bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitors in advanced malignant peritoneal mesothelioma: Clinical insights, immunopathologic profiling, and prognostic implications from a single-center study.
Authors: Strauss Gal Zvi , Gondra Helena , Schwartz Ignat , Appel Sarit , Weitzen Rony , Berger Yaniv , Ben Yaacov Almog , Nissan Aviram , Ben Ami Eytan Aharon 
Published: June 2024

e14665 Background: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the peritoneum. In patients with advanced disease, therapeutic options are limited, and prognosis is usually poor. While the role of immune-checkpoint inhibitors (ICI) in MPM is evolving, clinical data is scarce and there are currently no biomarkers to predict response to ICI therapy in this population. Methods: Patients treated at the Sheba Medical Center between 2016-2022 have been examined with the aim of delineating the clinical and immunopathologic characteristics of MPM, including programmed-death ligand-1 (PDL-1) status. Results: Forty-two patients with MPM were treated at Sheba during the study period. Eight patients (19%) have received immunotherapy as a single treatment in our cohort, all as ≥2 line of treatment. Of these patients, 3 patients (37.5%) had complete response (CR) or partial response (PR) as their best response, 3 patients (37.5%) had stable disease (SD), and 2 patients (25%) had progressive disease. Median overall survival (OS) among responding patients (CR/PR) and patients with clinical benefit (CR/PR/SD) were 6.8 years and 5.2 years, respectively, noticeably higher than the median OS for MPM (2.5 years). PDL-1 status was available for 23 patients: 17/23 (74%) had negative PDL-1 status and 6/23 (26%) had positive PDL-1 status. No correlation was observed in PDL-1 status among patients experiencing clinical benefit from treatment with ICIs. Conclusions: ICI therapy could be considered as a reasonable option for second-line therapy and beyond for MPM, with selected patients who may substantially benefit from these treatments. PDL-1 status did not correlate with treatment benefit, which highlights the limitation of this biomarker as a predictor of response in MPM patients.
Fusobacterium nucleatum to promote esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of macrophages to the tumour micro environment.
Authors: Su Yu , Yang Jin , Zhu xue Cong , Zuo Jing 
Published: June 2024

e14668 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignant tumor in China. Recent studies have shown that Fusobacterium nucleatum ( F. nucleatum) promotes ESCC progression through various mechanisms. One of them is about changing the tumor micro- environment through cytokine–cytokine receptor interaction. Methods: From January 2022 to June 2023, a total of 34 patients with ESCC from 4th Hospital of Hebei Medical University thoracic surgery were enrolled. All of the patients did not apply any neoadjuvant therapy before and received radical resection. Real-time reverse transcriptase - PCR (RT-PCR) were performed to examine the expressions of F. nucleatum in tumor tissues and para-tumor tissue. According to the CT values of the RT-PCR results, the level of the F. nucleatum infection could be separated in two groups - positive group and negative group. Immunohistochemistry (IHC) staining were used to examine the expressions of chemokine CCL20 in both groups. Immunofluorescence (IF) was characterised homing receptors CCR6 on CD206+ macrophages. In addition, transwell assay was carried on to quantify macrophages migration ability towards chemokines CCL20 in vitro. Results: F. nucleatum DNA positivity was significantly associated with higher expression of chemokine CCL20 and accumulation of CD68+CD206+ macrophages. F. nucleatum DNA positivity was also significantly correlated with worse histopathological grading. Otherwise, there were no significant correlation between F. nucleatum infection and gender, age, tobacco or alcohol use, T or N grade, TNM stage, tumor locations, blood vessel or nerve invasion and tumor size. IHC showed that the expression of CCL20 were higher in F. nucleatum DNA positive tumor tissue. After coculture with F. nucleatum and KYSE30 cell lines in vitro, the CCL20 production by KYSE30 cells were accelerated. In addition, immunofluorescence showed that CCL20 could recruit M2-like macrophages into the tumor environment by bonding CCR6 existed on the cell surface. Furthermore, the migration ability of macrophages was distinctly elevated by CCL20 result from F. nucleatum infection. Conclusions: F. nucleatum promotes esophageal squamous cell carcinoma progression via CCL20/CCR6-mediated migration of M2-like macrophages to the tumor micro- environment and deteriorates the suppression of the local immune micro- environment within the tumor. Such bacteria may be a biomarker to predict the efficacy of immunotherapy in ESCC. [Table: see text]
A rapid strategy to develop personalized cancer nanovaccines for different immunogenic tumors.
Authors: Li Xia , Shirahata Naoto , Yamazaki Tomohiko , Hanagata Nobutaka 
Published: June 2024

e14670 Background: Therapeutic cancer vaccines aim to train the immune system and elicit antitumor immune responses, which are expected to fill the unmet medical need of immune checkpoint inhibitors. Despite tremendous efforts over the past decades, it remains challenging to prepare personalized cancer vaccines using a facile and rapid approach due to tumor diversity. CpG-ODN is a promising immunoadjuvant in cancer immunotherapy, and many clinical trials have been performed or are ongoing. However, commonly used phosphorothioate-modified CpG ODN easily induces protein aggregation and its long-term side effects are concerned. Here, we designed hollow large-pore mesoporous organosilica with sulfide bond to simultaneously load unmodified CpG-ODN with guanine-quadruplex (G4) structures and different tumor antigens to prepare personalized cancer vaccines in a simple, fast, and effective way. Methods: High-immunogenicE.G7-OVA lymphoma or low-immunogenic Lewis lung carcinoma (LLC) cells were subcutaneously inoculated into the left flanks to establish tumor-bearing mice. On days 4, 7, and 10 post tumor inoculation, cancer vaccines prepared using model antigen (OVA) or autologous tumor antigen (LLC tumor cell lysate) were subcutaneously injected into the right flanks of mice, respectively. Saline group, free tumor antigen group, free tumor antigen + CpG-ODN group, tumor antigen + organosilica group were used as controls. The size of tumors was monitored. Results: Cancer vaccines against E.G7-OVA showed high loading efficiencies of >95% for both CpG-ODN and OVA, triggered antitumor immune response with high percentages of CD4+, CD8+, tetramer+CD8+ T cells in splenocytes, and effectively inhibited the growth of established tumor, compared with free OVA, free OVA + CpG-ODN, free OVA + organosilica groups. Cancer vaccines against LLC exhibited high loading efficiencies of >95% and >80% for CpG-ODN and LLC tumor cell lysate, activated antitumor immune response with high percentages of CD4+ and CD8+ T cells in splenocytes and CD8+ T, NK and M1 cells in tumor sites, and effectively inhibited the growth of established tumor, compared with control groups. Conclusions: Codelivery of CpG-ODN and different tumor antigens using hollow large-pore mesoporous organosilica elicits antitumor immunity against both high-immunogenic and low-immunogenic tumors.
In vitro cell killing proficiency of autologous immune cells educated with allogenic multi-cancer tumor cell lysate.
Authors: Datar Rajan , Page Raymond , Patil Darshana , Shanmugam Kirubakaran , Akolkar Dadasaheb 
Published: June 2024

e14675 Background: Allogenic tumor lysate therapies offer a novel approach in oncology, to initiate a measured immune system response to combat cancer. Loaded with tumor antigens, these lysates stimulate the patient's immune system for targeted cancer cell destruction. In vitro data suggesting efficacy is pivotal prior to clinical trials. Per-C-Vax is a novel, organ-agnostic, allogenic tumor lysate immuno-stimulant, and is intended to target solid organ malignancies via subcutaneous injection. It is derived from a multi-organ cell-line cocktail, which has been induced into apoptosis to capture diverse Tumor Associated Molecular Patterns (TAMPs) and Damage Associated Molecular Patterns (DAMPs). Our study assesses Per-C-Vax-educated patient-specific immunocytes' in-vitro cell-killing activity against their autologous tumor cells. Methods: We collected simultaneous blood and tumor tissue samples from 22 patients with solid organ tumors under approved protocols. The cohort included 10 head and neck (45%), 4 breast (18%), and 8 other cancers (36%) comprising colorectal, ovary, lung, gallbladder, prostate, uterine, cervix, and gastric cancers. Peripheral Blood Mononuclear Cells (PBMCs) from a 10 ml venous draw were split into control and Per-C-Vax incubated aliquots for each patient. Approximately 1,000 tumor cells, stained with Calcein AM, were co-cultured with about 20,000 cells from each of the Per-C-Vax and control PBMC aliquots (autologous). Imaging-based pre- and post-co-culture counts determined the cell-kill rate for each aliquot. Results: PBMCs not treated with Per C Vax showed a significantly reduced cancer cell killing activity against autologous tumor cells compared to Per-C-Vax -treated PBMCs, suggesting the tolerogenic characteristic of immunocytes to the malignancy (0%-32%, 95% CI 10.16 to 16.65). On the other hand, PBMCs treated with Per-C-Vax showed significant cell-kill activity ranging from 46% to 84% in head and neck (mean 62.1%, 95% CI 52.67 to 71.53), 51% to 73% in breast (mean 62%, 95% CI 44.33 to 79.67), 38% to 87% in other cancers (colorectal, ovary, lung, gallbladder, prostate, uterine, cervix, gastric) (mean 50.87%, 95% CI 37.71 to 64.04). A comparative analysis between the untreated group and the group treated with Per-C-Vax revealed a statistically significant result with a p-value <0.005. Conclusions: Patient-specific PBMCs incubated with Per-C-Vax tumor lysate immuno-stimulant show significant autologous cancer cell killing activity against multiple cancers in vitro. Human trials to establish safety and efficacy are planned.
Unveiling a novel NKG2A inhibitor based on monoclonal antibody to HLAE-peptide complex.
Authors: Abu Ahmad Muhammad Khalid , Radinsky Olga , Porgador Angel , Momburg Frank 
Published: June 2024

e14677 Background: HLAE is a non-classical MHC class I molecule complexed with the VMAPRTLFL nonapeptide, derived from the leader sequence of HLAG (HLAEpHLAG). HLAEpHLAG is overexpressed across a wide type of tumors prominently on Multiple Myeloma (MM). HLAEpHLAG complex is the ligand to CD94-NKG2A in the immune system which negatively regulates the activation of natural killer (NK) cells as well as NKG2A positive T cells. Harnessing of the HLAE-NKG2A axis by the cancer cells leads to evasion from the immune system attack resulting in cancer progression. Currently, several Immune Checkpoint Inhibitors (ICIs) target the NKG2A receptor which has a low specificity to cancer and high toxicity to the patient. Engineering a new ICI that targets the HLAEpHLAG complex can potentially yield improved outcomes in cancer therapy. Methods: Using the hybridoma system, a new mouse monoclonal antibody (mAb) called 4D7 that targets the HLAEpHLAG complex was developed. mAb 4D7 affinity was assessed in vitro with recombinant proteins and a panel of cell lines that expressed zero to high levels of HLAE. The functional impacts of the mAb 4D7 was examined in a system where various MM cell lines were separately co-cultured with primary NK (pNK) cells. pNK were isolated from the peripheral blood of 5 healthy donors, and their activity was examined in the presence of mAb 4D7 by CD107a degranulation assay. Also, the functional impacts of the mAb 4D7 on allogenic pNK and MM blast cells, isolated from the bone marrow of 6 MM patients were assessed. Results: mAb 4D7 was determined to be an IgG-kappa isotype showing a high specific binding to recombinant HLAEpHLAG. Cell lines with overexpression of membranal HLAEpHLAG: RPMI8226, U266, 721.221 HLAE, and 721.221 HLAG showed positive staining with the mAb 4D7. While cell lines with low to zero expression of HLA-E like 721.221 WT showed low or negative staining with the mAb 4D7. The degranulation of NKG2A+ pNK subset cells against MM target cells increased in presence of mAb 4D7. However, adding mAb 4D7 to NKG2A -pNK subset cells co-cultured with MM target cells did not affect the pNK activity. Similar results were obtained when the target and effector cells were isolated from the bone marrow of active treatment-naive MM patients. Conclusions: MAb 4D7 demonstrates a remarkably high affinity for binding to the HLAEpHLAG complex, ensuring the safety of its application. The ability of 4D7 mAb to effectively block the HLAEpHLAG complex and counteract the inhibition signal in NK cells. mAb 4D7 is a promising monoclonal antibody with substantial potential to serve as an ICI for clinical use in MM patients.
Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.
Authors: Wang Hongye , Geng Haigang , Wu Zhaorong , Zhong Yiqing , Song Zhenyu , Bian Linke , Cui Dan , Zhai Bo 
Published: June 2024

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.
Incidence of brain metastases within the VA Healthcare System.
Authors: LaBella Dominic , Salama Joseph Kamel , Boyer Matthew J. 
Published: June 2024

e14691 Background: Advancements in cancer detection and treatment are thought to underlie decreasing cancer mortality rates. The influence of these on the development of brain metastases, which can be a driving factor for mortality, has not been addressed in a modern cohort. Methods: The age adjusted incidence (AAI) of brain metastases (BMs) from any primary and those with an underlying breast, colorectal, lung, kidney, or melanoma primary were calculated by federal fiscal year from 2005 through 2019 in the VA Healthcare System (VAHS) based on the timing of the first documentation of ICD9 or ICD10 codes in the patient’s medical record, The AAI rates were calculated based on the age distribution in VAHS and US census in 2020. Incidence proportions (IPs) were calculated by dividing the number of brain metastases with an underlying primary by the number of cases of that primary from 2005-2009. Results: 36,598 new BM cases of any underlying primary were diagnosed from 2005-2019. 96.2% of diagnoses were in men, 17.9% in African-Americans. The median age at diagnosis was 66.4 years old. 67.9% of BMs cases had a prior lung cancer diagnosis. The IP of lung, colorectal, kidney, melanoma, and breast cancer were 13.7%, 1.87%, 3.67%, 4.31%, and 3.08%, respectively. Overall, the AAI of BMs in the VAHS increased from 22.5 in 2005 to 24.6 in 2012 then decreased to 16.8 in 2019. Similar trends in the AAI of BMs with a lung, colorectal, kidney, or melanoma primary were observed (Table). The AAI of BMs with a breast primary increased from 2005 to 2019 (Table 1). The decrease in BM AAI from 2005 to 2019 paralleled decreases in lung (104.6 to 73.4), colorectal (63.9 to 37.5), kidney (27.5 to 26.4) and breast (140.5 to 136.1) cancer AAI as well as melanoma (28.2 to 21.7) AAI over the same time, respectively. Conclusions: In a modern cohort from the largest integrated health care system in the United States, the IPs of BMs from five primary sites associated with BMs were lower compared to older cohorts and the AAI rates decreased over time. Future studies will assess the impact of modern screening and treatment on BM incidence. [Table: see text]
Impact of commonly prescribed medications on immune-related adverse events.
Authors: Brinzevich Daria , Falvello Virginia , Green Michael D , Bryant Alex 
Published: June 2024

e14704 Background: Commonly used medications may have immune modulating properties that affect the risk of immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) therapy. Methods: We identified 27,998 patients who received ICI from 2010 to 2023 in the national Veterans Affairs system, matched to 66,488 historical control patients treated with non-ICI systemic therapies. We extracted medication usage in the year before therapy start. We used propensity-weighted Cox regression analysis to assess the effect of each medication on severe irAE (treatment with prolonged course of high-dose steroids, adrenal insufficiency, or new insulin-dependent diabetes). To identify medication effects specific to ICI vs. other therapies, we report the adjusted hazard ratio (aHR) for each medication stratified by cohort (ICI vs. historical control) and the p-value for the interaction between each medication class and cohort. Results: Among ICI patients, 52% of patients were treated in the first line, 72% received ICI monotherapy, and 95% received PD-1/PD-L1 inhibitors alone. The most common cancer types were NSCLC (46%), melanoma (10%), and liver cancer (8%). Among 15 medication classes, metformin, loop diuretics, and PPIs were associated with small, marginally statistically significant differences in toxicity among ICI patients, but similar associations were observed in historical control patients (p for interaction >0.18; Table). After adjustment for multiple comparisons, no medication classes were associated with increased risk of severe irAE in ICI patients. Conclusions: Commonly prescribed medication classes have no significant effects on toxicity specific to ICI therapy. [Table: see text]
The timing of checkpoint inhibition in relation to stem cell transplantation increases the risk of inflammatory adverse events.
Authors: Varatharajalu Krishnavathana , Shatila Malek , Pizuorno Machado Antonio , Shah Jay Sanjay , Urias Rivera Andres Caleb , Naz Sidra , Glombicki Stephen , Lu Eric , Short Nicholas James , Thomas Anusha , Zhang Hao Chi , Wang Yinghong 
Published: June 2024

e14706 Background: Stem cell transplantation (SCT) and immune checkpoint inhibitors (ICIs) are both used to treat hematological malignancies. There may sometimes be an overlap in the patient’s exposure to both treatments. Theoretically, ICIs potentiate the graft-versus-tumor effect following SCT but may increase the risk of inflammatory adverse events (AEs). Conversely, immunosuppression following SCT may decrease the risk of immune-mediated AEs. We aim to explore the effect of immunotherapy on the risk and severity of inflammatory AEs following SCT. Methods: We performed a single-center, retrospective chart review including all patients with a hematological malignancy who were treated with immunotherapy and received SCT. Patients who did not receive immunosuppressive regimens after their transplant (e.g., autologous transplants) were excluded. Patients were divided into 2 groups based on the timing of ICI: pre-SCT ICI (group 1) and post-SCT ICI (group 2). We gathered clinical data including patient demographics, post-SCT immunosuppressive regimens, and pre- and post-SCT inflammatory AEs. Results: 63 patients were included. Around 82% of patients in group 1 experienced a post-transplant AE compared to 50% in group 2 ( p = 0.014). These AEs occurred earlier in group 1 patients (median 57 days in group 1 vs. 195 in group 2; p = 0.007). Roughly 80% of the inflammatory conditions involved the gastrointestinal system. Severity and complication rates did not differ between groups, but gastrointestinal inflammation in group 1 was more likely to require immunosuppressive medication (75.7% and 37.8% requiring corticosteroids and selective immunosuppressive therapy, respectively, in group 1 patients vs. 33.3% and 0% in group 2 patients; p < 0.05). Conclusions: To our knowledge, our study is one of few exploring the impact of ICI timing in relation to SCT on the risk of post-SCT inflammatory AEs. Administration of immunotherapy prior to SCT may predispose patients to inflammatory AEs after SCT, which may occur earlier and last longer than if ICIs are started after SCT. Future studies are needed to further explore this phenomenon. [Table: see text]