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Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. Conclusions: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. [ABSTRACT FROM AUTHOR]

Objective: Immunotherapy targeting programmed cell death 1 (PDCD1 or PD-1) and its ligands has shown remarkable promise and the regulation mechanism of PD-1 expression has received arising attention in recent years. PDCD1 exon 3 encodes the transmembrane domain and the deletion of exon 3 produces a soluble protein isoform of PD-1 (sPD-1), which can enhance immune response by competing with full-length PD-1 protein (flPD-1 or surface PD-1) on T cell surface. However, the mechanism of PDCD1 exon 3 skipping is unclear. Methods: The online SpliceAid program and minigene expression system were used to analyze potential splicing factors involved in the splicing event of PDCD1 exon 3. The potential binding motifs of heterogeneous nuclear ribonucleoprotein K (HNRNPK) on exon 3 predicted by SpliceAid were mutated by site-directed mutagenesis technology, which were further verified by pulldown assay. Antisense oligonucleotides (ASOs) targeting the exonic splicing silencer (ESS) on PDCD1 exon 3 were synthesized and screened to suppress the skipping of exon 3. The alternative splicing of PDCD1 exon 3 was analyzed by semiquantitative reverse transcription PCR. Western blot and flow cytometry were performed to detect the surface PD-1 expression in T cells. Results: HNRNPK was screened as a key splicing factor that promoted PDCD1 exon 3 skipping, causing a decrease in flPD-1 expression on T cell membrane and an increase in sPD-1 expression. Mechanically, a key ESS has been identified on exon 3 and can be bound by HNRNPK protein to promote exon 3 skipping. Blocking the interaction between ESS and HNRNPK with an ASO significantly reduced exon 3 skipping. Importantly, HNRNPK can promote exon 3 skipping of mouse Pdcd1 gene as well. Conclusions: Our study revealed a novel evolutionarily conserved regulatory mechanism of PD-1 expression. The splicing factor HNRNPK markedly promoted PDCD1 exon 3 skipping by binding to the ESS on PDCD1 exon 3, resulting in decreased expression of flPD-1 and increased expression of sPD-1 in T cells. [ABSTRACT FROM AUTHOR]

Abstract Background Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1+ lymphocytes. Due to solid tumor heterogeneity of PD-1+ populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1+ tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging. Methods We designed a 13 kDa β-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1. Results Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1+ populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with 68Galium isotope. Radiochemical purity of 68Ga-MBA proteins reached values 94.7–99.3% and in vitro stability in human serum after 120 min was in the range 94.6–98.2%. The distribution of 68Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1+ populations in solid tumors. Conclusions Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging. Graphical Abstract

Objective To investigate the effect of tumor-infiltrating B cells on the therapeutic efficacy of programmed death ligand-1 [PD-(L)1] inhibitors and elucidate the potential mechanisms. Methods Based on immunotherapy cohorts for melanoma patients in public databases, the relationship of B cells with progression-free survival (PFS) and response to immune checkpoint inhibitors treatment was analyzed. TC-1 and B16-OVA cells were implanted subcutaneously and in the liver in 6-8-week-old female C57BL/6 mice to establish tumor xenograft models. The effect of B cell clearance on PD-(L)1 therapy was compared. Flow cytometry was performed on the 15th day of TC-1 tumor microenvironment (TME) to confirm the number, function and phenotypic changes of T cells. Flow cytometry and quantitative real-time polymerase chain reaction (qPCR) were used to detect B cell surface molecules and cytokines. Results Based on ERP105482 data from the ICBatlas public database, high CD19 expression in the tumors was associated with longer PFS in melanoma patients (753 vs 95 d, HR=0.3, 95%CI: 0.13~0.65, P=0.003). B cells were significantly enriched in immunotherapy-responsive patients (P=0.01). In a mouse TC-1 liver-loaded tumor model, PD-(L)1 antibody treatment reduced tumor mass (P < 0.01), whereas B-cell clearance attenuated the therapeutic efficacy. B cells enhanced PD-(L)1 antibody treatment by promoting T cell infiltration and function, and the treatment resulted in changes in B cell subsets, as evidenced by an increase in PD-1 low-expressing subsets (P < 0.01). Conclusion After PD-(L)1 treatment, a decrease in PD-1 expression on B cell subsets might be one of the potential mechanisms by which B cells enhance the efficacy of PD-(L)1 therapy.

Simple Summary: This research revealed that the downregulation of fumarate hydratase in patients is associated with poor prognosis. Mechanistically, FH binds to RAN, which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. Importantly, combined therapy targeting PCSK9 and PD-1 may be beneficial for patients with CRC and low FH expression. Considering these results, our findings hold potential for future clinical applications. Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect. [ABSTRACT FROM AUTHOR]

BackgroundCreatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.MethodsOne hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023. A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates.ResultsThe CCR was positively correlated with SMI (r=0.43; P0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P

Introduction: Breast cancer is the most common malignant tumour and the leading cause of cancer-related death in women is breast cancer. The Immunohistochemistry (IHC) method utilised antigens and antibodies to interact to identify cellular or tissue constituents (antigens). This research has been employed as a diagnostic tool for specific cancers. When Programmed Cell Death Ligand 1 (PD-L1) binds to Programmed Cell Death 1 (PD-1), it suppresses the cellular immune response by killing and depleting T-cells. Monoclonal antibodies that block the PD-1/ PD-L1 pathway have shown promise as a treatment strategy currently being tested in human cancer trials. Need for the study: Breast cancer is a global issue, and PDL1 expression is emerging as a promising biomarker for breast cancer prognosis. It can provide valuable information treatment planning. Aim: The current study aims to examine the expression of PD-1 and PD-L1 in breast cancer using IHC in all subgroups of breast cancer patients. Both tests can serve as a biomarkers to guide immunotherapeutic interventions, improving prognosis, and correlating with other clinicopathological individual parameters such as age, tumour size, distant metastasis, lymph node involvement, Estrogen Receptor (ER) and Progesterone Receptor (PR) status, Her2neu expression, histological type, and TNM stage. Materials and Methods: This will be a two-year cohort study conducted in the Department of Pathology, Jawaharlal Nehru Medical College (JNMC), Maharashtra, India. The study will include 70 specimens from all cases with a histopathological diagnosis of breast cancer. The Nottingham variant of the Bloom-Richardson Grading System will be used to determine the histological grade of the tumour, and immunostaining for PD-1 and PD-L1 will be performed to evaluate their protein expression.

Introduction: Breast cancer is the most common malignant tumour and the leading cause of cancer-related death in women is breast cancer. The Immunohistochemistry (IHC) method utilised antigens and antibodies to interact to identify cellular or tissue constituents (antigens). This research has been employed as a diagnostic tool for specific cancers. When Programmed Cell Death Ligand 1 (PD-L1) binds to Programmed Cell Death 1 (PD-1), it suppresses the cellular immune response by killing and depleting T-cells. Monoclonal antibodies that block the PD-1/PD-L1 pathway have shown promise as a treatment strategy currently being tested in human cancer trials. Need for the study: Breast cancer is a global issue, and PDL1 expression is emerging as a promising biomarker for breast cancer prognosis. It can provide valuable information treatment planning. Aim: The current study aims to examine the expression of PD-1 and PD-L1 in breast cancer using IHC in all subgroups of breast cancer patients. Both tests can serve as a biomarkers to guide immunotherapeutic interventions, improving prognosis, and correlating with other clinicopathological individual parameters such as age, tumour size, distant metastasis, lymph node involvement, Estrogen Receptor (ER) and Progesterone Receptor (PR) status, Her2neu expression, histological type, and TNM stage. Materials and Methods: This will be a two-year cohort study conducted in the Department of Pathology, Jawaharlal Nehru Medical College (JNMC), Maharashtra, India. The study will include 70 specimens from all cases with a histopathological diagnosis of breast cancer. The Nottingham variant of the Bloom-Richardson Grading System will be used to determine the histological grade of the tumour, and immunostaining for PD-1 and PD-L1 will be performed to evaluate their protein expression. [ABSTRACT FROM AUTHOR]

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity. [ABSTRACT FROM AUTHOR]

Background: The level of C‑reactive protein (CRP) and alpha‑fetoprotein (AFP) in immunotherapy (CRAFITY) score was associated with the prognosis of hepatocellular carcinoma (HCC) patients treated with immunotherapy. Based on the CRAFITY score, this study aimed to investigate the efficacy and safety of locoregional-immunotherapy for treating HCC patients. Methods: HCC patients who received locoregional-immunotherapy were consecutively recruited at Sun Yat-sen University Cancer Center in 2019. CRAFITY 0 score was defined as the AFP level below 100 ng/ml and a CRP level of less than 1 mg/dl, CRAFITY 1 score was defined as the AFP level of at least 100 ng/ml or the CRP level of at least 1 mg/dl, and CRAFITY 2 score was defined as both the AFP level over 100 ng/ml and the CRP level of more than 1 mg/dl. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The second outcomes were tumor response rate and treatment-related adverse events (AEs). Results: The median PFS for HCC patients with the CRAFITY 0 score was not estimable. The PFS was 11.0 months [95% confidence interval (CI) 7.2–14.9] and 6.0 months (95% CI 4.2–7.8) for patients with CRAFITY 1 and 2 scores, respectively, with a significant difference between the two groups (p < 0.001). HCC patients with CRAFITY 0, 1, and 2 scores had 3 years OS rates of 63.8%, 60.8%, and 32.1%, respectively, with statistical differences among the three groups (p < 0.001). Patients with the CRAFITY 2 score were more likely to experience fever than those with other scores (p < 0.05). A greater CRAFITY score was correlated with a higher incidence of grade 3 and above liver injury (p < 0.01). Conclusions: The CRAFITY score is a superior predictor of prognosis and treatment-related AEs in HCC patients treated with locoregional-immunotherapy. [ABSTRACT FROM AUTHOR]

As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.

This study aims to determine the prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) in triple- negative breast cancer (TNBC). PD-L1 expression and TIL percentage were determined in TNBCs that did not receive neoadjuvant therapy. The relationship between PD-L1 expression and the percentage of TILs with survival was investigated. The presence of intratumoural PD-L1-positive tumour-infiltrating immune cells (TIICs) in tumours with ≥ 1% PD-L1 expression was identified as a new PD-L1 evaluation parameter. The presence of intratumoural PD-L1-positive TIICs as a new parameter in PD-L1-positive cases increased overall survival. The percentage of TILs increased in both overall and distant metastasis-free survival (p = 0.040 and p = 0.006, respectively). As a result, it was found that the risk of death was increased 5.18-fold (p = 0.013) in patients without intratumoural PD-L1-positive TIICs. This risk of death was calculated to be 5.40-fold higher in patients with TIL percentage ≤ 10% than in those with > 40% (p = 0.024), and the risk of distant metastasis was calculated to be 11.95 times higher. In our study, we discovered that the percentage of TILs made a statistically significant difference in TNBC survival. The presence of intratumoural PD-L1-positive TIICs in PD-L1-positive cases significantly increased survival.

This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer. Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3+ lymphocytes (including regulatory T cells (Tregs)), CD163+ monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)+ lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups. The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1+ cells in the ST, FOXP3+ lymphocytes in both areas, and CD163+monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed. In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1+ cells and inhibit the infiltration of FOXP3+ lymphocytes and CD163+monocytes into the tumor environment. [ABSTRACT FROM AUTHOR]

Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand 1 (PD-L1), have improved the survival in multiple types of cancers; however, ICIs may cause cardiovascular toxicity. Although rare, ICI-mediated cardiotoxicity is an extremely serious complication with a relatively high mortality. In this review, we discuss the underlying mechanism and clinical manifestations of cardiovascular toxicity induced by ICIs. According to previous studies, multiple signaling pathways are involved in myocarditis induced by ICIs. Further, we summarize the clinical trials of drugs for the treatment of ICI-associated myocarditis. Although these drugs have shown the beneficial effects of alleviating cardiac function and reducing mortality rates, their efficacy is not optimal. Finally, we discuss the therapeutic potential of some novel compounds as well as the underlying mechanisms of their action. [ABSTRACT FROM AUTHOR]

Sepsis is a multiple organ dysfunction syndrome caused by the host's immune response to infection, with extremely high incidence and mortality. Immunosuppression is an essential pathophysiological alteration that influences the clinical treatment and prognosis of sepsis. Recent studies have suggested that the programmed cell death 1 signaling pathway is involved in the formation of immunosuppression in sepsis. In this review, we systematically present the mechanisms of immune dysregulation in sepsis and elucidate the expression and regulatory effects of the programmed cell death 1 signaling pathway on immune cells associated with sepsis. We then specify current research developments and prospects for the application of the programmed cell death 1 signaling pathway in immunomodulatory therapy for sepsis. Several open questions and future research are discussed at the end. [ABSTRACT FROM AUTHOR]

Simple Summary: The immunological profile of pleomorphic invasive lobular cancer is poorly investigated. pILC is characterized by more aggressive behavior and a worse prognosis; however, this rare subtype lacks a specific treatment approach. Here, we investigated the expression of sTILs and analyzed the PD-L1 expression levels from sixty-six patients with pILC. Moreover, we analyzed the association between sTILs and PD-L1 expression with other prognostic or predictive biomarkers and correlated sTILs and PD-L1 expression with survival outcomes. sTILS (≥1%) was present in 64% of the patients, and 36% of the tumors demonstrated a positive PD-L1 using SP142 (≥1%) and 28% had a positive PD-L1 score of ≥1 using 22C3. We found no differences between the molecular subtypes, the clinicopathological features, and the immune parameters, probably due to the small sample size of the HER2+ and TN subgroups. Larger trials on the immune composition of the subtypes of lobular breast cancer are needed. Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area using the following cut-offs: 0%; <5%; 5–9%; and 10–50%. The PD-L1 expression was analyzed using IHC on formalin-fixed, paraffin-embedded tissue sections using SP142 and 22C3 antibodies. Results: A total of 82% of the sixty-six patients were hormone receptor positive and 8% of cases were triple negative (TN), while 10% showed human epidermal growth factor receptor 2 (HER2) amplification. sTILs (≥1%) were present in 64% of the study population. Using the SP142 antibody, 36% of tumors demonstrated a positive PD-L1 score of ≥1%, and using the 22C3 antibody, 28% had a positive PD-L1 score of ≥1. There was no correlation between sTILs or PD-L1 expression and tumor size, tumor grade, nodal status, expression of estrogen receptor (ER), or amplification of HER2. Our data did not show any difference in survival between the three molecular subtypes of pILC with respect to sTILs and PD-L1 expression. Conclusion: This study shows that pILCs show some degree of sTILs and PD-L1 expression; however, this was not associated with a survival improvement. Additional large trials are needed to understand immune infiltration in lobular cancer, especially in the pleomorphic subtype. [ABSTRACT FROM AUTHOR]

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies. [ABSTRACT FROM AUTHOR]

The important role of the immune system in the surveillance and control of keratinocyte cancers (KCs), namely squamous and basal cell carcinomas, is increasingly appreciated, as new immunotherapies have recently become available. As the field of immunotherapy is rapidly evolving, this review synthesizes key concepts and highlights important cellular components within the immune system responsible for attacking KCs. We review the most current data on the epidemiology, risk factors, and immunotherapy management for KCs. Patients will seek advice from dermatologists to help explain why immunotherapies work for KCs and whether they might be appropriate for different clinical scenarios. Collaboration with medical colleagues across different disciplines to evaluate KCs for response to immunotherapy and early recognition of immune-related adverse events will help to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Gastric cancer treatments are evolving rapidly. For example, immune checkpoint inhibitors, especially those that target PD-1 or PD-L1, have long-term efficacy in a subset of gastric cancer patients, and are currently the first-line therapy. Immunotherapies approved for use in untreated gastric cancer patients include monotherapy and chemotherapy-immunotherapy combinations. Major clinical trials have reported efficacy and safety data suggesting that PD-L1 expression is important for regimen selection, although other biomarkers, clinicopathologic factors, and patient preference might also be relevant in other situations. Currently, several novel biomarkers and therapeutic strategies are being assessed, which might refine the current treatment paradigm. In this review, we describe the current treatment regimens for patients with gastric cancer and detail the approach we use for the selection of first-line immunotherapy regimens. [ABSTRACT FROM AUTHOR]

This study aims to determine the prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC). PD-L1 expression and TIL percentage were determined in TNBCs that did not receive neoadjuvant therapy. The relationship between PD-L1 expression and the percentage of TILs with survival was investigated. The presence of intratumoural PD-L1-positive tumour-infiltrating immune cells (TIICs) in tumours with ≥ 1% PD-L1 expression was identified as a new PD-L1 evaluation parameter. The presence of intratumoural PD-L1-positive TIICs as a new parameter in PD-L1-positive cases increased overall survival. The percentage of TILs increased in both overall and distant metastasis-free survival (p = 0.040 and p = 0.006, respectively). As a result, it was found that the risk of death was increased 5.18-fold (p = 0.013) in patients without intratumoural PD-L1-positive TIICs. This risk of death was calculated to be 5.40-fold higher in patients with TIL percentage ≤ 10% than in those with > 40% (p = 0.024), and the risk of distant metastasis was calculated to be 11.95 times higher. In our study, we discovered that the percentage of TILs made a statistically significant difference in TNBC survival. The presence of intratumoural PD-L1-positive TIICs in PD-L1-positive cases significantly increased survival. [ABSTRACT FROM AUTHOR]

Background and purpose: The clinical role of postoperative adjuvant therapy in hepatocellular carcinoma (HCC) is still unclear. The purpose of our study was to explore the clinical value of postoperative adjuvant anti-programed cell death 1 antibody (PA-PD-1) on the prognosis of HCC patients with high relapse risks after surgery. Patients and methods: Data of consecutive HCC patients with high recurrence risks treated with liver resection at our center during January 2019 and March 2021 were prospectively collected. Baseline differences were balanced between HCC patients with (PA-PD-1 group) or without PA-PD-1 (non-PD-1 group) after hepatectomy by propensity-score matching (PSM). Between these two groups, we compared overall survival (OS) and recurrence-free survival (RFS). Independent prognostic risk factors for OS and RFS were confirmed by Cox regression analysis, and subgroup analysis was also performed. Results: 47 pairs of patients with or without PD-1 treatment after hepatectomy were matched. After PSM, the 1-year and 2-year RFS was 58.4% and 44.1% in the PA-PD-1 group, and 34.0% and 21.3% in the non-PD-1 group (p = 0.008). The OS at 1 year and 2 years was 91.2% and 91.2% in the PA-PD-1 group, compared with 85.1% and 61.7% in the non-PD-1 group (p = 0.024). Multivariable analyses demonstrated that PA-PD-1 was an independent protective predictor associated with RFS and OS. Through subgroup analysis, we concluded that HCC patients with portal venous tumor thrombus (PVTT) or tumor size ≥ 5 cm significantly benefited from PA-PD-1 therapy in RFS and OS. Conclusions: Adjuvant anti-PD-1 antibody can effectively improve the survival outcomes of HCC patients with high relapse risks after hepatectomy in this prospective observational study. This finding should be confirmed by results of the ongoing phase 3 randomized controlled trials. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.

Increased incidence of breast cancer has stimulated development of new diagnostic and therapeutic methods. The programmed cell death 1 (PD1) pathway and its inhibitors are promising avenues for investigation. PD1 includes PD ligands 1 (PDL1) and 2 (PDL2). We investigated the expression of PD1 and PDL1 in invasive breast carcinomas using immunohistochemical staining. We used 171 invasive breast carcinoma specimens from which tissue microarray blocks were created. Immunohistochemical staining of PD1 using NAT105, and PDL1 using CAL10 was performed on tissue microarray sections. NAT105 and CAL10 are useful clones for detecting expression of PD1 and PDL1. PD1 and PDL1 immunostaining was significantly stronger in carcinomas with basal-like phenotype compared to other molecular breast cancer types. PD1 and PDL1 expression also was associated with a high histologic grade and a high Ki-67 index. PD1 expression also was associated with lymphovascular invasion and axillary metastasis. PD1 and PDL1 expression is associated with aggressive tumor behavior and a basal-like phenotype in breast cancer. We suggest that inhibition of the PD1/PDL1 pathway, particularly in triple negative breast carcinomas with basal-like phenotype, might be useful for targeted immunotherapy. [ABSTRACT FROM AUTHOR]

The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through a retrospective analysis. Patients with resected stage III melanoma at Fudan University Shanghai Cancer Center from 2017 to 2021 were enrolled with all of their clinicopathologic characteristics collected. They were divided into three groups: PD-1 inhibitor, IFN, and OBS. Survival analyses were performed to indicate the significance of different adjuvant therapies. A total of 199 patients were enrolled (PD-1 n = 126; IFN n = 31; and OBS n = 42), with their median follow-up times being 21 months, 24 months, and 49 months, respectively. The PD-1 inhibitor significantly improved relapse-free survival (p = 0.027) and overall survival (p = 0.033) compared with conventional treatment (IFN+OBS). The superiority of the PD-1 inhibitor was witnessed in stage IIIC/D (p = 0.000) acral (p = 0.05) melanoma patients with ulceration (p = 0.011) or lymph node macrometastasis (p = 0.010). The PD-1 inhibitor significantly reduced local recurrence and systemic metastasis compared with conventional therapy (p = 0.002). In conclusion, adjuvant anti-PD-1 immunotherapy can achieve better survival outcomes in acral and cutaneous melanoma patients compared with conventional treatment, without considering adverse events. More clinical benefits were seen in later-stage acral melanoma patients with ulceration or lymph node macrometastasis. [ABSTRACT FROM AUTHOR]

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.

Background: Programmed cell death 1(PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an immune checkpoint implicated in immune tolerance and involved in the pathogenesis of several autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple immune dysregulation. This study aimed to determine PD-1 and PD-L1 expressed levels on both CD3 T and CD19 B lymphocytes in SLE patients compared to healthy donors and their associations with the clinical data and disease activity of those patients. Patients and Methods: A total of 25 healthy donors and 80 SLE patients were involved in the study. PD-1 and PD-L1 expressed levels on each of CD3 T and CD19 B lymphocytes were determined in the peripheral blood (PB) using flow cytometry. Results: The expressed levels of PD-1 and PD-L1 on both CD3 T and CD19 B lymphocytes were significantly higher in PB of SLE group than that of controls (P = 0.01, P = 0.001, P = 0.009, and P = 0.001). Significant positive associations were found between PD-1 and PD-L1 expressions on both CD3 T and CD19 B lymphocytes with disease activity in SLE group (P < 0.05). Conclusion: PD-1 and its ligand PD-L1 could have a role as regulators for immune activation in patients with SLE. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide. Traditional approaches, such as surgery, chemotherapy, and radiotherapy have been the main cancer therapeutic modalities in recent years. Cancer immunotherapy is a novel therapeutic modality that potentiates the immune responses of patients against malignancy. Immune checkpoint proteins expressed on T cells or tumor cells serve as a target for inhibiting T cell overactivation, maintaining the balance between self-reactivity and autoimmunity. Tumors essentially hijack the immune checkpoint pathway in order to survive and spread. Immune checkpoint inhibitors (ICIs) are being developed as a result to reactivate the anti-tumor immune response. Recent advances in nanotechnology have contributed to the development of successful, safe, and efficient anticancer drug systems based on nanoparticles. Nanoparticle-based cancer immunotherapy overcomes numerous challenges and offers novel strategies for improving conventional immunotherapies. The fundamental and physiochemical properties of nanoparticles depend on various cancer therapeutic strategies, such as chemotherapeutics, nucleic acid-based treatments, photothermal therapy, and photodynamic agents. The review discusses the use of nanoparticles as carriers for delivering immune checkpoint inhibitors and their efficacy in cancer combination therapy. [ABSTRACT FROM AUTHOR]

Introduction: The treatment of non-small cell lung cancer (NSCLC) has profoundly changed on account of the arrival of new therapies, like immunotherapy. Within this group of drugs, those aimed at the programmed cell death-1 or programmed cell death ligand-1(PD1/PDL-1) are very relevant, for example, Pembrolizumab. Although its adverse reactions are generally mild and well tolerated, it has been associated with certain immune-related adverse events (IrAEs) than can be serious and affect any organ. Case report: A 62-year-old woman diagnosed with stage IV NSCLC with a single bone metastasis and PD-L1 expression of 60% started treatment with cisplatin-pemetrexed-pembrolizumab, and maintenance with pembrolizumab. Management and outcome: The patient attended the ER with pericardial effusion that was assumed to be a Pembrolizumab IrAE and was managed with corticosteroids. The patient fully recovered but immunotherapy was not reintroduced due to the severity of the AE. Discussion: The cardiovascular system is among the least affected organs by immunotoxicity, with an incidence between 0.09–0.6%. However, some authors suspect the incidence is underestimated. Median time to onset is highly variable, ranging from 6 weeks since the first dose to 2 years after discontinuation of the treatment. There are not guidelines on the most effective management of the IrAEs, but according to the pharmaceutical reference, corticosteroids should be initiated followed by a progressive reduction. If no response is obtained, another immunosuppressive agent should be added. The determination to restart immunotherapy depends on the severity of the adverse reaction, the availability of other alternative treatments, and the cancer response. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1(PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an immune checkpoint implicated in immune tolerance and involved in the pathogenesis of several autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple immune dysregulation. This study aimed to determine PD-1 and PD-L1 expressed levels on both CD3 T and CD19 B lymphocytes in SLE patients compared to healthy donors and their associations with the clinical data and disease activity of those patients. Patients and Methods: A total of 25 healthy donors and 80 SLE patients were involved in the study. PD-1 and PD-L1 expressed levels on each of CD3 T and CD19 B lymphocytes were determined in the peripheral blood (PB) using flow cytometry. Results: The expressed levels of PD-1 and PD-L1 on both CD3 T and CD19 B lymphocytes were significantly higher in PB of SLE group than that of controls (P = 0.01, P = 0.001, P = 0.009, and P = 0.001). Significant positive associations were found between PD-1 and PD-L1 expressions on both CD3 T and CD19 B lymphocytes with disease activity in SLE group (P < 0.05). Conclusion: PD-1 and its ligand PD-L1 could have a role as regulators for immune activation in patients with SLE.

Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy has limited effects in the treatment of solid tumors. Sulforaphane (SFN) is known to play an important role in inhibiting tumor growth, but its effect on CAR-T cells remains unclear. The goal of the current study was to determine whether combined CAR-T cells and SFN could provide antitumor efficacy against solid tumors. Methods The effect of combined SFN and CAR-T cells was determined in vitro using a co-culture system and in vivo using a xenograft mouse model. We further validated the effects of combination therapy in patients with cancer. Results In vitro, the combination of SFN and CAR-T cells resulted in enhanced cytotoxicity and increased lysis of tumor cells. We found that SFN suppressed programmed cell death 1 (PD-1) expression in CAR-T cells and potentiated antitumor functions in vitro and in vivo. As a ligand of PD-1, programmed cell death ligand 1 (PD-L1) expression was also decreased in tumor cells after SFN treatment. In addition, β-TrCP was increased by SFN, resulting in higher activation of ubiquitination-mediated proteolysis of PD-L1, which induced PD-L1 degradation. The combination of SFN and CAR-T cell therapy acted synergistically to promote better immune responses in vivo compared with monotherapy. In clinical treatments, PD-1 expression was lower, and proinflammatory cytokine levels were higher in patients with various cancers who received CAR-T cells and took SFN orally than that in the control group. Conclusion SFN improves the cytotoxicity of CAR-T cells by modulating the PD-1/PD-L1 pathway, which may provide a promising strategy for the combination of SFN with CAR-T cells for cancer immunotherapy.

Background: The specific efficacy of immunotherapy for patients with liver metastases of gastric cancer is unclear. This study set out to explore the treatment response and related prognostic factors for patients with liver metastases of gastric cancer treated with immunotherapy. Patients and methods: This retrospective cohort study included 135 patients with unresectable advanced gastric cancer. According to the presence of liver metastases and/or first-line treatment with immunotherapy, patients were divided into the following three groups: I-LM(-) group(patients without liver metastases treated with immunotherapy, n=66), I-LM(+) group(patients with liver metastases treated with immunotherapy, n=36), C-LM(+) group(patients with liver metastases treated with chemotherapy and/or target therapy, n=33). Cox regression analyses were used to identify factors associated with survival in all patients and the three groups, respectively. Results: For the patients with liver metastases treated with immunotherapy, multivariate analysis showed that only the presence of peritoneal metastases was significantly associated with shorter PFS [hazard ratios (HR), 3.23; 95% CI, 1.12-9.32; P=0.030] and the patients with peritoneal metastases had shorter median PFS than patients without peritoneal metastases(3.1 vs 18.4 months; P=0.004), while the objective response rate was 100% in patients with HER2-positive (2 complete radiographic responses and 2 partial responses; 3 of 4 patients were still ongoing benefits [median follow-up time, 15.3 months; interquartile range(IQR), 6.3-17.9 months]). Conclusions: The findings suggest that patients with various types of gastric cancer liver metastases respond differently to immune checkpoint inhibitors, HER2-positive patients may derive clinical benefits from immune checkpoint inhibitors, while the presence of peritoneal metastases is associated with resistance. [ABSTRACT FROM AUTHOR]

Introduction: Camrelizumab is an antibody against programmed death protein 1 (PD-1) and is one of immune checkpoint inhibitors (ICI). ICI may lead to autoimmune myocarditis, which has a variety of clinical manifestations and usually has a poor prognosis. This article will discuss these clinical manifestations through 2 cases of ICI-related myocarditis caused by carrelizumab. Case report: We reviewed the patients who received tumor treatment in our hospital from September 2019 to June 2020. A total of 155 patients received camrelizumab treatment. there were 2 cases of acute myocarditis, accounting for 1.29%, and 8 cases of new-onset arrhythmia. Here we present 2 cases of active myocarditis in a 69-year-old man with primary liver cancer and a 75-year-old man with non-small-cell lung cancer after treatment with camrelizumab. Management and outcome: The first patient presented with severe heart failure and died of malignant arrhythmia after being treated with glucocorticoid. The second patient presented with numbness of the extremities, weakness, and mild dyspnea. The symptoms gradually improved after treatment with glucocorticoid. The Naranjo scores of these two cases were 6 and 7, which suggested that myocarditis was probably caused by carrelizumab. Discussion: ICI has been successfully used to treat a variety of malignant tumors with good results. However, blocking immune checkpoints by ICI may lead to autoimmune myocarditis with a poor prognosis. Early detection of cardiotoxicity may be possible through the patient's clinical manifestations and some commonly used cardiac examination methods. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs. [ABSTRACT FROM AUTHOR]

Background and Objective: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy., Methods: Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator's choice of chemotherapy (paclitaxel [175 mg/m 2 ], docetaxel [75 mg/m 2 ], or vinflunine [320 mg/m 2 ], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response., Key Findings and Limitations: An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing., Conclusions and Clinical Implications: When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC., (Copyright © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA., The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC)., Aim: To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC., Methods: Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m 2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m 2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group., Results: Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) ( P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) ( P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group ( P > 0.05)., Conclusion: Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: We aimed to identify the immune checkpoint Programmed cell death 1 (PD-1)-related gene signatures to predict the overall survival of lung adenocarcinoma (LUAD). Methods: RNA-seq datasets associated with LUAD as well as clinical information were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Based on the expression level of PD-1, Kaplan-Meier (K-M) survival analysis was performed to divide samples into PD-1 high- and low- expression groups. Then, differentially expressed genes (DEGs) between high- and low- expression groups were identified. Meanwhile, samples were divided into the high and low immune infiltration groups according to score of immune cell, followed by screening of DEGs between these two groups. Subsequently, DEGs related to both PD-1 expression and immune infiltration was integrated to obtain the overlapping genes. Lasso COX regressions were implemented to construct prognostic signatures. The prognostic model was validated using an independent GEO dataset and TCGA cohorts. In addition, the predictive ability of the seven-gene prognostic model with other molecular biomarkers was compared. Results: A seven-gene signature (DPT, ITGAD, CLECL1, SYT13, DUSP26, AMPD1, and NELL2) related to PD-1 was developed through Lasso Cox regression. Univariate and multivariate regression analyses indicated that the constructed risk model was an independent prognostic factor. K-M survival analysis indicated that patients in the high risk group had significantly worse prognosis than those in the low risk group. Further, the results of validation analysis showed that this model was reliable and effective. Conclusions: The constructed prognostic model can predict overall survival in LUAD patients with great predictive performance, and it may be applied for diagnosis and adjuvant treatment of LUAD in clinical trials.

Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area using the following cut-offs: 0%;

Gastric cancer treatments are evolving rapidly. For example, immune checkpoint inhibitors, especially those that target PD-1 or PD-L1, have long-term efficacy in a subset of gastric cancer patients, and are currently the first-line therapy. Immunotherapies approved for use in untreated gastric cancer patients include monotherapy and chemotherapy-immunotherapy combinations. Major clinical trials have reported efficacy and safety data suggesting that PD-L1 expression is important for regimen selection, although other biomarkers, clinicopathologic factors, and patient preference might also be relevant in other situations. Currently, several novel biomarkers and therapeutic strategies are being assessed, which might refine the current treatment paradigm. In this review, we describe the current treatment regimens for patients with gastric cancer and detail the approach we use for the selection of first-line immunotherapy regimens.

Simple Summary: We developed a method using cell-derived lipid membrane capsules—called extracellular vesicles (EVs)—to deliver a model cargo into cytosol. These EVs were fused with liposomes (to form hybrid EVs) because cargo molecules can be more easily encapsulated within liposomes than EVs. EVs were engineered that expressed programmed cell death 1 (PD-1) and baculoviral envelope glycoprotein (gp64), which enabled the hybrid EVs to be internalized in cells and fuse with acidic organelles. The model cargo, Texas Red-labeled dextran, was shown to be released to the cytosol from the hybrid EVs by fusion with acidic organelles, such as late endosomes and lysosomes. Thus, these hybrid EVs are potential drug delivery carriers. Extracellular vesicles (EVs) are cell-derived lipid membrane capsules that can deliver functional molecules, such as nucleic acids, to target cells. Currently, the application of EVs is limited because of the difficulty of loading cargo into EVs. We constructed hybrid EVs by the fusion of liposomes and insect cell-derived EVs expressing recombinant programmed cell death 1 (PD-1) protein and baculoviral fusogenic glycoprotein gp64, and evaluated delivery of the model cargo molecule, Texas Red-labeled dextran (TR-Dex), into the cytosol. When PD-1 hybrid EVs were added to HeLa cells, the intracellular uptake of the hybrid EVs was increased compared with hybrid EVs without PD-1. After cellular uptake, the PD-1 hybrid EVs were shown to be localized to late endosomes or lysosomes. The results of fluorescence resonance energy transfer (FRET) indicated that membrane fusion between the hybrid EVs and organelles had occurred in the acidic environment of the organelles. When TR-Dex-loaded liposomes were fused with the PD-1 EVs, confocal laser scanning microscopy indicated that TR-Dex was distributed throughout the cells, which suggested that endosomal escape of TR-Dex, through membrane fusion between the hybrid EVs and acidic organelles, had occurred. These engineered PD-1 hybrid EVs have potential as delivery carriers for biopharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer (CC) is the third most common cancer worldwide, with high mortality rates. The programmed cell death 1 (PD-1)/(PD-1 ligand) PD-L1 has been reported to be an effective indicator in cancer development. In this study, we aim to explore the role of PD-1/PD-L1 in the evaluation of concurrent chemoradiotherapy (CCRT) efficacy and prognosis in CC patients. Methods: We included 55 CC patients in this study. Immunohistochemistry and flow cytometry were employed to detect the expression of PD-1, Treg cells, CD8, and CD68 in tumor tissues, and the contents of PD-1+ CD8+ T cells, PD-1+ CD4+ T cells, and PD-1+ Treg cells in the peripheral blood. The relationships of these indexes with CCRT efficacy were measured by Spearman correlation analysis, overall survival (OS), and disease-free survival (DFS) of patients were analyzed by Kaplan–Meier estimator, and the diagnostic values of these indexes in CC were assessed by a receiver operating characteristic (ROC) curve. Results: The clinical effectivity rate of CCRT was 89.10%. The positive expressions of PD-L1, Treg cells, PD-1+ CD8+ T cells, PD-1+ CD4+ T cells, and PD-1+ Treg cells were reduced after CCRT, while the CD8 and CD68 increased. All 7 indexes had diagnostic values in evaluating CCRT efficacy and were considered the influencing factors of OS, DFS, and the prognosis of CC patients. Conclusion: These findings indicate that PD-1/PD-L1 may be a potential indicator for the efficacy evaluation of CCRT and the prognosis of CC. This study may offer potential targets for CC treatment. [ABSTRACT FROM AUTHOR]

Objective: The present network meta-analysis (NMA) was conducted to summarize the direct and indirect evidence of common programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors including avelumab, atezolizumab, cemiplimab, nivolumab, and pembrolizumab for the treatment of non-small cell lung cancer (NSCLC) patients and further to determine the optimal therapeutic regimen. Methods: We performed a systematic literature search to identify all potentially eligible studies in PubMed, Embase, and the Cochrane Library until August 7, 2021. The primary outcome was overall survival (OS), and the second outcome was treatment-related adverse events (TRAEs). We used random-effects model to conduct direct and network meta-analyses, which were performed by using RevMan 5.3 and R version 3.6.1, respectively. Results: Direct meta-analysis suggested that atezolizumab, cemiplimab, nivolumab, or pembrolizumab significantly improved OS compared with chemotherapy (CT), and NMA further established that atezolizumab [hazard ratio (HR), 0.77; 95% CrI, 0.62–0.96], nivolumab (HR, 0.75; 95% CrI, 0.62–0.93), or pembrolizumab (HR, 0.71; 95% Credible interval (Crl), 0.57–0.89) significantly and cemiplimab (HR, 0.68; 95% CrI, 0.46–1.02) numerically improved OS compared with CT. Meanwhile, NMA also indicated that cemiplimab was numerically superior to other PD-1/PD-L1 agents. Moreover, avelumab, atezolizumab, cemiplimab, nivolumab, and pembrolizumab were found to have fewer TRAEs compared with CT in direct meta-analysis, which were supported by the results from the NMA. Meanwhile, surface under the cumulative ranking curve (SUCRA) and ranking probability suggested that cemiplimab provided the most favorable balance between efficacy and safety, with the first ranking for the OS. Conclusions: Based on available evidence, cemiplimab may have the most favorable risk–benefit ratio for NSCLC patients compared with other common therapeutic management. However, future research with a large-scale, high-quality, and mature follow-up is needed to further determine which agents should be preferentially selected for NSCLC patients due to the limitations of our NMA and variations of eligible studies in treatment line and PD-L1 status. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) have been approved to prolong overall survival (OS), compared to other treatments. However, the recent studies reported consistent and inconsistent results. Hence, we conducted this meta-analysis to evaluate the efficacy of ICIs. Materials and Methods: The articles were identified by searching PubMed, Embase, and Google Scholar published up to December 2021. A total of 12,126 participants (6,450 cases and 5,676 controls) were involved in the meta-analysis. Median OS and median progression-free survival (PFS) were selected to evaluate the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab or pembrolizumab, and atezolizumab, respectively). Utilizing the random-effect model, hazard ratios (HRs) with 95 confidence intervals (CIs) were calculated by R software. Results: We observed a significant association between cancer patients and ICIs in OS (HR = 0.79, CI = 0.74–0.84) and PFS (HR = 0.80, CI = 0.75–0.86). Conclusions: The meta-analysis suggested that ICIs were associated with obvious improvements in PFS and OS compared with non-ICI therapies. [ABSTRACT FROM AUTHOR]