PD-1 Inhibitor Therapy Research Articles

Prognosis of patients with Hodgkin lymphoma and indeterminate response to PD-1 inhibitor therapy: considerations for application of LYRIC criteria in real clinical practice.

PD-1 inhibitors have shown unconventional response patterns in classic Hodgkin lymphoma (cHL). These include the phenomenon of pseudoprogression, highlighting the need for specialized response criteria such as the LyRIC, which stringened definitions for disease progression with introduction of indeterminate response category. Despite their potential utility, these provisional criteria are currently underutilized and require further refinement through clinical practice data collection. In this retrospective study LyRIC criteria were systematically used for response assessments in 180 patients with refractory cHL treated with nivolumab. Median follow-up was 60months. Indeterminate response (IR) was a frequent phenomenon in study population: at 3months of therapy 63 (35%) patients had an indeterminate response (IR1 7%, IR2 23%, IR3 6%). Among them 18 (29%) achieved an objective response with continued monotherapy. There were no differences in OS or TTNT depending on the type of IR. IR was the best achieved response in 45 (25%) patients. Patients with IR had favorable prognosis with no difference in OS, PFS and TTNT comparing to patients with PR when subsequent therapy was initiated due to disease progression. Patients with IR may achieve prolonged disease control or a deeper response upon continuing treatment. These findings support the broader implementation and adjustment of LyRIC criteria in clinical practice to enhance decision-making in cHL patients treated with immunotherapy.

Cardiovascular risks of PD1 inhibitor therapy in cancer: impact of prior ischemic events on heart failure - a retrospective cohort study

Abstract Introduction Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but concerns remain about their cardiac risks. Limited recent basic evidence suggests a possible link between ICIs that target PD1 and adverse cardiac events such as heart failure. Purpose This study explores the connection between PD1 inhibitor therapy and incident heart failure in cancer patients. Methods In our retrospective study at a tertiary medical center, 1,671 cancer patients receiving PD1 inhibitors were analyzed. Individuals with a history of heart failure, who developed myocarditis on PD-1, or had missing data were excluded. Data from pharmacy records and the Research Patient Data Registry provided clinical and ICI-related details. Cases were defined as patients who developed incident heart failure after ICI started. Controls were patients who did not develop incident heart failure after ICI start. Sensitivity analyses, including propensity score matching and comparison with non-ICI-treated cancer patients, ensured result robustness. Multivariate logistic regressions were performed. Results Among 1,671 ICI treated patients, 109 (6.5%) developed heart failure without evidence of myocarditis over a median follow-up of 332.0 days. In both the full cohort and the 3:1 matched cohort (n=380), multivariate logistic regression showed increased odds of incident heart failure in patients with prior ischemic cardiac events: 2.34 (95%CI 1.26-4.16, p=0.005) and 2.11 (95%CI 1.05-4.2, p=0.033) respectively. Among the non-ICI treated cancer patients, multivariate logistic regression found no association between prior ischemic events and incident heart failure (1.23, 95%CI 0.53-2.63, p=0.6), but hypertension showed an association (1.74, 95%CI 1.07-2.87, p=0.027). Conclusion This study emphasizes vigilance for cardiovascular complications in PD1 inhibitor-treated cancer patients. The incidence of heart failure was 6.5% over a follow-up period of less than 1 year. Prior ischemic events correlate with increased heart failure risk, suggesting a need for nuanced patient management. Understanding ICIs' cardiovascular safety is crucial for risk assessment, treatment optimization, and patient well-being.

Predictive and Dynamic Signature for Antiangiogenics in Combination with a PD1 Inhibitor in Soft-Tissue Sarcoma: Correlative Studies Linked to the IMMUNOSARC Trial.

The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial. Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.

Morphological and Immunohistochemical Aspects with Prognostic Implications and Therapeutic Targets of Primary Sinonasal Mucosal Melanoma: A Retrospective Study.

Sinonasal mucosal melanoma originates from melanocytes and it is a rare malignancy in the sinonasal tract. It is an aggressive melanocytic neoplasm with a very poor prognosis. The symptoms are nonspecific and the diagnosis is delayed, usually until the advanced stages of the disease. The current study performs a correlation between the histopathological aspects of sinonasal mucosal melanoma and different types of immune cells present in the microenvironment, with prognostic and therapeutic implications. The endpoint is to quantify the cellular immune microenvironment and correlate it with patient survival. This study presents nine cases of primary sinonasal mucosal melanomas diagnosed at the Emergency City Hospital Timisoara, Romania during a period of 15 years. The histopathological examination was performed in the Department of Pathology of the same hospital, using morphological hematoxylin-eosin staining. Additional immunohistochemical reactions were performed to confirm the diagnosis and evaluate the components of the tumor immune microenvironment. This study identifies eosinophils, macrophages, natural killer cells and plasma cells as favorable prognostic factors. Therefore, a CD8:CD4 ratio of more than 3 is correlated with a good response to PD-1 inhibitor therapy.

Inhibition of KIF20A enhances the immunotherapeutic effect of hepatocellular carcinoma by enhancing c-Myc ubiquitination

Immune therapy has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients, yet its efficacy remains limited, underscoring the urgency to identify new therapeutic targets and biomarkers. Here, we investigated the pathological and physiological roles of KIF20A and assess its potential in enhancing HCC treatment efficacy when combined with PD-1 inhibitors. We initially assess KIF20A's oncogenic function using liver-specific KIF20A knockout (Kif20a CKO) mouse models and orthotopic xenografts. Subsequently, we establish a regulatory axis involving KIF20A, FBXW7, and c-Myc, validated through construction of c-Myc splicing mutants. Large-scale clinical immunohistochemistry (IHC) analyses confirm the pathological relevance of the KIF20A-FBXW7-c-Myc axis in HCC. We demonstrate that KIF20A overexpression correlates with poor prognosis in HCC by competitively inhibiting FBXW7-mediated degradation of c-Myc, thereby promoting glycolysis and enhancing tumor proliferation. Conversely, KIF20A downregulation suppresses these effects, impairing tumor growth through c-Myc downregulation. Notably, KIF20A inhibition attenuates c-Myc-induced MMR expression, associated with improved prognosis in HCC patients receiving PD-1 inhibitor therapy. Furthermore, in Kif20a CKO HCC mouse models, we observe synergistic effects between Kif20a knockout and anti-PD-1 antibodies, significantly enhancing immunotherapeutic efficacy against HCC. Our findings suggest that targeting the KIF20A-c-Myc axis could identify HCC patients likely to benefit from anti-PD-1 therapy. In conclusion, we propose that combining KIF20A inhibitors with anti-PD-1 treatment represents a promising therapeutic strategy for HCC, offering new avenues for clinical development and patient stratification.

Cardiotoxicity in tumor-bearing mice receving thoracic radiation plus tumor radiation and PD-1 inhibitor therapy.

e20509 Background: At present, most preclinical studies explore the cardiotoxicity caused by radiotherapy combined with Anti-PD1s in tumor-free mice. we assessed the overall cardiotoxicity of radiotherapy combined with Anti-PD1, the possibility that blocking HMGB1 does not affect the anti-tumor effect, and the possibility that radiotherapy combined with Anti-PD1 reduces heart damage in tumor-bearing mice. Methods: 25 tumor-bearing C57BL/6 mice on both hind limbs were treated with anti-PD1 or PBS or Anti-HMGB1 with or without thoracic irradiation 20gy and right hind limb tumor 8gy×3F irradiation. HE staining was used to observe the cardiac structure and morphological changes. Flow cytometry was used to observe the distribution of CD3+, CD4+, CD8+T cells in cardiac and peripheral blood. Cardiac function was examined by echocardiography. The expression of myocardial injury marker LDH in peripheral blood was detected by Elisa. Results: Five group was established:A = Control;B = anti-PD1,C = RT,D = RT+Anti-PD1,E = RT+Anti-PD1+Anti-HMGB1.HE showed the myocardial injury in A(without any treatment) was the most severe,and and B and D was slightly severe than C group, administration of Anti-HMGB1 partially attenuated myocardial injury in D. Elisa showed the LDH of A was highest, B were consistent with D in LDH expression, RT was lower. Cardiac function showed no difference in ejection fraction and fractional shortening in five groups. Peripheral blood flow cytometry showed the absolute counts of CD3+T-cell and cd8+T cells were greatest in B group, followed by A, C, D, and E groups. Absolute CD4+ T cell values were highest in the B. The results of myocardial tissue infiltrating lymphocytes showed that the absolute CD3+T-cell and cd8+T cells counts were biggest in the B group, followed by A, C, D, and Egroups. Absolute CD4+T cell counts were highest in B group. C, D had the best anti-tumor effect, and the use of Anti-HMGB1 partially attenuated the cardiac injury caused by D group. Conclusions: (1)Without any treatment, the cancer cachexia induced by tumor will cause serious damage to myocardial. (2) The overall cardiotoxicity of radiotherapy combined with Anti-PD1 group was only slightly increased compared to RT or anti-PD1 alone. Maybe radiotherapy killed part of the Anti-PD1-activated lymphocytes, only resulting in a slight increase in cardiac infiltrating lymphocytes. Anti-HMGB1 maintain the anti-tumor effect of RT+Anti-PD1 and partially attenuated the cardiac damage. [Table: see text]

Tislelizumab plus tyrosine kinase inhibitor versus active surveillance in patients with ablated high-risk hepatocellular carcinoma: An open-label, parallel controlled, prospective cohort study.

e16238 Background: In IMbrave050, adjuvant atezolizumab plus bevacizumab demonstrated improvement in recurrence-free survival vs active surveillance in patients at high risk of hepatocellular carcinoma (HCC) recurrence following resection or ablation with curative intent. However, there is limited study on programmed cell death protein 1 (PD-1) inhibitor plus tyrosine kinase inhibitor (TKI) as postoperative adjuvant therapy for HCC. We aimed to assess the safety and efficacy of tislelizumab (a PD-1 inhibitor) plus TKI as adjuvant therapy versus active surveillance in patients at high risk of HCC recurrence after curative ablation. Methods: This study enrolled patients with HCC at high risk of recurrence following curative ablation. Patients were paralleled to Arm A (tislelizumab plus TKI) or Arm B (active surveillance). Patients in Arm A received tislelizumab (200 mg, IV, q3w) plus TKI for three months (4 cycles) following curative ablation, while those patients in Arm B underwent active surveillance. Primary endpoints were safety and tumor recurrence rate. Secondary endpoint was disease free survival (DFS). Exploratory endpoints included biomarkers related to the recurrence. Results: A total of 48 patients were enrolled with a median follow-up time of 283 days (IQR: 123-460 days, clinical cutoff date: 1 Jan 2024). Nine patients (37.5%) reported at least one adverse event of any degree in Arm A and three patients (12.5%) reported in arm B, most of which were mild. Only one patient in arm A experienced a grade 3 treatment-related adverse event, which improved after administration of symptomatic treatment. The recurrence rate of patients in arm A was 20.83%, which was significantly lower than the 58.3% in arm B (OR = 0.188 [95% CI: 0.052 - 0.674], P = 0.017). Four cycles of adjuvant tislelizumab plus TKI therapy was associated with significantly improved DFS (median, not evaluable [NE]) compared with active surveillance (median, 188 days [95% CI: 78.4 - 297.6 days]; HR = 0.396 [95% CI: 0161 - 0.973], P = 0.044). The absence of tislelizumab treatment (OR = 4.823 [95% CI: 1.091 - 21.329], P = 0.038) and multiple tumor lesions (OR = 7.651 [95% CI: 1.270 - 46.114], P = 0.026) were risk factors for recurrence of HCC after curative ablation. Conclusions: The safety of tislelizumab plus TKI combination therapy were generally manageable. Statistically significant and clinically meaningful improvement in tumor recurrence rate and DFS were seen in patients receiving combination therapy vs active surveillance. This study was a positive attempt to undergo short-course PD-1 inhibitor plus TKI combination therapy in patients with HCC at high risk of recurrence following curative ablation, showing promising efficacy in preventing HCC recurrence. Clinical trial information: NCT06059885 .

PD-1 inhibitor combined with ablation in liver metastasis: A retrospective, multicenter study.

e14644 Background: This study aimed to retrospectively evaluate the efficacy of ablation combined with programmed cell death protein 1 (PD-1) inhibitor versus PD-1 inhibitor monotherapy in patients with liver metastasis. Methods: We retrospectively enrolled patients with liver metastasis who received PD-1 inhibitor therapy with or without ablation at three medical institutions between January 2017 and September 2022. Progression-free survival (PFS) and 1-year survival rates were compared after propensity score matching. Additionally, intrahepatic and extrahepatic lesion progression and treatment-related adverse events were recorded during follow-up. Finally, prognostic factors for the combined therapy group were analyzed. Results: We included 172 patients and classified them into the combined therapy and PD-1 inhibitor monotherapy (n = 86 each) groups. Patients in the combined therapy group had better median PFS and 1-year survival rates than those in the PD-1 inhibitor monotherapy group. Combined therapy was an independent prognostic factor for PFS in the univariate and multivariate analyses. New lesions constituted the main pattern of progression, with combined therapy showing significantly lower intrahepatic progression, but similar extrahepatic progression rates. Adverse events associated with PD-1 inhibitors were comparable between the two groups. Additionally, 8 (9.3%) patients experienced ablation-related complications. However, neither univariate, nor multivariate analyses revealed the predictive factors for PFS in the combined therapy group. Conclusions: Ablation combined with a PD-1 inhibitor was superior to PD-1 inhibitor monotherapy in improving the survival of patients with liver metastasis.

Clinical features and treatment outcomes of PD-1 inhibitor therapy in elderly patients (≥ 65years) with advanced esophageal squamous cell carcinoma: a real-world study.

This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2months (95% CI: 5.1-7.3), and the median OS was 15.3months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. The study demonstrated that individuals older than 65years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.

Risk factors and outcomes of pericardial effusion in cancer patients receiving PD-1 inhibitors

BackgroundProgrammed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. MethodsWe conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. ResultsA total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70–14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431–61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276–72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879–26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. ConclusionsIn cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.

Integrative analysis unveils ECM signatures and pathways driving hepatocellular carcinoma progression: A multi-omics approach and prognostic model development.

Liver hepatocellular carcinoma (LIHC) is a highly lethal form of cancer that is among the deadliest cancer types globally. In terms of cancer-related mortality rates, liver cancer ranks among the top three, underscoring the severity of this disease. Insufficient analysis has been conducted to fully understand the potential value of the extracellular matrix (ECM) in immune infiltration and the prognostic stratification of LIHC, despite its recognised importance in the development of this disease. The scRNA-seq data of GSE149614 was used to conduct single-cell analysis on 10 LIHC samples. CellChat scores were calculated for seven cell populations in the descending cohort to investigate cellular communication, while PROGENy scores were calculated to determine tumour-associated pathway scores in different cell populations. The pathway analysis using GO and KEGG revealed the enrichment of ECM-associated genes in the pathway, highlighting the potential role of the ECM in LIHC development. By utilizing the TCGA-LIHC cohort, an ECM-based prognostic model for LIHC was developed using Lasso regression. Immune infiltration scores were calculated using two methods, and the performance of the ECM-related risk score was evaluated using an independent cohort from the CheckMate study. To determine the precise expression of ECM-associated risk genes in LIHC, we evaluated hepatocellular carcinoma cell lines using a range of assays, including Western blotting, invasion assays and Transwell assays. Using single-cell transcriptome analysis, we annotated the spatially-specific distribution of major immune cell types in single-cell samples of LIHC. The main cell types identified and annotated included hepatocytes, T cells, myeloid cells, epithelial cells, fibroblasts, endothelial cells and B cells. The utilisation of cellchat and PROGENy analyses enabled the investigation and unveiling of signalling interactions, protein functionalities and the prominent influential pathways facilitated by the primary immune cell types within the LIHC. Numerous tumour pathways, including PI2K, EGFR and TGFb, demonstrated a close correlation with the involvement of ECM in LIHC. Moreover, an evaluation was conducted to assess the primary ECM-related functional changes and biological pathway enrichment in LIHC. Differential genes associated with ECM were identified and utilised to create prognostic models. The prognostic stratification value of these models for LIHC patients was confirmed through validation in multiple databases. Furthermore, through immune infiltration analysis, it was discovered that ECM might be linked to the irregular expression and regulation of numerous immune cells. Additionally, histone acetylation was mapped against gene mutation frequencies and differential expression profiles. The prognostic stratification efficacy of the ECM prediction model constructed in the context of PD-1 inhibitor therapy was also examined, and it exhibited strong stratification performance. Cellular experiments, including Western blotting, invasion and Transwell assays, revealed that ECM-associated risk genes have a promoting effect on the development of LIHC. The creation of biomarkers for LIHC using ECM-related genes unveiled substantial correlations with immune microenvironmental infiltration and functional mutations in various tumour pathways. This enlightens us to the possibility that the influence of ECM on tumours may extend beyond simply promoting the fibrotic process and the stromal composition of tumours.

Leukoencephalopathy is a rare complication of PD1 inhibitor therapy

The indications for immunotherapy are expanding every year and the therapeutic algorithms for most types of solid tumors are steadily evolving towards the wider and earlier use of immune checkpoint inhibitors (ICI). However, everything has its price, and along with the treatment response, this class of drugs has brought a number of peculiar autoimmune complications associated with ICI and called immune-related adverse events (irAEs). Taking into account the peculiarities of the mechanism of action, the range of complications of this therapy is limited only by the list of structures and tissues of the human body. A special place is occupied by neurological adverse events due to their diversity, complexity of diagnosis requiring multidisciplinary approach, and relatively low prevalence.The purpose of this work is to describe the peculiarities of the course and diagnosis of leukoencephalopathy on the background of skin melanoma treatment with the use of checkpoint inhibitors. A clinical case of a patient with melanoma IIC who developed retrograde amnesia and convulsive syndrome on the background of immunotherapy is presented. On the basis of clinical picture and examination data the diagnosis of «leukoencephalopathy» was established. Any organs and systems can be affected during the whole period of ICT treatment. Clinicians should keep in mind the possibility of leukoencephalopathy development after the start of this therapy.

Impact of programmed cell death protein 1 inhibitor therapy on the survival of patients with advanced or recurrent uterine cancers: a meta-analysis.

No prior meta-analysis has investigated the impact of programmed cell death protein 1 (PD-1) inhibitor therapy on survival outcomes in patients with advanced or recurrent uterine cancers (including both corpus and cervical cancers). A comprehensive search of PubMed and Embase databases was conducted, covering the past 10 years (up to August 2023) and encompassing all clinical research related to uterine cancer. Five randomized controlled trials and one cohort study met the inclusion criteria and were included in the meta-analysis. Data on patient demographics, clinical characteristics, treatment regimens, and survival outcomes were extracted. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as the relative risk of grade 3 or higher adverse events, were pooled using random-effects models. Patients receiving PD-1 inhibitors had better OS (HR, 0.65, 95% CI, 0.59-0.72; P<.001) and PFS (HR, 0.59, 95% CI, 0.49-0.70; P<.001) than those receiving variable non-PD-1 inhibitor therapies among 3452 uterine cancer patients. The leave-one-out meta-analysis of the HR of OS showed no individual study impact on the estimation of the overall effect size. Subgroup analysis revealed better OS in the PD-1 inhibitors use than the controls in cervical cancer (HR, 0.68, 95% CI, 0.59-0.79), endometrial cancer (HR, 0.62, 95% CI, 0.54-0.72), and pembrolizumab use (HR, 0.66, 95% CI, 0.57-0.75) subgroups. Patients with advanced cervical cancer, who had CPS > 1, receiving PD-1 inhibitors have statistically significant benefits in OS compared to controls (HR, 0.65, 95% CI, 0.53-0.80). The pooled HR for overall survival was 0.71 (95% CI, 0.60-0.82; P<.001) in patients who received PD-1 inhibitors as compared to those who did not receive PD-1 inhibitors in proficient mismatch repair (MMR) endometrial cancer patients. However, in deficient MMR patients, the HR was 0.30 (95% CI, 0.13-0.70). The relative risk of grade 3 or higher adverse events was not higher in the PD-1 inhibitor group (relative risk, 1.12, 95% CI, 0.98-1.27). Survival was significantly better using PD-1 inhibitor therapy than variable non-PD-1 inhibitor chemotherapies among patients with advanced or recurrent uterine cancers.

The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy.

Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

Abstract A008: Intermittent fasting in combination with PD-inhibitor treatment as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer

Abstract Objective: Endometrial cancer (EC) incidence and mortality continue to rise, with obesity a well-known driver of this disease. Obesity is associated with excess estrogen, hyperinsulinemia, activation of the Akt/mTOR pathway, chronic inflammation and a heightened capacity to harvest dietary energy, which all contribute to the development and progression of EC. Intermittent energy restriction (IER) is thought to have anti-tumorigenic benefits and has been shown to have synergistic effects with chemotherapy and hormonal therapy in various cancer types. IER may also promote anti-tumor immune responses by stimulating CD4+ and CD8+ cells, making this dietary strategy an innovative therapeutic partner with PD-1 inhibitors, which are commonly used in EC. Thus, we evaluated the anti-tumorigenic effects of a switch from high fat diet (HFD) to either IER or low-fat diet (LFD) with PD-1 inhibitor treatment in a mouse model of obesity-driven endometrioid EC. Methods: Lkb1fl/flp53fl/fl mice were fed either HFD or LFD starting at 4 weeks of age. At 12 weeks of age, the HFD-fed mice were randomized to three treatment groups: HFD, HFD-LFD switch or HFD-IER switch. The LFD-fed mice were maintained on LFD. At 16 weeks of age, all mice were injected with AdCre into the left uterine horn to induce EC development. At 26 weeks of age, mice were treated with placebo or a mouse PD-1 inhibitor (BioXCell) (10mg/kg, 2 times/wk, intraperitoneal) for 4 wks (N=8-10 mice per group). RNAseq was performed to determine differences in immune pathways between ECs of obese and lean mice. CD4+ and CD8+ T cells in tumors of obese and lean mice were evaluated by flow cytometry. Results: Obesity resulted in a 52% increase in tumor size, comparing obese versus lean mice (p&amp;lt;0.05). Expression of genes related to T-cell/B-cell receptors, NF-kappa B and TNF pathways were upregulated in the ECs of obese versus lean mice. PD-1 inhibitor therapy increased PD-1 expression on CD4+ and CD8+ T cells in both obese and lean ECs. In addition, PD-1 inhibitor treatment led to an increase in percentage of CD4+ T cells in obese and lean ECs but increased the percentage of CD8+ T cells in only lean ECs. At sacrifice and after PD-1 inhibitor treatment, mean body weights were significantly higher (p&amp;lt;0.05) in the HFD group (42g) than groups receiving LFD (29g), HFD-LFD switch (34g) or HFD-IER switch (23g). EC incidence was lowest in the HFD-IER group (~61%) and highest in the HFD group (~80%); rates were similar in the other diet groups (~75%). In placebo-treated groups, mean tumor weights were significantly lower in mice fed LFD (0.45g), HFD-LFD switch (0.41g) and HFD-IER switch (0.29g) relative to continuous HFD-fed mice (0.94g; p=0.001-0.05). PD-1 inhibitor treatment reduced EC size 24-68% across all diet groups (p=0.05-0.001); size reduction was greatest in the HFD-IER group (0.18g) relative to mice receiving continuous HFD (0.30g), HFD-LFD (0.31g) or LFD (0.31g). Conclusion: IER with PD-1 inhibitor treatment may be an innovative strategy in the management of EC, a highly obesity-driven cancer. Citation Format: Jennifer Haag, Olivia Lara, Chunxiao Zhou, Stephen D. Hursting, Victoria Bae-Jump. Intermittent fasting in combination with PD-inhibitor treatment as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A008.

Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis.

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell-cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.

Utility and predictive value of the CRAFITY score in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus tyrosine kinase inhibitors and PD-1 inhibitor

BackgroundThe prognostic significance of the CRAFITY score (CRP and AFP in ImmunoTherapY) has been demonstrated in hepatocellular carcinoma (HCC) patients receiving immunotherapy. The purpose of this study was to investigate the utility and the predictive value of CRAFITY score in HCC after transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) and immunotherapy.Materials and methodsData from patients with advanced HCC treated with TACE plus TKIs and PD-1 inhibitor from January 2019 to June 2022 were collected and analyzed retrospectively. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. Patients were divided into three groups according to their CRAFITY score (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). The differences in overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared among the three groups. Tumor response was evaluated at 3, 6 and 12 months after the first combination treatment. Risk factors for OS and PFS were assessed.ResultsA total of 70 patients were included. The patients were assigned CRAFITY scores of 0 points (CRAFITY-low, n = 25 [35.71%]), 1 point (CRAFITY-intermediate, n = 29 [41.42%]), and 2 points (CRAFITY-high, n = 16 [22.81%]). Multivariate analysis showed that lower CRAFITY score was an independent factor for the improved OS (P =.045) and PFS (P <.001). TACE session was also associated with the OS (P =.048) in the multivariate analysis. The CRAFITY-low cohort achieved a higher objective response rate (ORR) at the 3-month evaluation of tumor response. However, there was no significant difference in ORR and disease control rate (DCR) observed at the 6-month follow-up. DCR showed a statistically significant difference among three groups during the 12-month follow-up period. The percentage of patients with protein urea was highest in the CRAFITY-high group. No significance differences were observed in grade ≥ 3 AEs in three groups.ConclusionThe CRAFITY score is simple and could be useful for predicting treatment outcomes, tumor response and AEs of the HCC patients receiving TACE plus TKIs and PD-1 inhibitor therapy.

Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma.

A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy. Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs. TLS+, TLSHigh, TLS+GC+ and CD8High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs. We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

The impact of sarcopenia on the efficacy of PD-1 inhibitors in non-small cell lung cancer and potential strategies to overcome resistance.

Recent studies have revealed that sarcopenia can adversely affect the efficacy of PD-1 inhibitors in the treatment of non-small cell lung cancer (NSCLC). PD-1 inhibitors are immune checkpoint inhibitors widely used in the treatment of various cancers. However, NSCLC patients may have poorer outcomes when receiving PD-1 inhibitor treatment, and sarcopenia may affect the efficacy of PD-1 inhibitors through immune and metabolic mechanisms. In this article, we summarize the reported negative impact of sarcopenia on the effectiveness of PD-1 inhibitors in the treatment of NSCLC in recent years. Based on existing research results, we analyze the possible mechanisms by which sarcopenia affects the efficacy of PD-1 inhibitors and discuss possible strategies to address this issue. This could help to understand the impact of sarcopenia on the treatment of PD-1 inhibitors and provide more accurate expectations of treatment outcomes for clinicians and patients. Additionally, we present tailored intervention strategies for sarcopenic patients undergoing PD-1 inhibitor therapy, aiming to optimize treatment efficacy and enhance patient quality of life. Nevertheless, further research is warranted to elucidate the mechanisms through which sarcopenia impacts PD-1 inhibitors and to identify more efficacious intervention approaches for improving the effectiveness of PD-1 inhibitor treatment in sarcopenic patients.