI were also analyzed as independent prognostic factors. CONCLUSION: Our results demonstrated an association between pre-RT sarcopenia and poor survival, concurrent chemotherapy dose adjustments, and impaired lymphocyte recovery after definitive CCRT. Moreover, CCRT-induced lymphopenia not only contributed to poor prognosis but may have also impaired the therapeutic efficacy of subsequent maintenance ICI, ultimately worsening treatment outcomes.

Complete and long-lasting response to immunotherapy in a stage IV non-small cell lung cancer with brain metastasis.

Approximately 20% of lung cancer patients have brain metastasis at diagnosis, which is associated with a worse prognosis and a negative impact on quality of life. The emergence of new systemic treatment options such as immune checkpoint inhibitors (ICI) and targeted therapies changed the prognosis for stage IV lung cancer patients. However, the impact of local and systemic treatment sequencing in patients with stage IV lung cancer and brain metastasis is still unclear. We present the case of a 51-year-old man with stage IV non-small cell lung cancer and brain metastasis at diagnosis who underwent whole brain radiotherapy (WBRT) and achieved intracranial and extracranial complete response after second-line treatment with an ICI. Currently, the patient has an overall survival of 87 months and a progression-free survival of 73 months with an optimal quality of life. We hypothesized that treatment sequencing of WBRT and immunotherapy could explain this unexpected outcome.

Prediction of PD-L1 expression in unresectable hepatocellular carcinoma with gadoxetic acid-enhanced MRI.

OBJECTIVES: To develop a model to predict programmed death-ligand 1 (PD-L1) expression in unresectable hepatocellular carcinoma (HCC) based on gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings and clinical characteristics. MATERIALS AND METHODS: We enrolled patients with unresectable HCC who underwent gadoxetic acid-enhanced MRI between January 2021 and May 2023. Immunohistochemical staining of PD-L1 was performed on a biopsy specimen. Patients with a history of any prior treatment for HCC or those lacking an MRI scan within 30 days of the biopsy date were excluded. Using the clinical and MRI findings, we developed a PD-L1 prediction score using logistic regression. RESULTS: This study included 49 patients with HCC (median age, 64 years; interquartile range, 57-73 years; 44 men). Among these, 15 (31 %) were positive for PD-L1 expression. The PD-L1 prediction score was defined as the sum of arterial phase hypoenhancement (score 1), necrosis (score 1), and AFP >4000 ng/mL (score 2). The AUC value of the PD-L1 prediction score was 0.838 (95 % confidence interval [CI], 0.715-0.962). When the PD-L1 prediction score was ≥3, the sensitivity, specificity, and positive predictive value of PD-L1 positivity were 67 %, 91 %, and 77 %, respectively. CONCLUSION: We developed a PD-L1 prediction score for unresectable HCC with high specificity that could potentially contribute to the identification of effective candidates for immune checkpoint inhibitors.

Efficacy and safety of HAIC-FOLFOX plus tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for unresectable advanced hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries. However, further investigation is necessary to assess the efficacy and safety of this triple therapy. METHOD: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies conducted within the past 5 years on HAIC combined with immunotherapy and targeted therapy as first-line treatment for advanced HCC. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted this meta-analysis. Additionally, the quality of included studies was assessed using the Joanna Briggs Institute (JBI) scale. Outcomes such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)were extracted and pooled from eligible studies. RESULT: Twelve studies involving 1072 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 65.7% (95% CI, 58.7%-72.7%) (I2 = 83%, P = 0.000) and 89.2% (95% CI, 83.9%-93.6%) (I2 = 83%, P = 0.000), respectively. When analyzing PFS, the upper limit of 95% confidence interval of PFS in one study was not reached, which could potentially impact the statistical analysis. Therefore, we analyzed the remaining 11 studies a total of 1019 patients to pool mPFS, ultimately the pooled mPFS was 9.77months (95% CI, 7.73-11.80) (I2 = 93.9%, P = 0.000). Follow-up time in some studies was insufficient, only eight studies reported OS, we systematically analyzed these eight studies and extracted the pooled mOS was 16.65 months (95% CI, 14.17-19.14) (I2 = 76.9%, P = 0.000). In terms of safety, the incidence rates of any grade AEs, ranked from high to low, were as follows: aminotransferase increased (61.3%), nausea and vomiting (40.5%), hypertension (37.8%), thrombocytopenia (37.4%), hyperbilirubinemia (36.7%), abdominal pain (35.6%), leukopenia (34.6%), hypothyroidism (19.0%), rash (14.4%). Grade 3-4 AEs ranked from high to low were as follows: aminotransferase increased (10.8%), thrombocytopenia (7.9%), hypertension (7.4%), leukopenia (5.0%). No treatment-related deaths occurred, patients receiving this triple therapy demonstrated favorable tolerability. CONCLUSION: The combination of hepatic arterial infusion chemotherapy with tyrosine kinase inhibitors and immune checkpoint inhibitors as a first-line therapy for unresectable advanced HCC demonstrates promising therapeutic efficacy and favorable safety.

Respiratory adverse effects in patients treated with immune checkpoint inhibitors in combination with radiotherapy: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to assess the risk of respiratory adverse effects in patients with solid tumors treated with immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 inhibitors) in combination with radiation therapy. METHODS: We selected eligible studies through the following databases: PubMed, Embase, Cochrane Library, and Clinicaltrials ( https://clinicaltrials.gov/ ). The data was analyzed by using Rstudio. RESULTS: Among 3737 studies, 26 clinical trials, including 2670 patients, were qualified for the meta-analysis. We evaluated the incidence rates of adverse respiratory events, including cough, pneumonia, upper respiratory tract infections, and others: grades 1-5 cough, 0.176 (95%CI: 0.113-0.274, I2 = 92.36%); grades 1-5 pneumonitis, 0.118 (95%CI: 0.067-0.198, I2 = 88.64%); grades 1-5 upper respiratory tract infection, 0.064 (95%CI: 0.049-0.080, I2 = 0.98%); grades 3-5 cough, 0.050 (95%CI: 0.012-0.204, I2 = 8.90%); grades 3-5 pneumonitis, 0.052 (95%CI: 0.031-0.078, I2 = 83.86%); grades 3-5 upper respiratory tract infection, 0.040 (95%CI: 0.007-0.249, I2 = 45.31%). CONCLUSIONS: Our meta-analysis demonstrated that ICI combined with radiotherapy for solid tumors can produce respiratory adverse effects. ICIs combination treatment, a tumor located in the chest, is more likely to cause adverse reactions, and SBRT treatment and synchronous treatment will bring less incidence of adverse reactions. This study provide insights for clinicians to balance the risks of radiotherapy in the course of treating oncology patients.

Higher Nodal expression is often associated with poorer survival in patients diagnosed with melanoma and treated with anti-PD1 therapy.

Advanced melanoma is considered the most aggressive and deadly form of skin cancer whose incidence has been rising over the past three decades. In the absence of treatment, the median overall survival for advanced-stage metastatic disease is less than 6 months. Although most melanomas detected at an early stage can be cured with surgery, a subset of these eventually metastasize. Therefore, a critical need exists to identify unique molecular features that would be predictive of long-term outcome and response to specific therapies. Recent promising therapeutic regimens have included the use of immune checkpoint inhibitors, such as anti-PD1 antibodies. However, the ability to identify responders and non-responders to this therapy remains elusive. To address this challenge at the molecular level, previously our laboratory identified the emergence of a stem cell phenotype associated with advanced melanoma and other aggressive forms of cancer. Underlying this phenotype is the aberrant re-expression of the embryonic morphogen "Nodal". Particularly noteworthy, we have observed Nodal to remain in advanced tumors of non-responders to standard-of-care therapies (i.e., BRAFi). This pilot study is the first proof-of-principle attempt to predict treatment response survival outcome in a small cohort of melanoma patients receiving anti-PD1 immune checkpoint inhibitor therapy - based on their Nodal expression profile. Using advanced multiplex immunohistochemistry-based digital pathology, the major finding of this preliminary study indicates that higher Nodal expression is often associated with poorer overall survival after anti-PD1 therapy, reaching nearly statistical relevance.

Role of Immunotherapy in the Management of Advanced Hepatocellular Carcinoma: A Systematic Review.

INTRODUCTION: The most prevalent histologic subtype of primary liver cancer, hepato-cellular carcinoma, is also the third most lethal malignancy worldwide and a significant cause of cancer death. When diagnosed, it is frequently too late for curative therapies. To add to the difficulty, it is resistant to conventional systemic therapies like chemotherapy. METHOD: Re-cently, more attention has been given to the use of immunotherapy for this condition. Immuno-therapy has had a major impact on the outcome of several malignancies; several studies have revealed the potential role of immunotherapy in advanced hepatocellular carcinoma. To provide an overview of the current literature, justification, and clinical evidence for the use of immuno-therapy in advanced hepatocellular carcinoma, we employed a systematic literature review (SLR) approach in this work. Additionally, we explored the benefits and rationales of various treatment combinations and described the molecular mechanisms behind resistance to a number of immunotherapy drugs. RESULTS: A total of 188 articles from credible journals published be-tween 2013 and August 7, 2023, were screened. Eight of those articles were chosen for in-depth study. This systematic review concluded that the current immunotherapeutic approaches have the potential to improve outcomes for aHCC patients; however, several clinical and biological hurdles have to be overcome, and predictive markers are still eagerly needed. CONCLUSION: To fully realize the potential of immunotherapy agents and their combination therapies to enhance health outcomes for patients with aHCC, additional investigation and research are required.

A Review of Immunotherapy for Head and Neck Cancer.

The introduction of immune checkpoint inhibitors (ICIs) to oncological care has transformed the management of various malignancies, including head and neck squamous cell carcinoma (HNSCC), offering improved outcomes. The first-line treatment of recurrent and malignant HNSCC for many years was combined platinum, 5-fluorouracil, and cetuximab. Recently, the ICI pembrolizumab was approved as a first-line treatment, with or without chemotherapy, based on tumor and immune cell percentage of programmed-death ligand 1 (PD-L1). Multiple head and neck (HN) cancer trials have subsequently explored immunotherapies in combination with surgery, chemotherapy, and/or radiation. Immunotherapy regimens may be personalized by tumor biomarker, including PD-L1 content, tumor mutational burden, and microsatellite instability. However, further clinical trials are needed to refine biomarker-driven protocols and standardize pathological methods to guide combined regimen timing, sequencing, and deescalation. Gaps remain for protocols using immunotherapy to reverse oral premalignant lesions, particularly high-risk leukoplakias. A phase II nonrandomized controlled trial, using the ICI nivolumab, showed a 2-y cancer-free survival of 73%, although larger trials are needed. Guidelines are also needed to standardize the role of dental evaluation and care before, during, and after immunotherapy, specifically in regard to oral immune-related adverse events and their impact on cancer recurrence. Standardized diagnostic and oral care coordination strategies to close these gaps are needed to ensure continued success of HN cancer immunotherapy.

Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma.

Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.

A comprehensive review of immune checkpoint inhibitors for cancer treatment.

Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

Resolution of Immune Checkpoint Inhibitors-Induced Inflammatory Arthritis while Maintaining Active Treatment with Checkpoint Inhibitors and After Its Discontinuation: an Observational Study.

INTRODUCTION: Immune checkpoint inhibitors-induced inflammatory arthritis (ICI-IA) affects about 5% of ICI recipients. We aimed 1) to characterize the resolution of ICI-IA during ICI treatment and after ICI discontinuation and 2) to assess how ICI-IA influences ICI management across time. METHODS: All ICI-treated patients referred to rheumatology at Bordeaux University Hospital were identified and patients with ICI-IA with a follow-up of ≥ 6 months after ICI-IA onset were included. Resolution of ICI-IA was defined by discontinuation of ICI-IA medications without recurrence of ICI-IA symptoms. RESULTS: Resolution of ICI-IA occurred in 13 of 80 patients (16%) while maintaining active ICI treatment, mainly in patients with polymyalgia rheumatica (PMR)-like clinical presentation (p=0.03). Synovitis was more frequent in those whose ICI-IA persisted throughout ICI treatment. In patients with persistent ICI-IA throughout ICI treatment, 34 (50%) and 47 (70%) resolved at 6- and 12-months post ICI discontinuation, respectively. Reason for terminating ICI was more frequently cancer stable or in remission in those who still had active ICI-IA at 6- and 12- months post ICI discontinuation. Both progression-free survival and overall survival were longer in the groups with active ICI-IA at 6- and 12-months after ICI discontinuation. DISCUSSION: In this cohort, ICI was safely continued in most patients experiencing ICI-IA. About one sixth of ICI-IA resolved despite maintaining active ICI treatment and allowing ICI-IA treatment discontinuation without recurrence of symptoms, mainly in those with PMR-like presentation. Larger studies are needed to determine predicting factors of resolving ICI-IA to minimize exposure to immunosuppressive treatment.

Optimized patient-specific immune checkpoint inhibitor therapies for cancer treatment based on tumor immune microenvironment modeling.

Enhancing patient response to immune checkpoint inhibitors (ICIs) is crucial in cancer immunotherapy. We aim to create a data-driven mathematical model of the tumor immune microenvironment (TIME) and utilize deep reinforcement learning (DRL) to optimize patient-specific ICI therapy combined with chemotherapy (ICC). Using patients' genomic and transcriptomic data, we develop an ordinary differential equations (ODEs)-based TIME dynamic evolutionary model to characterize interactions among chemotherapy, ICIs, immune cells, and tumor cells. A DRL agent is trained to determine the personalized optimal ICC therapy. Numerical experiments with real-world data demonstrate that the proposed TIME model can predict ICI therapy response. The DRL-derived personalized ICC therapy outperforms predefined fixed schedules. For tumors with extremely low CD8 + T cell infiltration ('extremely cold tumors'), the DRL agent recommends high-dosage chemotherapy alone. For tumors with higher CD8 + T cell infiltration ('cold' and 'hot tumors'), an appropriate chemotherapy dosage induces CD8 + T cell proliferation, enhancing ICI therapy outcomes. Specifically, for 'hot tumors', chemotherapy and ICI are administered simultaneously, while for 'cold tumors', a mid-dosage of chemotherapy makes the TIME 'hotter' before ICI administration. However, in several 'cold tumors' with rapid resistant tumor cell growth, ICC eventually fails. This study highlights the potential of utilizing real-world clinical data and DRL algorithm to develop personalized optimal ICC by understanding the complex biological dynamics of a patient's TIME. Our ODE-based TIME dynamic evolutionary model offers a theoretical framework for determining the best use of ICI, and the proposed DRL agent may guide personalized ICC schedules.

Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors.

The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.