bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of peritoneal metastases in mismatch repair deficient (dMMR) cancers treated with immune checkpoint inhibitors and variables associated with response.
Authors: Mosalem Osama M , Elhariri Ahmed , Wiest Nathaniel , Imperial Robin John Lester , Sonbol Mohamad B. , Jin Zhaohui , Jones Jeremy Clifton , Starr Jason S. 
Published: June 2023

e14576 Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many solid malignancies. ICI appears particularly effective when tumors exhibit high microsatellite instability (MSI-H) and/or mismatch repair deficient (dMMR) status. Although the response is typically quite good in this setting, there are scenarios where benefit is less than anticipated. In this study, we aimed to explore the efficacy of ICIs in patients with MSI-H/dMMR cancers with peritoneal metastasis (PM). Methods: We conducted a retrospective chart review to identify patients (pts) with PM from primary MSI-H/dMMR cancers treated with immunotherapy between 2010 and 2022 at Mayo Clinic. Data was collected to include pt demographics, tumor characteristics, pathology, tumor markers, imaging, mutational profile, and previous and subsequent treatments. The primary endpoint was disease control rate (DCR), defined as objective response rate (RECIST v1.1 criteria) or stable disease. Results: Forty-six pts with MSI-H/dMMR and PM treated with ICIs. Most of our cohort were female (61%) with a median age at diagnosis of 61 years. Colorectal cancer was the most common primary site (69.6%), followed by endometrial (6.5%). Most pts received treatment with PD-1 antibodies as second-line therapy following systemic chemotherapy. DCR of the PM was 71.6 % (n= 13 PR, 9 CR, and 9 SD), with a median duration of response of 12.6 months. Thirteen pts (28.4%) had progressive peritoneal disease on ICI with a median PFS of 2.2 months. Ascites was a poor prognosticator and predicted a lack of benefit from ICI (HR 6.6, 95% CI=2.24-19.9, p= 0.006). Mucinous and signet ring histology were common in pts with peritoneal progression (61.5%); however, this was not statistically significant (HR=1.6; 95%CI= 0.4383 to 3.899, p 0.5). Multivariate analysis for the presence or absence of BRAF and/or RAS mutations was not statistically significant in predicting response. Neither was the specific MMR gene mutation(i.e., MLH1 or PMS2). Interestingly, discordant responses between the peritoneum and other sites of metastasis to immunotherapy were seen in 13 pts (28.4%), primarily as primary peritoneal progression compared to other tumor sites. Conclusions: In our cohort, the DCR of metastatic peritoneal disease in MSI-H/dMMR tumors was approximately 71%. The presence of ascites was identified as a poor prognosticator in this setting and was associated with a lack of response/benefit from ICIs. Histologic subtype (i.e., mucinous/signet ring) did not show statistical significance in predicting ICI response. The subpopulation with discordant response to ICI suggests that peritoneal immunobiology may differ from other sites. Further research on immunotherapy response in the peritoneum is needed for this special subset of pts.
A study to evaluate the safety, tolerability, and efficacy of IBI939 in combination with sintilimab in patients with previously untreated locally advanced unresectable or metastatic PD-L1–selected non–small-cell lung cancer (NSCLC): Updated efficacy and safety results.
Authors: Wu Chunjiao , Liu Baogang , Wu Lin , Zhang Tongmei , Wang Ke , Miao Liyun , Wu Jingxun , Wang Huijuan , Fang Jian , Li Xingya , Zhang Wei , Hu Yanping , Mei Xiaodong , Song Yong , Zhu Jing , Xin Ying , He Yue , Chen Yuling , Ye Jiawei , Cheng Ying 
Published: June 2023

e14578 Background: According to studies in patients (pts) with solid tumors, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) plays an important role in tumor immunosurveillance. The preliminary results showed that IBI939 plus sintilimab demonstrated improved PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC pts with no prior systemic treatment (Ying Cheng et al. ESMO-IO, 2022). Here we report updated efficacy and safety data of this study. Methods: Eligible pts with systemic treatment-naïve, advanced or metastatic NSCLC, PD-L1 TPS ≥ 50%, and driver gene negative were enrolled and randomized 2:1 to IBI939 20 mg/kg plus sintilimab 200 mg IV Q3W (arm A) or sintilimab 200 mg monotherapy IV Q3W (arm B). The primary objective was to evaluate the ORR per RECIST v1.1. The secondary objectives include evaluation of PFS per RECIST v1.1, OS, and safety. Results: Of 42 pts enrolled, 28 pts (median age: 65; adenocarcinoma: n=19; brain metastasis: n=7) and 14 pts (median age: 58; adenocarcinoma: n=6; brain metastasis: n=1) were in arm A and arm B, respectively. As of Jan 1st, 2023, with a median PFS follow-up of 12.2 months (95% CI, 11.1-13.9) in arm A and 11.3 months (95% CI, 10.8-13.6) in arm B. The median PFS per investigator was 13.2 months (95% CI, 6.7-16.5) in arm A vs 6.4 months (95% CI, 1.4-NA) in arm B (HR: 0.62; 95% CI, 0.26-1.43). All 42 pts were included for safety analysis. The overall safety profile was consistent with the latest previous report, with no new safety signals identified in each arm. The incidence of TRAEs was 96.4% vs 78.6% (5 pts in arm A and 6 pts in arm B experienced ≥ grade 3 events), respectively. Grade ≥ 3 immune-related AEs (determined by the investigator) were reported in 3 (10.7%) pts in arm A and 4 (28.6%) pts in arm B. All reported irAEs were manageable. One pt in each arm experienced TEAE leading to end of treatment. There was no TEAE leading to death happened in arm A. Two pts experienced grade 5 TEAE in arm B, which was unknown cause of death and respiratory failure. Conclusions: With longer follow-up time, IBI939 plus sintilimab demonstrated durable PFS benefit and manageable safety profile in PD-L1 TPS ≥ 50% NSCLC patients with no prior systemic treatment. Clinical trial information: NCT04672369 .
Effect of machine learning-based integration develops M2 macrophage-activation genes signature on outcomes in nasopharyngeal carcinoma.
Authors: Huang Zongwei , Li Ying , Chen Xiaochuan , Qiu Sufang 
Published: June 2023

e14581 Background: The M2 macrophages are independent prognostic factors in nasopharyngeal carcinoma (NPC). Nevertheless, the clinical significance of M2 macrophages remains largely unexplored. Methods: We applied public single-cell sequencing data (GSE150825) to reconstruct a pseudotime trajectory of macrophage polarization in NPC and analyzed the gene expression patterns along the trajectory. GeneSwitches was used to identify the order of the critical regulatory gene during M2 macrophage activation. A novel computational framework was constructed to screen the M2 macrophage-activation genes (MAGens) for developing MAGens signature by integratively analyzing the transcriptomes data of single-cell, published dataset (GSE102349, N=88) and Fujian NPC dataset (N=188) using 10 machine learning algorithms (101 combinations). Results: Combining single-cell transcriptomics with GeneSwitches analyse, we identified SPP1 as the top switching gene and the order at which the switch takes place for the state of M2 macrophage activation. At the bulk transcriptome level, we found that the high expression of SPP1 had poor prognosis and more infiltration of M2 macrophages. Immunohistochemistry was used to validate the association between the critical regulatory gene expression and M2 macrophages. Then we analyzed the differential expressed genes (DEGs) upregulated by M2 macrophages at the single-cell transcript level. And the NPC transcriptome data was used to identify SPP1-related genes and prognostic genes. Based on the share genes of M2 macrophage DEGs，SPP1-related genes and prognostic genes, we established a five-gene MAGens signature which exhibited highly diagnostic accuracy in predicting progression-free survival in patients with NPC. Conclusions: We explored the role of SPP1 in NPC progression, M2 macrophage polarization and established an MAGens signature related prognostic model for NPC. MAGens signature could serve as a robust and promising tool to improve clinical outcomes for individual NPC patients.
Pharmacokinetics (PK) of epacadostat in combination with sirolimus in advanced malignancy.
Authors: Huang Chao Hui , Komiya Takefumi , Kasi Anup , Williamson Stephen K. , Weir Scott James , Baranda Joaquina Celebre 
Published: June 2023

e14589 Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients (pts) with advanced solid tumors and performed PK studies. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at d -7 followed by 1mg/d with E added on d1 of Cycle(C) 1 starting at 100mg bid in a 28d C at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400mg bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. PK samples from plasma samples for determination of plasma E concentrations were obtained on C1d1, prior to administration of the first E dose. Plasma samples were also obtained on C1d1 at two hours post-dose, coinciding with the previously reported Tmax for E. For pts continuing E treatment, plasma samples were obtained on C2d1, prior to dosing (representing trough drug concentrations) as well as at two hours (representing Cssmax). Results: The phase I study enrolled 15 pts. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). Mean values as well as the range of plasma E concentrations observed in the three dose cohorts at each collection time are summarized. Conclusions: The combination of SE showed results consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion. Plasma concentrations of E observed across the three dose cohorts are also consistent with those previously reported. Due the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality. Mean (range) plasma E concentrations (ng/mL) determined in samples obtained from pts at trough and two hours post-dose during treatment C1 and C2. Clinical trial information: NCT03217669 . [Table: see text]
T cell redirecting and TLR7/8 agonist encapsulated liposomes targeting HER2+ tumors: Preclinical efficacy, pharmacokinetics and safety evaluations.
Authors: Zheng Anjie , Jin Shanshan , Wang Shuhang , Wu Xuan , Xie Danting , Long Jinfeng , Dai Yongchao , Xu Fengwei , Li Ning , Xu Yuhong 
Published: June 2023

e14590 Background: T-cell dependent bispecific antibodies (TDBs) have shown limited success in solid tumor treatments. We hypothesized that it may be due to TDBs limited distribution in solid tumor tissues. We therefore propose to take advantage of the EPR (enhanced permeability and retention) effect of the liposome system to improve the PKPD properties of TDBs. The liposomes are named TRAFsomes (T cell Redirecting Antibody Fragment-anchored Liposomes). HF5050 is a TRAFsome containing on average 6 anti-CD3 and 10 anti-Her2 on each liposome surface and the toll-like TLR-7/8 agonist Resiquimod encapsulated inside at specific lipid to drug ratios. It preclinical efficacy, pharmacokinetics and safety evaluation studies are conducted to support the IND application. Methods: The T cell redirecting and target specific cytotoxic effect of HF5050 were evaluated in five PBMC co-cultured cancer cell models with different Her2 expression. Tumor cells derived from adenoid cystic carcinoma tumor tissues was also included. T cell redirection and activation are examined by T cell surface markers CD25/CD69 and secretion of IFN gamma, Perforin, and granzymes B in the absence and presence of cancer cells. For the incorporation of TLR7/8 agonist Resiquimod, we evaluated the effect of drug dose by varying the drug loading ratios in order to achieve a synergistic effect. For the in vivo efficacy studies, the N87 gastric cancer CDX model and an adenoid cystic carcinoma tumor PDX model were set on PBMC reconstructed humanized NCG-B2M mice. Pharmacokinetic and tissue distribution studies are carried out in tumor bearing mouse models as well. Results: HF5050 has shown to be a highly effective anti-cancer agent in both in vitro and in vivo studies. It mediates T cells-tumor cells redirection and cytotoxicity in a dose-dependent manner, especially in Her-2 highly expressing cell lines. HF5050 also effectively stimulates T cell activation and displays high efficacy in PBMC reconstruct humanized NCG-B2M tumor-bearing mice. Pharmacokinetic research confirms liposome successfully maintains drug levels in the bloodstream, and improves drug accumulation within tumor tissues. Conclusions: Overall, these data demonstrate that HF5050 processing a novel cell bridging function between T cells and tumor cells, and with the capability of activating immune cells. Based on the encouraging preclinical results, HF5050 exhibits promising development potential.
A phase I/II trial of NOX66 in combination with nivolumab in patients (pts) with advanced cancer.
Authors: de Souza Paul L. , Gao Bo , Marx Gavin M. , Cooper Adam James , Wilkinson Kate Jessica , McPherson Luke , Erskine Amy , Nixdorf Sheri , Putterill Leigh , Mann Timothy , Sajinovic Mila , Fatima Shadma , Scott Kieran 
Published: June 2023

e14591 Background: NOX66 (idronoxil) targets ENOX2 and suppresses STING-mediated inflammatory pathways, reducing IFN and NFκB driven cytokine production by cancer cells. Adding NOX66 to nivolumab may help overcome resistance mechanisms to checkpoint inhibitors and improve responses in patients. Methods: IONIC-1, is an open label Phase I/II trial evaluating safety and preliminary efficacy of NOX66 (suppositories daily x 1 week, then 1 week rest) combined with nivolumab (240mg IV every 2 weeks). Three dose cohorts of NOX66 are planned (1200mg daily, 1800mg daily, 2400mg daily). Objectives include safety, tolerability, and clinical and radiological responses. Two groups are being studied: 1) Pts who have prior progression on a checkpoint inhibitor; 2) Pts naïve to checkpoint inhibitors. Results: 11 pts have been treated to date; 3 in Group 1, and 8 in Group 2. All pts have received at least 2 cycles of the combination treatment; 2 pts completed 8 cycles, and 2 pts remain on study. Tumour types include lung, prostate, gastric, pancreatic, nasopharyngeal and metastatic squamous carcinoma. Early signals of tumour response based on RECIST 1.1 criteria include stable disease in 2 pts (SD at 8 weeks and at 16 weeks); partial response (PR) in 1 patient at 16 weeks; complete response (CR) in 2 pts, both with ongoing CR at 24 weeks. Five pts had disease progression, and 1 pt was withdrawn due to suspected immune mediated myositis and hepatitis resulting from nivolumab and was not evaluable. The most common AE was local perineal irritation, readily managed with topical corticosteroid cream. Two pts developed an erythematous rash over the trunk and limbs after 2 cycles, suspected to be related to the combination treatment. Using a 32 multiplexed immune cytokine assay to evaluate the single-cell functional states of CD4+ and CD8+ T cells in patients’ peripheral blood mononuclear cells (PBMCs) at pre-treatment and at Cycle 3 Day 1, we found a significant increase in polyfunctionality in both effector CD4+ and CD8+ve T cells compared to baseline in responder patients. Conclusions: Preliminary analysis shows promising tumour responses from the combination therapy which appears to be well-tolerated, with no safety signals evident to date. Clinical trial information: ACTRN12621001537842 .
A functional immuno-oncology (IO) assay to assess patient response to immunotherapeutics in metastatic disease.
Authors: Hsu Shiaowen David , Hammer Joshua , Wang Lihua , Steele Shaun , Rupprecht Gabrielle , Wang Zhaohui , Metzger Steven 
Published: June 2023

e14592 Background: Immuno-Oncology (IO) therapy such as anti-PD1 and anti-CTLA4 blockade has rapidly become the standard of care in melanoma, lung, and other solid tumors. However, current biomarkers such as PDL1 expression (TPS/CPS) do not accurately predict which patients will respond to anti-PD1 therapy. There is an unmet clinical need to develop better assays to predict which cancer patients will derive benefit from anti-PD1 and anti-CTLA4 therapy. Our recently developed MicroOrganoSpheres (MOSTM) technology partitions patient tumor samples into many tiny droplets containing the patient's native tumor microenvironment, including immune cells. The patients’ MOS can then be divided across multiple test conditions, enabling the development of a functional IO assay to predict response to IO therapy. Methods: Patient tumor samples from lung, melanoma, hepatocellular carcinoma (HCC), and colorectal cancer (CRC) containing resident immune cells were partitioned into individual immunologically active MOS. Tissue digest and culture conditions were optimized to maintain native immune cell viability and functionality for 8 days, enabling immune-mediated response to immune checkpoint inhibitors to be assessed using a variety of bioanalytic methods. MOS were dosed with nivolumab/panitumumab (anti-PD1 inhibitor), atezolizumab (anti-PDL1 inhibitor), ipilimumab (anti CLTA-4 inhibitor) or an isotype control antibody (IgG). Biological response was assessed using a combination of flow cytometry, imaging, and ELISA based high-sensitivity interferon gamma (IFNy) secretion quantification. Results: Using 35 cancer specimens including lung, melanoma, ovarian and renal cell carcinoma (RCC), a functional IO assay was developed to assess cell populations within patient-derived MOS, including relevant T cell populations, and characterize IFNy secretion after exposure to immunotherapy. The assay was then validated on three patient samples with metastatic HCC, melanoma, and MSI CRC. The samples were first interrogated using the optimized immunotherapeutic assay to determine cell populations within MOS by flow cytometry, imaging including immunofluorescence labeling of cell populations, and functionality by IFNy secretion quantification, to generate aMOS IO Index (MII) with MII < 1 representing no response to therapy and MII > 1 representing response to therapy. Of the three samples, the HCC had a MII < 1 while the melanoma and CRCr had MII > 1. Each patient subsequently received either anti-PD1/PDL1 and/or anti-CTLA therapy and their response to therapy was predicted by their MII. Conclusions: These preliminary data suggest our immunotherapeutic assay represents a first-of-its-kind functional assessment that can potentially predict patient response to immune checkpoint inhibitors. Further validations of our assay are now underway in our functional precision oncology MOS IO trial.
The first cold atmospheric plasma phase I clinical trial for the treatment of advanced solid tumors: A novel 4th treatment arm for cancer.
Authors: Canady Jerome , Cheng Xiaoqian , Zhuang Taisen , Murthy Saravana , Nissan Aviram , Gitelis Steven , Ly Lawan , Jones Olivia , Adele Mohammad , Blank Alan T. , O'Donoghue Cristina , Stenson Kerstin , O'Hara Karen , Keidar Michael , Basadonna Giacomo 
Published: June 2023

e14596 Background: Local recurrence contributes to the poor prognosis for patients with Stage IV metastatic or recurrent solid tumors, despite advances in standard care. We report the clinical outcome of intra-operative Cold Atmospheric Plasma (CAP) combined with standard surgical procedures. Methods: The trial was a Phase I, multi-center, open-label, prospective, controlled study. Eligible patients undergoing surgery for advanced Stage IV metastatic or recurrent solid tumors were enrolled and preoperative treatments (neoadjuvant chemotherapy, immunotherapy, radiation, and primary surgery) were permitted. Participants were recruited from Rush University Medical Center in Chicago, Illinois and Sheba Medical Center in Tel HaShomer, Israel. Twenty patients (age 26-85 years) between March 2020 to April 2021 received intra-operative CAP treatment following surgical macroscopic tumor removal. The primary endpoint was safety, and the secondary endpoint was ablation of the local microscopic tumor bed without damaging the surrounding normal tissue. Results: Physiological data (blood pressure, pulse, body temperature, End Tidal CO2, and oxygen saturation) was recorded continuously throughout surgery. There were no significant changes (p > 0.05) during intra-operative CAP treatment. One adverse event grade 3 or higher was reported but no adverse events were related to CAP. As of February 13, 2023, 10 patients died of their disease between 3-32 months. Kaplan-Meier overall survival curves show the interim 31-month rate is 24% (95% confidence interval [CI], 5.0 – 100.0%). Median survival is 23 months. For R0 patients, the Kaplan Meier local non-recurrence probability showed that the interim 28-month rate is 75% (n=8; 95% CI, 50.3 – 100.0%) as of February 13, 2023. Histological staining, TUNEL assay, and confocal imaging of the surgical margins revealed cancer cell death and no damage to the surrounding normal tissue. Primary culture of the tumor confirmed total cessation of cancer cell survival. Conclusions: CAP treatment in combination with surgery for high-risk stage IV solid tumors is safe and induces cancer cell death at the surgical bed without damaging non-cancerous tissue. The survival rate in R0-resected CAP-treated patients was significantly improved compared to R1 and R2 patients and local non-recurrence rate for R0 patients was noteworthy. Clinical trial information: NCT04267575 . [Table: see text]