bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of distinct circulating cytokine/chemokine profiles with clinical benefits of Pexa-Vec (thymidine kinase-deactivated vaccinia virus plus GM-CSF) and cemiplimab (REGN2810; anti-PD-1) in metastatic or unresectable renal cell carcinoma (mRCC).
Authors: Merchan Jaime R. , Bae Woo Kyun , Kim Chan , Oh Sung Yong , Lee Hyo Jin , Park Kwonoh , Mar Nataliya , Pachynski Russell Kent , Beom Seung-Hoon , Carranza Lucia , Ma Seunghyun , Mathias Melissa Divya , Seebach Frank A. , Rha Sun Young 
Published: June 2024

e14539 Background: This study explores the transformation of 'cold' tumour microenvironments into 'hot' ones in mRCC, focusing on the potential of Oncolytic Viruses (OVs) for personalized immunotherapy. Recognizing the variability in patient responses, the research underscores the necessity for reliable biomarkers. The objective is to examine the correlation between plasma cytokine/chemokine levels and the efficacy of Pexa-Vec and cemiplimab, proposing that these biomarkers could predict treatment outcomes and contribute to more personalized cancer treatment protocols. Methods: In this study, mRCC patients from the REN026 trial were categorized into three treatment groups: Pexa-Vec (Intratumoral and intravenous) and cemiplimab combination therapy (N=65), intravenous Pexa-Vec and cemiplimab combination therapy (N=54), and cemiplimab monotherapy (N=14). Blood samples were collected at baseline, during treatment, and at end of treatment (EOT) for analysis. Subsequently, the plasma samples underwent analysis using the Human Cytokine 96-Plex Discovery Assay through the Luminex 200 system. The statistical approach included the Mann–Whitney U-test or Wilcoxon signed-rank test, along with a Cox proportional hazards model. The False Discovery Rate (FDR) method was employed to control type I error. Results: During the follow-up period from June 2018 to February 2023, key outcomes were observed as follows (Table): In the Pexa-Vec and cemiplimab cohort, a lower baseline of MCP-3 or an increased rate of change in post-treatment levels of IFNβ, Eotaxin, IL-1α, and sFasL were associated with improved Progression-Free Survival (PFS). Specifically, a low baseline of MCP-3 or an increased level of Eotaxin and sFasL post-treatment correlated with enhanced Overall Survival (OS). In the intravenous Pexa-Vec and cemiplimab group, a rise in post-treatment levels of IFNβ, Eotaxin, IL-17F, and sFasL were indicative of better PFS, with elevated Eotaxin also suggesting improved OS. Within the cemiplimab monotherapy group, an increase in post-treatment IP-10 was linked to favourable PFS. Conclusions: Our findings suggest the potential utility of plasma cytokine and chemokine profiles in clinical benefits of mRCC patient to the combination of Pexa-Vec and cemiplimab, thereby aiding in future personalized treatment approaches.
Platelet-mediated circulating tumor cell evasion from natural killer cell killing via immune checkpoint CD155-TIGIT.
Authors: Sun Yun-Fan , Li Tong , Ding Lin , Wang Jiyan , Chen Chen , Liu Te , Liu Yu , Li Qian , Wang Chuyu , Huo Ran , Wang Hao , Tian Tongtong , Zhang Chunyan , Pan Baishen , Zhou Jian , Fan Jia , Yang Xin-Rong , Yang Wenjing , Wang Beili , Guo Wei 
Published: June 2024

e14552 Background: Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear. The interaction between platelets and CTCs is the most extensively studied of all blood cells, and it is well known that CTCs are surrounded by platelets, which form microplots on their surface and play a crucial role in cancer metastasis. The precise mechanisms platelets employ to contribute to CTC immune evasion have not been fully elucidated. Our previous single-cell RNA sequencing data indicated high expression of platelet-related genes in CTCs. Here, our study demonstrated that platelet adhesion to CTCs is prevalent in multiple cancers and is indispensable for CTCs metastasis. Methods: CTC isolation was performed by our self-established ChimeraX-i120 platform. CTC-platelet adhesions were identified by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. The cytotoxicity of natural killer (NK) cells was assessed by the reduction in tumor cell numbers measured using the xCELLigence system. In vitro and ex vivo co-culture systems were established by using platelets and NK cells isolated from the peripheral blood of patients for direct or indirect co-culturing with cell lines and patient-derived organoids (PDOs). The effects of platelets and NK cells on metastasis and immune responses were investigated in vivo by utilizing mouse models. Results: Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from NK cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis. Conclusions: Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.
Potential of near real-time detection of cancer and immuno-oncology failure, within weeks of initiating therapy.
Authors: Taub Floyd , Russo Matthew , Wright Suzin Mayerson , Henry Charles 
Published: June 2024

e14555 Background: For most areas of internal medical practice, biochemical and/or clinical tests rapidly allow physicians to evaluate if a drug being administered has activity in that patient. Unfortunately, for most of oncology, measuring response is by imaging after delay of months. Methods: In 2018 the Trau lab published that the pan-cancer DNA methylation pattern (general hypomethylation with specific hypermethylation) resulted in physico-chemical alteration in purified circulating tumor DNA (ctDNA) as well as genomic DNA. Detecting these changes were not sequence dependent, but rather the epigenetic alterations resulted in altered binding to a specific electrode, easily and quickly measured by differential pulse voltammetry. In 2022 our group using the “aiElectrode” method showed significantly improved ability to cleanly separate cfDNA from people with cancer and those without, as well as anecdotal success in using the method to separate progression from regression. The improved method is used here. Results: Here we present analysis of samples from 18 cancer patients from 3 small series with cfDNA taken before and after treatment; 20 pairs could be analyzed. The Scripps Clinic Bio-Repository supplied samples from 8 lymphoma patients before and after treatment with chemotherapy and a bone marrow transplant; all showed initially clinical improvement and decrease in the ctDNA by the aiElectrode. Subsequently 2 relapsed and in both cases ctDNA analysis showed increased ctDNA. The Drammen Hospital in Norway supplied 18 samples from 7 patients (2 or 3 time points each) with NSCLC treated with pembrolizumab immunotherapy. One responded and 6 had progression. The aiElectrode ctDNA results were concordant for all but one of the 7 patients. The University of Colorado provided before and after therapy specimens from three patients. In total, 20 pairs of specimens were analyzed and 19 were concordant, generating an accuracy of 95%. Some of the post treatment samples from Drammen were as early as 2 weeks after therapy initiation. Conclusions: As IO may result in cures, but also may result in pseudoprogression or hyperprogression, a simple, rapid turnaround, inexpensive, blood test to aid clinicians in the early detection of failing IO, and thus individualized switching to an alternative therapy (which typically costs much less) may be beneficial, even life saving for that patient, while reducing direct as well as indirect costs. Unlike other ctDNA technologies, this can eventually be offered in a small, point-of-care device that is simple and inexpensive enough for use at every oncologist office visit to provide near real-time tracking of treatment response. [Table: see text]
Cytotoxic function of human natural killer cells is transiently inhibited by transforming growth factor beta (TGFβ).
Authors: Patel Anjali , Maiocco Giuseppe , Mirto Catherine , Torry Donald S. , Wilber Andrew 
Published: June 2024

e14557 Background: Natural killer (NK) cells can eliminate early neoplastic cells, however, their efficacy as an adoptive therapy for solid tumors is limited. We have shown that NK cells recovered from human kidney tumors are CD56pos/CD16dim/neg, poorly cytotoxic, and produce vascular endothelial growth factor (VEGF). These features are analogous to human decidual NK (dNK) cells that support the development and growth of the placenta during implantation. Transforming growth factor beta (TGFβ) is found at high levels in the decidua and kidney tumor environment, and is known to convert peripheral blood NK (pNK) cells to dNK-like cells in vitro. We hypothesized that TGFβ-mediated inhibition of NK cell proliferation and function is transient and therefore reversible. Methods: pNK cells were isolated from healthy donors (HD) by negative selection or purchased from ATCC (NK-92; CRL-2407). RT-qPCR and flow cytometry were used to assess NK markers: CD56, CD16 NKp46, CD49a, CD69; TGFβ receptors R1, R2, R3; VEGF; and cytokines IFNγ, TNFα. NK cells were cultured for 4-5 days with proliferative cytokines IL2 or IL15 alone and in combination, and without or with TGFβ (2-5 ng/mL). Cytotoxic function of NK cells (effectors) was quantified by lysis of human K562 cells engineered to express firefly luciferase (targets). Statistics (ANOVA/t-test) were performed using GraphPad Prism with p≤0.05 considered significant. Results: pNK cells from HD were CD56pos/CD16pos and NK-92 cells were CD56pos/CD16neg as reported. Both expressed all three TGFβ receptors, required IL2 or IL15 to survive in culture and were potently cytotoxic against K562 targets. TGFβ treatment of NK cells cultured with IL2 or IL2 plus IL15 suppressed proliferation by 20% and potently inhibited cytotoxic ability (85% reduction; p≤0.05). TGFβ caused significant changes in CD49a (35% increase), CD69 (45% increase) and IFNγ (50% decrease) but had no effect on NKp46, VEGF, or TNFα. TGFβ-mediated changes in NK cell phenotype and function reverted to normal when NK cells were returned to standard culture conditions for 4-5 days. Conclusions: Despite differences in CD16 expression, pNK cells and NK-92 cells are potently cytotoxic and represent an effective anti-cancer therapy. TGFβ limits this potential by blocking the proliferative effects of IL2 and IL15 and quelling cytotoxic function. TGFβ caused increased expression of integrin CD49a, a marker of tissue resident immune cells, and the early lymphocyte activation marker CD69. Augmentation of these surface markers was concomitant with diminution of IFN-γ, a cytokine critical for cell-mediated responses to tumors. These collective changes are akin to dNK cells that are not cytotoxic and instead support the implant. Importantly, all alterations were restored if NK cells were no longer exposed to TGFβ. Thus, inhibition of TGFβ signaling could preserve NK function in the tumor environment.
An exhaustive pre-clinical study of a circRNA drug candidate (cmRNA1210) encoding IL-12sc for anti-tumor therapeutics.
Authors: Wang Shuhang , Yang Jiali , Wei Lixiang , Tan Yiling , Sun Jiaojiao , Wu Fan , Huang Lingkun , Ma Peiwen , Zhou Jiawei , Zhao Guo , Wang Yuning , Tang Qiyu , Zuo Chijian , Li Ning 
Published: June 2024

e14569 Background: Circular RNA as emerging technology hasn't been approved of acceptance of any IND application. What’s the pharmacokinetics, pharmacodynamics and toxicity study of circular RNA drug candidate would be like is still unpublished. Here we provide an exhaustive pre-clinical study of a novel circular RNA drug candidate encoding IL-12sc, the immune stimulatory effector. Methods: Here, we performed an exhaustive pre-clinical study of a circular RNA drug candidate(cmRNA1210) encoding IL-12sc, including pharmacokinetics, pharmacodynamics, pharmacology and toxicology study. Meanwhile, we explored the bioactivity and cross reactivity of cmRNA1210 in vitro and the pharmacokinetics in vivo. Results: cmRNA1210 and its replace molecule exhibits robust therapeutic effect and good safety in syngeneic mouse tumor model and humanized human tumor mouse model. In situ administration of cmRNA1210 achieves abscopal effect and inhibits lung metastasis progression. Treatment with cmRNA1210 leads to cytokines change in plasma and tumor, cytotoxic immune cells accumulation in tumor and tumor tissue necrosis. Dynamic transcriptome profiling of tumor tissue post cmRNA1210 treatment. Combination with checkpoint inhibitor exhibits synergy effect and significantly decreases tumor relapse rate. Kaplan-Meier survival curve in TCGA dataset shows strong correlation of high IL-12A/B expression and long survival. Conclusions: The bioactivity and cross reactivity in rodents and primates of cmRNA1210 were validated in vitro. The advantage of pharmacokinetics of circular RNA was confirmed in vivo. cmRNA1210 exhibits robust anti-tumor effect in various tumor models, indicating its wild application situation in clinical. In situ treatment achieves abscopal effect and significantly inhibits lung metastasis progression. Systemic anti-tumor effect has been successfully initiated. The pharmacodynamics study reveals there are cytokine changes, immune cells activation or accumulation at tumor site and tumor tissue necrosis after cmRNA1210 treatment. cmRNA1210 as immune stimulatory effector works synergistically with checkpoint inhibitor. Kaplan-Meier survival analysis of IL-12 expression based on TCGA dataset shows there is a strong correlation of high expression and long survival. Overall, this pre-clinical study provides elaborate results of cmRNA1210 as anti-tumor therapeutics and demonstrates the great potential to enter clinical trial in the future.
Therapeutic potential of immune-cold solid tumors through homologous recombination deficiency.
Authors: Shafi Gowhar , Ramesh Aarthi , D'Souza Alain , Prajapati Sangeeta , Jadhav Bhagwat , Hariramani Kanchan , Basavalingegowda Madhura , Jadhav Vikas Leelavati Balasaheb , Kothavade Hrishita , Mobeen Fauzul , Bharde Atul , Khandare Jayant 
Published: June 2024

e14585 Background: Genome-wide homologous recombination deficiency (HRD) score is an important parameter to select patients for HRR pathway inhibitors. HRD scores are independent therapeutic predictors unlike tumor mutation burden (TMB), and microsatellite instability (MSI) values to stratify tumors for predicting immunogenicity. Since solid tumors often choose the hallmark of immune evasion to disseminate to distant tissues, their identification and treatment through genomic signatures for immunotherapy is essential. Low TMB and MSI values are often associated with immune evasion and immune cold tumors. For such patients HRD scores can be important determinants to inform on the therapeutic potential of HRR pathway inhibitors and immune checkpoint inhibitors (ICI). In this study, we retrospectively investigated solid tumors with metastatic phenotypes exhibiting microsatellite stable (MSS), MSI-Low and TMB low phenotypes. The presence of HRR pathway deficiency in these patients may lead to chromosomal instabilities and cell surface neo-antigens thereby offering potential therapeutic benefit to PARP inhibitors and ICI. Methods: 53 metastatic cancer patients were retrospectively analysed for genome-wide HRD, TMB and MSI scores based on OncoIndx comprehensive gene panel (CGP). OncoIndx CGP targets 1080 cancer related genes along with 47 HRR genes and 1600 MSI signature sites. HRD, TMB and MSI scores were determined by sequencing the individual sample libraries in pair end mode on Illumina Nextseq platform (depth 5500X). Cutoff scores HRD high (≥50), TMB high (≥10 Mutations/MB), MSI high (≥20). Results: A cohort of 53 solid tumor patients were evaluated retrospectively of which 71.6% (n=38) patients showed metastasis (brain, Popliteal fossa, skeletal, and nodal metastasis). Of these, 9.4% (n=5) patients were detected with MSI-high, 56.6% (n=30) were MSI-Low and 1.8% (n=1) were MSS. 13.2% (n=7) patients were TMB-High, 3.7% (n=2) were TMB intermediate and 41.0% (n=22) were TMB-Low. Most importantly, 41.0% (n=22) patients were both MSI and TMB low thus transforming the tumor suggestively immune-cold. Only 22.7% (n=5) patients showed PD-L1 expression on IHC with scores ranging from TPS: 2% to 20%. In this dominantly immune-cold patient cohort, 40.9% (n=9) patients showed high/intermediate HRD (22.7% high (n=5); 18.18% Intermediate (n=4)). Conclusions: The presence of HRD in 40.9% patients in the dominant immune-cold patients was observed with increased chromosomal instability and cell surface neo-antigens. Thus, HRD could potentially transform tumors to become immune-hot to benefit from PARP inhibitors and ICI.
Synergistic antitumor activity of METTL3 peptide degrader and immune checkpoint inhibitor in advanced urothelial cancer.
Authors: Shang Shihao , Han Hong , Liu Kepu , Li Zenghui , Zhang Jie , Zhang Lei , Ju Dongen , Wei Di , Yuan Jianlin , Zhu Zheng , Shi Junfeng 
Published: June 2024

e14623 Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed the pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in immune escape and the progression of aUC. This study aimed to develop a novel METTL3 peptide degrader RKL and investigate its synergistic effects and underlying mechanisms in combination with ICI for aUC. Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while the prognostic implications of METTL3 expression in response to ICI were analyzed in the IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate the mechanistic insights. The METTL3 peptide degrader RKL was synthesized using Fmoc solid-phase peptide synthesis and purified with high-performance liquid chromatography. In vivo and in vitro experiments were conducted to assess the impact of RKL, ICI, and their combination on aUC inhibition. Results: In aUC, METTL3 exhibited the most significant up-regulation among m6A methyltransferases, while METTL14 and WTAP showed down-regulated expression. In the IMvigor210 cohort study, aUC patients with elevated METTL3 expression and treated with ICI demonstrated a poorer prognosis. scRNA-seq revealed that METTL3 upregulation promoted the expression of genes regulating cancer-associated fibroblast proliferation, contributing to enhanced tumor resistance to immunotherapy. RKL demonstrated high toxicity to urothelial carcinoma cell lines, inhibiting their proliferative, migratory, and invasive capacities in vitro. The combined treatment of RKL and ICI significantly reduced tumor volume (P<0.001), with a complete response achieved in 87.5% (7/8) of mice in the combination group, 12.5% (1/8) in the RKL group, and 25.0% (2/8) in the ICI group. Conclusions: METTL3 overexpression in aUC is associated with immune escape and resistance to ICI therapy. The METTL3 peptide degrader RKL, when combined with ICI, demonstrates synergistic antitumor effects in aUC, warranting further exploration in clinical research.
Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors.
Authors: Zhang Songling , Zhu Xiaoxue , Gao Lei , Qi Yaling , Jia Xiao , Li Yongguo , Guo Ye , Ding Yanhua 
Published: June 2024

e14627 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. It modulates the tumor immune microenvironment by decreasing tumor Treg and myeloid-derived suppressor cells (MDSC) and improves the immune response to checkpoint inhibitors (CPI) in preclinical models. Methods: The Phase Ib study was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical activity, to determine recommended phase 2 dose (RP2D) of WX390 combined with Toripalimab in patients with advanced solid tumors. WX390 was administered orally daily at escalating doses of 0.7 mg, 0.9mg and 1.1mg, with Toripalimab at 240 mg IV every 3 weeks until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma PK samples were collected up to 24 hours after the first dose at C1D1, and up to 24 hours before and after the morning dose at C1D21. Results: As of December 31, 2023, total 18 patients had been treated in 3 WX390 cohorts: 0.7 mg (n = 3), 0.9 mg (n = 3), and 1.1 mg (n = 12) once daily (QD). No dose limit toxicity (DLT) was observed, and the RP2D of WX390 in combination was 1.1 mg QD, which was consistent with the single agent RP2D. The treatment related adverse events (TRAEs) (≥20%) included hyperglycemia (17/18, 94.4%), creatinine increased (12/18, 66.7%), weight loss (10/18, 55.6%), diarrhea (9/18, 50%), proteinuria (9/18, 50%), nausea (7/18, 38.9%), lymphocytopenia (7/18, 38.9%), vomiting (7/18, 38.9%), rash (7/18, 38.9%), decreased appetite (6/18, 33.3%), hypokalemia (6/18, 33%), fatigue (5/18, 27.8%), hyponatremia (4/18, 22.2%), and thrombocytopenia (4/18, 22.2%). Grade 3 TRAEs included hyperglycemia (5/18), lymphocytopenia (4/18), rash (2/18), weight loss (2/18), leukopenia (1/18), infusion-related reaction (1/18), nausea (1/18), and stomatitis (1/18). There was no TRAE leading to treatment permanent discontinuation and no grade 4/5 TRAE were observed. PK of WX390 in combination showed similar PK profile with the single agent. Among the 16 efficacy-evaluable patients with cervical (N=8), head and neck (N=5), and urothelial cancer (N=3), 5 patients (31.3%) previously received immune checkpoint inhibitors. 3 of 5 (60%) cervical cancer patients at RP2D and 2 of 5 head and neck cancer patient (40%) have achieved confirmed partial response (PR). In addition, 3 cervical patients who were treated with 0.7 or 0.9mg QD and 1of 3 urothelial carcer patients experienced tumor shrinkage (SD). The medium progression free survival (PFS) was 5.49 months (95% CI: 2.53, 6.37). Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and encouraging antitumor effects in patients with advanced solid tumors. An RP2D of 1.1 mg qd of WX390 in combination was selected to be explored in further phase II study, which is ongoing in different tumor types. Clinical trial information: NCT06117566 .