Intratumor injection of BCG Ag85A high-affinity peptides enhanced anti-tumor efficacy in PPD-positive melanoma.

As one of the scheduled immunization vaccines worldwide, virtually all individuals have been vaccinated with BCG vaccine. In order to verify the hypothesis that delivering BCG high-affinity peptides to tumor areas could activate the existing BCG memory T cells to attack tumor, we firstly predicted the HLA-A*0201 high-affinity peptides of BCG Ag85A protein (KLIANNTRV, GLPVEYLQV), and then, A375 melanoma cells and HLA-A*0201 PBMCs (from PPD-positive adults) were added to co-incubated with the predicted peptides in vitro. We found that the predicted BCG high-affinity peptides could be directly loaded onto the surface of tumor cells, enhancing the tumor-killing efficacy of PBMCs from PPD-positive volunteer. Then, we constructed PPD-positive mice model bearing B16F10 subcutaneous tumors and found that intratumor injection of BCG Ag85A high-affinity peptides (SGGANSPAL, YHPQQFVYAGAMSGLLD) enhanced the anti-tumor efficacy in PPD-positive melanoma mice. Along with the better anti-tumor efficacy, the expression of PDL1 on tumor cell surface was also increased, and stronger antitumor effects occurred when further combined with anti-PD1 antibody. For microenvironment analysis, the proportion of effector memory T cells was increased and the better treatment efficacy may be attributed to the elevated effector memory CD4 + T cells within the tumor. In conclusion, using the existing immune response of BCG vaccine by delivering high-affinity peptides of BCG to tumor area is a safe and promising therapy for cancer.

A multi-omics analysis-based model to predict the prognosis of low-grade gliomas.

Lower-grade gliomas (LGGs) exhibit highly variable clinical behaviors, while classic histology characteristics cannot accurately reflect the authentic biological behaviors, clinical outcomes, and prognosis of LGGs. In this study, we carried out analyses of whole exome sequencing, RNA sequencing and DNA methylation in primary vs. recurrent LGG samples, and also combined the multi-omics data to construct a prognostic prediction model. TCGA-LGG dataset was searched for LGG samples. 523 samples were used for whole exome sequencing analysis, 532 for transcriptional analysis, and 529 for DNA methylation analysis. LASSO regression was used to screen genes with significant association with LGG survival from the frequently mutated genes, differentially expressed genes, and differentially methylated genes, whereby a prediction model for prognosis of LGG was further constructed and validated. The most frequently mutated diver genes in LGGs were IDH1 (77%), TP53 (48%), ATRX (37%), etc. Top significantly up-regulated genes were C6orf15, DAO, MEOX2, etc., and top significantly down-regulated genes were DMBX1, GPR50, HMX2, etc. 2077 genes were more and 299 were less methylated in recurrent vs. primary LGG samples. Thirty-nine genes from the above analysis were included to establish a prediction model of survival, which showed that the high-score group had a very significantly shorter survival than the low-score group in both training and testing sets. ROC analysis showed that AUC was 0.817 for the training set and 0.819 for the testing set. This study will be beneficial to accurately predict the survival of LGGs to identify patients with poor prognosis to take specific treatment as early, which will help improve the treatment outcomes and prognosis of LGG.

Trauma plays an important role in acral melanoma: A retrospective study of 303 patients.

INTRODUCTION: Acral melanoma (AM) is the most common subtype of malignant melanoma in China, with a very poor prognosis. Despite the frequent reporting of trauma events in AM cases, the precise etiology of AM remains elusive. METHODS: A retrospective analysis was conducted on a cohort of 303 AM patients at Nanjing Drum Tower Hospital. The patients were categorized into four distinct groups based on different patterns of disease onset: trauma type (Type 1), pigmented nevus type (Type 2), pigmented nevi with trauma (Type 3), and pigmented nevi with natural ulceration (Type 4). Differences in clinicopathological features, genetic alterations, and tumor immune microenvironment (TIME) were analyzed. RESULTS: Traumatic events accounted for a large proportion of AM cases. Among these categories, Type 1 patients displayed the least favorable pathological traits and an immunosuppressive TIME. Common copy number variations (CNVs) were observed in CCND1, RB1, FGF19, and IL7R, while CNVs in CDK4 and TERT occurred less frequently in patients with a history of trauma (Type 1 and Type 3). Type 2 patients exhibited the most favorable pathological characteristics and genetic profiles, and demonstrated the lowest incidence of CCDN1 and RB1 CNVs but had the highest CDK4 CNVs. In contrast, the pathological behavior of Type 3 and Type 4 patients was in between Type 1 and Type 2. And patients in Type 3 and Type 4 displayed a more favorable overall microenvironment. CONCLUSION: This study provides a clinical classification of Chinese AM based on diverse clinical onset characteristics and highlights the important role of trauma in AM. These findings may help to guide the diagnosis, treatment, and prognosis of AM patients. Further investigations are imperative to elucidate the underlying mechanisms governing the association between trauma and AM.

Enhanced systemic tumor suppression by in situ vaccine combining radiation and OX40 agonist with CpG therapy.

BACKGROUND: In situ tumor vaccine has been gradually becoming a hot research field for its advantage of achieving personalized tumor therapy without prior antigen identification. Various in situ tumor vaccine regimens have been reported to exert considerable antitumor efficacy in preclinical and clinical studies. However, the design of in situ tumor vaccines still needs further optimization and the underlying immune mechanism also waits for deeper investigation. METHODS: A novel triple in situ vaccine strategy that combining local radiation with intratumoral injection of TLR9 agonist CpG and OX40 agonist was established in this sturdy. Local and abscopal antitumor efficacy as well as survival benefit were evaluated in the bilateral tumors and pulmonary metastasis model of B16F10 melanoma. In situ vaccine-induced immune responses and immune-associated variation in tumor environment were further investigated using multiparameter flow cytometry and RNA sequencing. Base on the analysis, the RT + CpG + αOX40 triple in situ vaccine was combined with checkpoint blockade therapy to explore the potential synergistic antitumor efficacy. RESULTS: Enhanced tumor suppression was observed with minimal toxicity in both treated and untreated abscopal tumors after receiving RT + CpG + αOX40 triple vaccine. The introduction of local radiation and OX40 agonist benefit more to the inhibition of local and abscopal lesions respectively, which might be partially attributed to the increase of effector memory T cells in the tumor microenvironment. Further analysis implied that the triple in situ vaccine did not only activate the microenvironment of treated tumors, with the upregulation of multiple immune-associated pathways, but also enhanced systemic antitumor responses, thus achieved superior systemic tumor control and survival benefit. Moreover, the triple in situ vaccine synergized with checkpoint blockade therapy, and significantly improved the therapeutic effect of anti-programmed cell death protein (PD)-1 antibody. CONCLUSION: This triple combining in situ vaccine induced intensive antitumor responses, mediated effective systemic tumor control and survival benefit, and displayed impressive synergistic antitumor effect with checkpoint blockade therapy. These data preliminary confirmed the efficacy, feasibility and safety of the triple combining in situ vaccine, suggesting its great application potential as both monotherapy and a part of combined immunotherapeutic regimens in clinical scenario.

Rapid Response to the Combination of Lenvatinib and Sintilimab in a Pancreatic Acinar Cell Carcinoma Patient With Elevated Alpha-Fetoprotein: A Case Report.

A 48-year old woman was diagnosed with metastatic pancreatic acinar cell carcinoma (PACC) and with a marked elevation in alpha-fetoprotein (AFP), this being a recognized but uncommon feature of PACC. As she refused chemotherapy, the combined therapy of lenvatinib and sintilimab (lenvatinib 8 mg, orally, qd; and sintilimab 100 mg, intravenous glucose tolerance test, q21d) was given, which conferred significant tumor shrinkage and long progression-free survival (>21 months). This study is the first report and description of a PACC demonstrating favorable response to the combination therapy of an antiangiogenic agent and immunotherapy.