Immune Checkpoint Inhibitors Research Articles

Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments

Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment’s immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life.

Novel Therapies for Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) unfortunately remains a highly fatal disease with a 5-year survival rate of only 11%. If surgical resection is not possible, systemic chemotherapy represents the standard-of-care approach to management. Combination chemotherapy regimens using fluorouracil (fluorouracil, oxaliplatin, leucovorin, and irinotecan; and fluorouracil, leucovorin, and oxaliplatin) or gemcitabine with albumin-bound paclitaxel have the potential to improve overall survival for patients with advanced disease. With the increasing understanding of the molecular drivers of pancreatic cancer, novel therapeutic approaches have made incremental progress for these patients. The molecular landscape of PDAC has been studied extensively. Approximately 90% of PDACs harbor mutations in the KRAS gene, a driver mutation that has long been considered undruggable. However, novel KRAS inhibitors have shown therapeutic promise in early-phase clinical trials, with larger studies ongoing. Less frequently encountered genomic aberrations that have therapeutic potential include NRG, BRAF, NTRK, HER2, BRCA, PALB2, and claudin. Immune checkpoint inhibitors have unfortunately yielded disappointing efficacy for the majority of patients with pancreatic cancer, except for those with tumors exhibiting deficiency in mismatch repair proteins. Alternative approaches to incorporate immunotherapy have shown more promise such as use of immune checkpoint inhibitors for selected patients in the maintenance setting and potential vaccine therapies in the postsurgery adjuvant setting. It is vital to perform molecular profiling in all patients with PDAC to identify potential treatment targets, and to enroll patients in clinical trials whenever possible.

Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immunotherapy in melanoma patients

Abstract High-dimensional, spatial single-cell technologies such as CyTOF imaging mass cytometry (IMC) provide detailed information regarding locations of a large variety of cancer and immune cells in microscopic scales in tumor microarray (TMA) slides obtained from patients prior to immune checkpoint inhibitor (ICI) therapy. An important question is how the initial spatial organization of these cells in the tumor microenvironment (TME) change with time, regulate tumor growth and eventually outcomes as patients undergo ICI therapy. Utilizing IMC data of melanomas of patients who later underwent ICI therapy, we develop a spatially resolved interacting cell systems model that is calibrated against patient response data to address the above question. We find that the tumor fate in these patients is determined by the spatial organization of activated CD8+ T cells, macrophages, and melanoma cells and the interplay between these cells that regulate exhaustion of CD8+ T cells. We find that fencing of tumor cell boundaries by exhausted CD8+T cells is dynamically generated from the initial conditions that can play a pro-tumor role. Furthermore, we find that specific spatial features such as co-clustering of activated CD8+ T cells and macrophages in the pre-treatment samples determine the fate of the tumor progression, despite stochastic fluctuations and changes over the treatment course. Our framework enables determination of mechanisms of interplay between a key subset of tumor and immune cells in the TME that regulate clinical response to immune checkpoint inhibitors.

The promises and perils of circulating tumor DNA for monitoring immunotherapy response in non-small cell lung cancer

There has been a rapid expansion of immunotherapy options for non-small cell lung cancer (NSCLC) over the past two decades, particularly with the advent of immune checkpoint inhibitors. Despite the emerging role of immunotherapy in adjuvant and neoadjuvant settings though, relatively few patients will respond to immunotherapy which can be problematic due to expense and toxicity; thus, the development of biomarkers capable of predicting immunotherapeutic response is imperative. Due to the promise of a noninvasive, personalized approach capable of providing comprehensive, real-time monitoring of tumor heterogeneity and evolution, there has been wide interest in the concept of using circulating tumor DNA (ctDNA) to predict treatment response. Although the use of ctDNA to detect actionable mutations such as EGFR is now integral in the standard of care for patients with NSCLC, several large studies have also shown its potential as a biomarker of immunotherapeutic response. Ongoing ctDNA interventional clinical trials, such as the BR.36 trial, will help to clarify the potential role of ctDNA for therapeutic guidance. Despite the promise of this technology, there are many limitations and considerations that clinicians need to be aware of prior to widespread implementation in clinical practice, such as the effect of underlying comorbidities, ctDNA fraction, stage of underlying malignancy, and concordance between aberrations detected in ctDNA and tumor tissue.

Exploring Genomic Biomarkers for Pembrolizumab Response: A Real-World Approach and Patient Similarity Network Analysis Reveal DNA Response and Repair Gene Mutations as a Signature

Purpose: Single-agent immune checkpoint inhibitor (IO) therapy is the standard for non-oncogene-addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score ≥ 50%. Smoking-induced harm generates high tumor mutation burden (H-TMB) in smoking patients (S-pts), while never-smoking patients (NS-pts) typically have low TMB (L-TMB) and are unresponsive to IO. However, the molecular characterization of NS-pts with H-TMB remains unclear. Experimental design: Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways and enrichment analysis identified patient subgroups based on mutated pathways. Additionally, a patient similarity network was constructed to analyze molecular characterization. Results were validated using data from 853 aNSCLC patients in POPLAR and OAK trials. Results: Among the patients, S-pts had higher TMB than NS-pts. Interestingly, 11 (8%) NS-pts exhibited H-TMB and were enriched in β-catenin/Wnt and DDR pathway mutations. DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB using data from POPLAR and OAK trials. In the real-world cohort, the NS/H-TMB subgroup with DDR pathway mutations demonstrated improved IO outcome. Patient similarity network analysis confirmed the clustering of NS/H-TMB patients with DDR mutations and their association with improved overall survival in both the real-world cohort and the trials. Conclusions: The DDR signature has a potential role as an additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis. Our findings suggest that DDR-based mutational profiling may help identify NS-pts who could benefit from IO therapy.

IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy.

Tumor cells are characterized by rapid proliferation. In order to provide purines for DNA and RNA synthesis, inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo guanosine biosynthesis, is highly expressed in tumor cells. In this study we investigated whether IMPDH was involved in cancer immunoregulation. We revealed that the IMPDH inhibitors AVN944, MPA or ribavirin concentration-dependently upregulated PD-L1 expression in non-small cell lung cancer cell line NCI-H292. This effect was reproduced in other non-small cell lung cancer cell lines H460, H1299 and HCC827, colon cancer cell lines HT29, RKO and HCT116, as well as kidney cancer cell line Huh7. In NCI-H292 cells, we clarified that IMPDH inhibitors increased CD274 mRNA levels by enhancing CD274 mRNA stability. IMPDH inhibitors improved the affinity of the ARE-binding protein HuR for CD274 mRNA, thereby stabilizing CD274 mRNA. Guanosine supplementation abolished the IMPDH inhibitor-induced increase in PD-L1 expression. In CT26 and EMT6 tumor models used for ICIs based studies, we showed that despite its immunosuppressive properties, the IMPDH inhibitor mycophenolate mofetil did not reduce the clinical response of checkpoint inhibitors, representing an important clinical observation given that this class of drugs is approved for use in multiple diseases. We conclude that PD-L1 induction contributes to the immunosuppressive effect of IMPDH inhibitors. Furthermore, the IMPDH inhibitor mycophenolate mofetil does not antagonize immune checkpoint blockade.

Effect of immortal time bias on the association between immune-related adverse events and oncological outcomes following immune checkpoint inhibitors therapy for head and neck squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) are pharmacological agents indicated for recurrent and metastatic head and neck squamous cell carcinoma (HNCSCC). Immune-related adverse events (irAEs) have been reported as predictors of therapeutic response to ICIs. However, previous studies have not adequately addressed the immortal time bias. Therefore, we aimed to investigate the association between the onset of irAEs and oncological outcomes, accounting for immortal time bias. We conducted a retrospective study involving 130 patients with HNSCC who were treated with ICIs. The objective response, progression-free survival (PFS), and overall survival (OS) were assessed using logistic regression analysis, the Kaplan-Meier method, and the Cox proportional hazard (PH) model. The immortal time bias was considered using a landmark analysis and an extended Cox (EC) model. The odds ratios for response and disease control were smaller in the landmark than in the naïve analyses. In the landmark analysis, the 1-year PFS rates were 47.6% and 27.2% for irAE+ and irAE- patients, respectively (p = 0.049), and the 1-year OS rates were 85.7% and 66.5%, respectively (p = 0.006). Regarding PFS, the adjusted HRs for irAEs were 0.49 (95% confidence interval (CI) 0.28-0.85) in the PH analysis and 0.75 (95% CI 0.40-1.40) in the EC analysis. As for OS, the adjusted HRs for irAEs were 0.36 (95% CI 0.19-0.66) in the PH analysis and 0.51 (95% CI 0.27-0.95) in the EC analysis. IrAEs were an independent prognostic factor for OS but not PFS. Without considering the immortal time bias, the association between irAEs and oncologic outcomes in patients with HNSCC treated with ICIs was overestimated. Therefore, the balance between the benefits and risks of ICI therapy must be carefully weighed in clinical settings.

Potential predictive biomarkers in antitumor immunotherapy: navigating the future of antitumor treatment and immune checkpoint inhibitor efficacy

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment modality, offering promising outcomes for various malignancies. However, the efficacy of ICIs varies among patients, highlighting the essential need of accurate predictive biomarkers. This review synthesizes the current understanding of biomarkers for ICI therapy, and discusses the clinical utility and limitations of these biomarkers in predicting treatment outcomes. It discusses three US Food and Drug Administration (FDA)-approved biomarkers, programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and microsatellite instability (MSI), and explores other potential biomarkers, including tumor immune microenvironment (TIME)-related signatures, human leukocyte antigen (HLA) diversity, non-invasive biomarkers such as circulating tumor DNA (ctDNA), and combination biomarker strategies. The review also addresses multivariable predictive models integrating multiple features of patients, tumors, and TIME, which could be a promising approach to enhance predictive accuracy. The existing challenges are also pointed out, such as the tumor heterogeneity, the inconstant nature of TIME, nonuniformed thresholds and standardization approaches. The review concludes by emphasizing the importance of biomarker research in realizing the potential of personalized immunotherapy, with the goal of improving patient selection, treatment strategies, and overall outcomes in cancer treatment.

RNA N6-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer.

Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

Dedifferentiated endometrial carcinoma/undifferentiated endometrial carcinoma with loss of expression of SMARCA4: clinicopathological features analysis

Objective: To investigate the clinicopathological characteristics of dedifferentiated endometrial carcinoma/undifferentiated endometrial carcinoma (DDEC/UDEC) with loss of expression of SMARCA4. Methods: A total of 10 cases with loss of expression of SMARCA4 were diagnosed at Fujian Cancer Hospital between January 2019 and December 2023. A retrospective analysis was conducted on the clinical characteristics, morphology, immunophenotype, molecular classification, and prognosis. Results: (1) Clinical characteristics: among 10 cases of DDEC/UDEC with loss of expression of SMARCA4, the patients' age ranged from 48 to 65 years, with a median age of 56 years.Five cases were classified as International Federation of Gynecology and Obstetrics (FIGO) stages Ⅰ-Ⅱ, while the remaining five were categorized as stages Ⅲ-Ⅳ. (2) Pathological features: tumor cells exhibited poor cell adhesion, with common intravascular tumor emboli (8/10), occasional vacuolated nuclei (6/10), rhabdoid cells (4/10), and starry sky phenomenon formed by tissue cell phagocytosis apoptosis bodies or fragments (4/10). Six cases (6/10) showed loss of mismatch repair (MMR) protein expression, two cases (2/10) exhibited p53 mutant expression, and five cases (5/10) tested positive for programmed cell death ligand 1 (PD-L1). (3) Molecular subtyping: molecular subtyping revealed POLEmut in 1 case (1/10), mismatch repair deficient (MMR-d) in 5 cases (5/10), p53 abn in 1 case (1/10), and no specific molecular profile (NSMP) in 3 cases (3/10). (4) Prognosis: the follow-up period ranged from 7 to 42 months, with a median of 20 months. Five patients succumbed to the tumor, whereas the remaining five exhibited no recurrence during subsequent postoperative evaluations. The 2-year progression-free survival rates and overall survival rates were 58.3% and 52.5%, respectively. Conclusions: Loss of expression of SMARCA4 occurs in approximately 1/5 of DDEC/UDEC, which presents with an aggressive clinical course and a poor prognosis. About half of them show MMR protein loss expression and PD-L1 positive expression, suggesting that there might be benefit from treatment with immune checkpoint inhibitors.

From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape

Lactic acid, a key metabolic byproduct within the tumor microenvironment, has garnered significant attention for its role in immune evasion mechanisms. Tumor cells produce and release large amounts of lactic acid into the tumor microenvironment through aberrant glycolysis via the Warburg effect, leading to a drop in pH. Elevated lactic acid levels profoundly suppress proliferation capacity, cytotoxic functions, and migratory abilities of immune effector cells such as macrophages and natural killer cells at the tumor site. Moreover, lactic acid can modulate the expression of surface molecules on immune cells, interfering with their recognition and attack of tumor cells, and it regulates signaling pathways that promote the expansion and enhanced function of immunosuppressive cells like regulatory T cells, thereby fostering immune tolerance within the tumor microenvironment. Current research is actively exploring strategies targeting lactic acid metabolism to ameliorate tumor immune evasion. Key approaches under investigation include inhibiting the activity of critical enzymes in lactic acid production to reduce its synthesis or blocking lactate transporters to alter intracellular and extracellular lactate distribution. These methods hold promise when combined with existing immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies to enhance the immune system’s ability to eliminate tumor cells. This could pave the way for novel combinatorial treatment strategies in clinical cancer therapy, effectively overcoming tumor immune evasion phenomena, and ultimately improving overall treatment efficacy.

Unraveling impact and potential mechanisms of baseline pain on efficacy of immunotherapy in lung cancer patients: a retrospective and bioinformatic analysis

ObjectivePain is a prevalent discomfort symptom associated with cancer, yet the correlations and potential mechanisms between pain and the efficacy of cancer immunotherapy remain uncertain.MethodsNon-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitors (ICIs) in the inpatient department of Guangdong Provincial Hospital of Chinese Medicine from January 1, 2018, to December 31, 2021, were retrospectively enrolled. Through cox regression analysis, prognostic factors and independent prognostic factors affecting the efficacy of ICIs were identified, and a nomogram model was constructed. Hub cancer-related pain genes (CRPGs) were identified through bioinformatic analysis. Finally, the expression levels of hub CRPGs were detected using an enzyme-linked immunosorbent assay (ELISA).ResultsBefore PSM, a total of 222 patients were enrolled in this study. Univariate and multivariate cox analysis indicated that bone metastasis and NRS scores were independent prognostic factors for the efficacy of ICIs. After PSM, a total of 94 people were enrolled in this study. Univariate cox analysis and multivariate cox analysis indicated that age, platelets, Dnlr, liver metastasis, bone metastasis, and NRS scores were independent prognostic factors for the efficacy of ICIs. A nomogram was constructed based on 6 independent prognostic factors with AUC values of 0.80 for 1-year, 0.73 for 2-year, and 0.80 for 3-year survival. ELISA assay results indicated that the level of CXCL12 significantly decreased compared to baseline after pain was relieved.ConclusionBaseline pain is an independent prognostic factor affecting the efficacy of ICIs in lung cancer, potentially through CXCL12-mediated inflammation promotion and immunosuppression.

Breathing down resistance: Tackling hypoxia to overcome immunotherapy barriers in lung cancer.

In this issue of JEM, Robles-Oteiza et al. (https://doi.org/10.1084/jem.20231106) present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.

IAPP blocks anti-breast cancer function of CD8+T cells via targeting cuproptosis

BackgroundBreast cancer (BRCA) is the most prevalent type of cancer worldwide. As a highly heterogeneous cancer, it has a high recurrence rate. Since its biological behavior can be regulated by immunity and cuprotosis, so exploring potential therapeutic target to mediate immunity and cuprotosis is of great significance for BRCA therapy.MethodsThe immune-related genes and immune-cuprotosis-related deferentially expressed genes (ICR-DEGs) were identified by mining the TCGA database. Prognostic analysis, differential expression analysis, univariate and lasso regression analyses were used to determine their independent prognostic values. To evaluate the relationship between ICR-DEGs and immune scores, we constructed a prognostic risk model to evaluate immune checkpoints, and then the role of tumor immune microenvironment in BRCA was explored. Furthermore, anti-BRCA function and mechanism of islet amyloid poly-peptide (IAPP) mediated CD8+T cells were verified by means of flow cytometry, ELISA, and subcutaneous transplantation tumor model.ResultsAll results suggested that immune-cuprotosis-related genes were a potential predictor of BRCA’s response to immune checkpoint inhibitors and immunotherapy biomarkers. Thereby downregulation of IAPP reduced cuprotosis of CD8+T or Her2-CAR-T cells to promote the anti-BRCA function both in vitro and in vivo.ConclusionOur research had clarified the function and mechanism of IAPP in CD8+T cells, providing new ideas for improving the diagnosis and treatment of BRCA.

Hepatic Events During Immune Checkpoint Inhibitor Treatment Between Liver and Non-Liver Malignancies in Hepatitis B Endemic Areas.

Notable advances have been made in immune checkpoint inhibitors (ICIs) for cancer treatment. However, the adverse effects of ICIs, especially hepatotoxicity, remain a challenging problem. Whether patients in hepatitis B virus (HBV)-endemic areas are prone to developing hepatic adverse events during ICI treatment warrants further exploration. From 2014 to 2020, the data of all patients with cancer who received ICI treatment at Taipei Veterans General Hospital were retrospectively reviewed. The incidence of and risk factors for hepatic adverse events, including hepatitis flare, immune-related hepatitis (irHepatitis) and HBV reactivation (HBVr), were analysed through a Cox proportional hazard regression model. A total of 1283 patients with cancer (190 hepatocellular carcinoma [HCC] patients and 1093 patients with non-HCC malignancies) were eligible for analysis, of whom 283 (22.1%) were HBsAg-positive. The incidence of hepatitis flare events of any grade was significantly higher in HCC patients than in non-HCC patients (45.8% vs. 25.6%, p < 0.001). HCC and baseline alanine aminotransferase (ALT) > 40 U/L were independent risk factors for ≥ grade 3 hepatitis flare events. No difference was observed in irHepatitis risk between HCC patients and non-HCC patients. ALT > 40 U/L was an independent risk factor for irHepatitis. Among 283 HBsAg-positive patients, six patients (2.1%) experienced HBVr. HCC patients had a higher risk of HBVr than non-HCC patients (4.4% vs. 0.6%). No specific risk factor for HBVr could be identified. However, none of the patients under nucleos/tide analogue (NUC) prophylaxis experienced HBVr in this study. Under ICI treatment, HCC patients had a higher risk of hepatitis flare events than non-HCC patients. Abnormal baseline ALT levels are a risk factor for hepatic adverse events. NUC prophylaxis can minimise the risk of HBVr.

Analysis of risk factors and establishment of prediction model for immune checkpoint inhibitor related myocarditis and major adverse cardiovascular events

Objectives: To explore the risk factors of major adverse cardiovascular events (MACEs) in immune checkpoint inhibitor (ICI) related myocarditis and establish a predictive model. Methods: This was a retrospective case-control study. Tumor patients diagnosed with ICI related myocarditis in the First Affiliated Hospital of Guangzhou Medical University from May 2019 to August 2023 were selected and divided into non-MACE group and MACE group based on whether MACE occurred. Clinical and imaging data of the two groups were collected. Univariate and multivariate logistic regression models were used to analyze the risk factors for MACE in patients with ICI related myocarditis. According to the results of multivariate logistic regression analysis, R 4.1.0 software was used to construct the MACE risk prediction model for these patients and draw a nomogram. The receiver operating characteristic curve was used to evaluate the prediction ability of the prediction model. Results: A total of 35 patients with ICI related myocarditis, aged (63.9±8.2) years, were included, including 28 males (80%). There were 18 patients in the non-MACE group and 17 patients in the MACE group. Multivariate logistic regression analysis showed that elevated neutrophil to lymphocyte ratio (OR=1.115, 95%CI 1.007-1.235, P=0.036) and ST-T segment changes (OR=24.942, 95%CI 1.239-502.194, P=0.036) were risk factors for MACE in patients with ICI related myocarditis. The receiver operating characteristic curve indicated that the area under the curve of the prediction model was 0.967 (95%CI 0.916-1.000, P<0.001), with a sensitivity of 88.2% and specificity of 100%, demonstrating good predictive ability. Conclusion: Elevated neutrophil to lymphocyte ratio and ST-T segment change are independent risk factors for MACE in patients with ICI related myocarditis. Risk prediction model based on the above two indicators can assist in the early identification and individualized intervention of ICI related myocarditis patients.

Immune Signatures of Solid Tumor Patients Treated With Immune Checkpoint Inhibitors: An Observational Study.

Our study aimed to comprehensively describe the features of peripheral blood multiple immune cell phenotypes in solid tumor patients during pretreatment and after immunotherapy, providing a more convenient approach for studying the prognosis of immunotherapy in different solid tumor patients. We prospectively recruited patients with advanced solid tumors from Peking Union Medical College Hospital (PUMCH) between February 2023 and April 2024. Using multicolor flow cytometry, our study comprehensively observed and described the signatures of peripheral blood lymphocyte subsets including activation, proliferation, function, naïve memory, and T cell exhaustion immune cell subsets in this population of pretreatment and after immunotherapy. Our study enrolled 59 advanced solid tumor patients with immunotherapy and 59 healthy controls were matched by age and gender. The results demonstrated a marked upregulation in the expression of lymphocyte activation markers CD38 and HLA-DR, as well as exhaustion and proliferation markers PD-1 and Ki67, in solid tumor patients compared to healthy controls. After immune checkpoint blockade (ICB) treatment, mainly the expression of Ki67CD4+T and HLA-DRCD38CD4+T, was significantly upregulated compared to pretreatment levels (p = 0.017, p = 0.019, respectively). We further found that gynecological tumors with better prognoses had higher baseline activation levels of CD4+ T cells compared to other solid tumors with poorer prognoses. Our study elucidated the characteristics of different lymphocyte subsets in the peripheral blood of solid tumor patients. Further research revealed changes in the phenotypes of different lymphocyte subsets after ICIs treatment, with the activated phenotype of CD4+ T cells playing a crucial role in the antitumor effect. This lays the groundwork for further exploration of prognostic biomarkers and predictive models for cancer patients with immunotherapy.

Clinical and histopathological features of immune checkpoint inhibitor-induced lung toxicity.

A new era in cancer therapy emerged with the arrival of immune-checkpoint inhibitors (ICIs), followed by a new cadre of immune-related adverse events that affect up to 40% of patients. Literature on the pathological features associated with these events is still limited. Therefore, to expand our knowledge of the histopathologic spectrum of pulmonary changes, we conducted a case study series analysis on 16 non-neoplastic lung samples collected during or after ICI therapy. A set of predefined histological features related to the four different "compartments" (interstitium, pneumocyte, alveolar space, and bronchial mucosa), the CD4/CD8 T cell ratio, and the SP263 PD-L1 expression in the immune cells was assessed in three study categories [ICI + radiotherapy with/without chemotherapy (RT-based), ICI + chemotherapy (CT-based), ICI-based monotherapy (ICI-mono)]. Our results identified interstitial thickening, interstitial lymphocytic infiltrate, pneumocyte desquamation, intra-alveolar fibrin, or foamy macrophages in at least half of the cases in each of the study categories; all five features were present in 4 (RT-based), 3 (CT-based) and 1 (ICI-mono) patients. Hyaline membrane was a frequent finding in CT-based (80%) and ICI-mono (100%) compared to RT-based (44%) category. Moreover, CD4/CD8 ratio was ≤ 1 for almost all cases of the three study categories. Finally, a positive SP263 PD-L1 expression was identified in 50% or more of each study category. In conclusion, our results indicate that histopathologic findings in patients treated with ICI therapy are not diagnostic and varied. Additionally, these results are in line with recent studies showing an expansion on CD8+ T cell subset in patients under ICI treatment and highlight the synergism of polytherapy.

Recent Advances in the Treatment of Multiple Myeloma in the Era of New Drug Development

Multiple myeloma (MM) is a malignant hematologic disease characterized by the neoplastic proliferation of plasma cells in the bone marrow. It exhibits high heterogeneity, a tendency for relapse, and resistance to treatment. The primary goal of first-line therapy is to achieve deep remission and durable disease control. Current conventional treatment approaches can improve patient prognosis but have significant limitations. The emergence of novel therapies, including proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors, marks a new era in MM treatment. However, due to the relapsed and refractory nature of MM, future applications should consider various factors and tailor treatment strategies to individual circumstances to optimize therapeutic efficacy.

Pneumonitis after normofractionated radioimmunotherapy: a method for dosimetric evaluation

BackgroundPost-Therapy-Pneumonitis (PTP) is a critical side effect of both, thoracic radio(chemo)therapy (R(C)T) and immune checkpoint inhibition (ICI). However, disease characteristics and patient-specific risk factors of PTP after combined R(C)T + ICI are less understood. Given that RT-triggered PTP is strongly dependent on the volume and dose of RT [1], driven by inflammatory mechanisms, we hypothesize that combination therapy of R(C)T with ICI influences the dose-volume-effect correlation for PTP. This study focuses on the development of a method for evaluation of alterations of dosimetric parameters for PTP after R(C)T with and without ICI.Methods and materialsPTP volumes were delineated on the follow-up diagnostic Computed Tomography (CT) and deformably matched to the planning CT for patients with PTP after thoracic R(C)T + ICI or R(C)T. Dose data was converted to 2-Gy equivalent doses (EQD2) and dosimetrically analyzed. Dosimetric and volumetric parameters of the segmented PTP volumes were analyzed. The method was exemplarily tested on an internal patient cohort including 90 patients having received thoracic R(C)T + ICI (39) and R(C)T (51). Thirtytwo patients with PTP were identified for further analysis. Additional data on previous chemotherapy, RT, smoking status and pulmonary co-morbidity were conducted. A matched pair analysis with regard to planning target volumes (PTV) was conducted for curative intended (definitive) and palliative patient cohorts individually.ResultsThe presented method was able to quantify and compare the dosimetric parameters of PTP for the different therapies. For our study group, no significant differences between R(C)T + ICI and R(C)T only was observed. However, the dosimetric analysis revealed large volumetric fractions (55%) of the PTP volumes to be located outside of high dose (EQD2 < 40 Gy) regions for R(C)T + ICI. There was a non-significant trend towards increased area under the curve of the dose volume histogram (AUC) values for R(C)T + ICI compared to R(C)T only (3743.6 Gy∙% vs. 2848.8 Gy∙%; p-value = 0.171). In contrast to the data for the palliative intended treatment group, for definitive R(C)T + ICI, data tended towards increased volumes with higher doses.ConclusionsThe proposed method was capable to quantify dosimetric differences in the dose-volume-effect relationship of PTP for patients with R(C)T + ICI and patients with R(C)T only. In this exploratory analysis, no significant dosimetric differences within PTP volumes for the different groups could be observed. However, our observations suggest, that for safe application of thoracic R(C)T + ICI, further careful investigation of dosimetric prescription and analysis concepts with larger and conformer study groups is recommendable.