bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of B-cell maturation antigen (BCMA)-specific CD8+ cytotoxic T lymphocytes using induced pluripotent stem cell technology for multiple myeloma.
Authors: Bae Jooeun , Kitayama Shuichi , Herbert Zach , Daheron Laurence , Munshi Nikhil C. , Kaneko Shin , Ritz Jerome , Anderson Kenneth Carl 
Published: June 2022

2542 Background: A strategy for reversal of T cell exhaustion is reprograming of antigen-specific CTL to early lineage memory T cells with selective anti-tumor activities. To accomplish this goal, we epigenetically reprogrammed BCMA-specific CD8+ CTL to a pluripotent state through key defined transcription factors, established “induced Pluripotent Stem Cells (iPSC)” exhibiting transcriptional and epigenetic features, re-differentiated them back into antigen-specific CTL and evaluated their properties and functional activities against multiple myeloma (MM). Methods: Functionally activeIFN-g producing HLA-A2 heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ CTL were applied for iPSC via transduction of four reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC). Upon characterization of the BCMA-specific iPSC with high pluripotency potential, embryoid body was formed from the iPSC and further polarized into mesoderm layer development as evidenced by upregulation of transcriptional regulators (ABCA4, BMP10, CDH5, FOXF1, HAND1, PLVAP, SNAI2, TBX3). Next, BCMA-specific embryoid body-derived hematopoietic progenitor cells (HPC; CD34+ CD43+/CD14- CD235a-) were sorted and induced to undergo T cell differentiation in the presence of Fc-DLL4 signaling and rectonectin. Results: Our RNAseq analyses demonstrated unique transcriptional profiles of HPC from different iPSC clones committing to CD8+ T cells or other cell lineages (monocytes/granulocytes, B lymphocytes/NK cells). Principal component analyses demonstrated a high similarity and low variability of transcription profiles within the replicates of HPC committed to the same cell lineage. In addition, distinct genome-wide shifts and differential gene expression profiles were detected in HPC committed to each specific cell differentiation pathway. Specifically, the HPC commit to CD8+ T cells utilized a diverse repertoire of modulators promoting development of T cell maturation, specific immune response regulation, memory T cells, cytotoxicity and interferon induction, which were significantly higher than shown in HPC that differentiate to other cell lineages. In parallel, specific repression genes were identified in the HPC commit to CD8+ T cells, which develop TGF-β receptor, rearrangement of Ig heavy chain genes and inhibitory receptors. The T cells differentiated were mainly CD45RO+ memory CTL and fully rejuvenated without immune checkpoints expression and regulatory T cells and with high anti-MM activities. Conclusions: These findings identify genetic and epigenetic mechanisms and regulatory elements, which play key roles during lineage specific commitment of HPC developed in iPSC into CD8+ CTL and help to further design a next generation of regenerative medicine that provide the appropriate signals for T cell lineage commitment from progenitor cells.
Systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of patients with cancer treated with immune checkpoint inhibitors.
Authors: Zalcman Gerard , Crespin Athéna , Cervesi Julie , Le Bescop Clément , Buffet Renaud , de Gunzburg Jean , Vitry Fabien , Bandinelli Pierre-Alain 
Published: June 2022

2585 Background: In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs) and antibiotic (ABX) exposure has repeatedly been shown to impair clinical outcomes of patients suffering from different cancer types and treated with ICIs. We published in 2020 a meta-analysis confirming that ABX use hampered survival of non-small cell lung cancer (NSCLC) patients treated with ICIs. The present study aims to determine whether ABX use also reduces survival of patients receiving ICIs for other cancers. Methods: PubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of cancer patients treated with ICIs. Studies were included when reporting data on Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) and Progressive Disease Rate (PD), according to ABX exposure. Pooled Hazard Ratios (HRs) for OS and PFS and Odds Ratios (ORs) for ORR and PD were calculated, as well as HRs for OS and PFS according to different cancer types and different ABX exposure time windows (TWs). Results: Overall, 94 independent cohorts were included, representing 26,174 patients suffering from various types of cancer. The pooled HRs for PFS (61 cohorts, 13,224 patients) and OS (88 cohorts, 25,480 patients) were 1.47 [95% Confidence Interval (CI) 1.31-1.66] and 1.66 [95% CI 1.50-1.83], respectively, confirming a significant harmful impact of ABX on patient’ survival, observed across all cancer types (Table). The analyses of OS and PFS based on ABX exposure TWs suggested a stronger deleterious effect of ABX when taken around ICI treatment initiation. The response to treatment among ABX users was also impaired: the pooled ORs for ORR (30 cohorts, 4,590 patients) and PD (33 cohorts, 4,972 patients) were 0.55 [95% CI 0.39-0.77] and 1.97 [95% CI 1.48-2.64], respectively. Conclusions: ABX were shown to impair the clinical outcomes of cancer patients treated with ICIs, regardless of cancer type. [Table: see text]
Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.
Authors: Li Jin , Qin Shukui , Zhong Haijun , Jin Chuan , Chen Lili , Yuan Xianglin , Fan Qingxia , Chen Kehe , Cao Peiguo , Xiao Jianjun , Jiang Da , Zhang Tao , Zhang Hongyu , Wang Xicheng , Wang Wei , Han Lin , Wang Qingyu , Zhu Jun ,   HLX10-010-MSI201 Investigators
Published: June 2022

2592 Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.
Predictors of immunotherapeutic benefits in patients with advanced melanoma and other malignancies treated with immune checkpoint inhibitors utilizing ORIEN “real-world” data.
Authors: Tarhini Ahmad A. , Tan Aik Choon , Xie Mengyu , El Naqa Issam , Ghasemi Saghand Payman , Dai Donghai , Chen James Lin , Ratan Aakrosh , McCarter Martin , Carpten John D. , Colman Howard , Ikeguchi Alexandra , Tripathi Abhishek , Puzanov Igor , Arnold Susanne M. , Churchman Michelle L. , Hwu Patrick , Conejo-Garcia Jose , Dalton William S. , Weiner George J. 
Published: June 2022

2618 Background: Despite the significant improvements in treating cancer with immune checkpoint inhibitors (ICIs), many patients (pts) do not achieve disease control. Using Oncology Research Information Exchange Network (ORIEN) Avatar real-world data conducted under the Total Cancer Care protocol we investigate predictive biomarkers of ICI benefits in pts with advanced malignancies. Methods: Clinical data were normalized as part of ORIEN Avatar. RNA-seq was performed on tumor samples following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM). Gene expressions (GE) were log2(TPM+1) transformed. Mann-Whitney U-test was used to compute differences between groups, and Kaplan-Meier survival analysis was performed. Results: Pts (n=1214) with 27 cancer types treated with ICIs were retrieved from the database, where 1143 and 875 patients were profiled by WES and RNA-seq, respectively. 804 pts had both WES and RNA-seq data. The top six cancer types were renal cell carcinoma (n=206), non-small cell lung cancer (n=173), head and neck cancer (n=157), melanoma (n=154), sarcomas (n=99) and bladder cancer (n=87). The ICI regimens included therapy with atezolizumab (n=87), avelumab (n=12), cemiplimab (n=6), ipilimumab (n=47), nivolumab (n=424), pembrolizumab (n=525) and ipilimumab+nivolumab (n=113). Median overall survival (OS) for the entire cohort was 21.9 months. Patients had significant improvement in OS if ICI was given in the first line ( P<0.0001). Previously published GE signatures were tested in the melanoma cohort. Signatures related to IFNg, effector T cells, chemokines, MHC II and Tertiary Lymphoid Structures were significantly prognostic and predictive of ICI benefits in advanced melanoma (Table). Analyses in the other cancer types are ongoing. Conclusions: GE data analyses validate the predictive value of immune related gene signatures following ICI immunotherapy in melanoma. Ongoing analyses are investigating these signatures in other malignancies and integrating the GE data with data related to TMB, somatic mutations and germline genetic variations.[Table: see text]
Automated tumor immunophenotyping and response to immunotherapy in non-small cell lung cancer using a spatial statistics approach.
Authors: Orlova Darya , Li Xiao , Eastham-Anderson Jefferey , Zou Wei , Tabatsky Evgeniy , Giltnane Jennifer M. , Patil Namrata S. , Peterson Maureen , Zijlstra Andries , Koeppen Hartmut 
Published: June 2022

2626 Background: Based on the clinical success of immuno-oncology therapeutics, tissue-based, biomarker analyses have shifted from a focus on tumor cell phenotypes to spatial and functional analyses of the tumor immune environment. Distribution and composition of immune infiltrates have shown prognostic or predictive value in various studies; however, standardized approaches to categorize tumors into “Desert”, “Excluded” or “Inflamed” immunophenotypes based on the density and pattern of immune infiltrates are missing. This categorization is typically based on visual inspection of a stained tissue section; it is labor-intensive and associated with poor inter-observer concordance. To eliminate these barriers we developed an automated approach that relies on a set of derived spatial features and named this analysis pipeline LATIS (metric Learning based Automated Tumor Immunophenotyping with Spatial statistics). Methods: We used two clinical trials, POPLAR (phase II; n=258) and OAK (phase III; n=623) that compared anti-PD-L1 treatment vs chemotherapy in patients with advanced non-small cell lung cancer to develop and validate this approach. LATIS utilizes scans of slides stained immunohistochemically for CD8 and cytokeratin (CK); images were tiled and classified according to CK status (positive/negative). First, CD8 positive and CK density was calculated for each tile. Twenty six spatial features were then extracted for each tiled image scan. We used a labeled (manual immunophenotype calls) POPLAR dataset to learn a metric that separates classes of labeled data best with respect of spatial features provided for each data point. Then, to co-embed OAK dataset with POPLAR dataset into the same space, we used that learned metric as a measure of distance between new unlabeled points (OAK data set). K-means clustering in the embedded space was used to identify clusters of data points followed by QFMatch to assign class labels (“Inflamed”, “Excluded”, “Desert”) to each data point. Results: LATIS successfully relates spatial features to both, manual reads and patient response to therapy. In OAK, anti-PD-L1 treated patients experienced longer median overall survival (OS) when tumors showed intra-epithelial CD8+ cells (Inflamed) compared to tumors with a stromal pattern of CD8+ cells (Excluded) or a low density of CD8+ cells (Desert): 17.6 months vs 10.3 (Excluded) vs 12.1 (Desert) [p=0.0061]. Median progression-free survival (PFS) was 3.2 months (Inflamed) vs 2.6 (Excluded) vs 1.4 (Desert) [p=0.00058]. OS and PFS were not significantly different for the three categories in chemotherapy only arm. Conclusions: We suggest that tumor immunophenotype categories generated in an automated fashion by LATIS can serve as predictive biomarker for cancer immunotherapy.
Systematic assessment of tumor mutational burden calculation across different sequencing platforms and cancer types and its implication in clinical decision-making.
Authors: Sun Daqiang , Tang Hongzhen , Luo Haitao 
Published: June 2022

2631 Background: Tumor mutation burden (TMB) has been validated as a biomarker to predict the response of immune checkpoint inhibitors (ICIs) treatment in various cancers. However, the effects of different sequencing platforms, cancer types and calculation methods on TMB as well as its cut-off value for predicting immunotherapy efficacy are still need to be further investigated. Methods: 4140 tumor samples were performed with targeted panel sequencing or whole exome sequencing (WES) in different platforms such as illumina and MGI. Public sequencing data from 3680 samples which contained targeted panel sequencing, WES and whole genome sequencing were obtained. The impact of different sequencing platforms, sequencing methods and calculation methods on the calculation of TMB were assessed. Further, targeted panel sequencing data from 71 sample of lung cancer patients treated with ICIs were used to determine the best cut-off value of TMB for predicting immunotherapy response. Results: TMB values calculated by different platforms and different sequencing methods were similar and there was no significant difference. The distribution of TMB at different sequencing depths and tumor purity were analyzed. We found that there was no significant difference in the distribution of TMB when the sequencing depth was greater than 500´, the HE purity was greater than 0.1 or NGS purity was greater than 0.3. In addition, the correlation of TMB calculated from single-sample and paired-sample is 0.95. Further, the optimal cut-off value of TMB in lung cancer treated with ICIs was determined to be 8 through ROC curve analysis, and patients with TMB ≥ 8 had better outcomes than patients with TMB < 8. Conclusions: This study systematically analyzed the factors which influenced the TMB calculation, and verifies the feasibility of TMB calculation from single-sample. More importantly, the cut-off value of TMB for predicting immunotherapy efficacy in lung cancer was defined as 8 in East Asian populations, which can help in clinical decision-making.
Promising clinical benefit rates in advanced cancers alongside potential biomarker correlation in a phase I/II trial investigating bexmarilimab, a novel macrophage-guided immunotherapy.
Authors: Bono Petri , Pasanen Annika , Verlingue Loic , de Jonge Maja J.A. , de Miguel Maria J. , Skytta Tanja , Iivanainen Sanna , Shetty Shishir , Ma Yuk Ting , Graham Donna M. , Arora Sukeshi Patel , Jaakkola Panu , Yap Christina , Jalkanen Sirpa , Hollmen Maija , Koivunen Jussi , Minchom Anna Rachel 
Published: June 2022

2645 Background: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-CLEVER-1 IgG4-antibody capable of inducing a phenotypic M2 to M1 immune switch of tumor-associated macrophages. Methods: MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a first-in-human phase I/II study (NCT03733990) to assess safety and preliminary efficacy of Bexmarilimab in patients with refractory advanced solid tumours. Part I has been completed with initial good safety profile of the IMP, preliminary signs of efficiency, and recommended dose of 1mg/kg Q3W for part II (ESMO 2020). In Part II (ESMO 2021), 10 distinct solid tumour types were enrolled to assess preliminary efficacy (overall survival (OS), progression free survival (PFS), and clinical benefit rate (CBR). Clever-1 IHC in pre-treatment biopsies with Ventana platform using a primary antibody 4G9 (Santa Cruz) was scored by % of positive cells compared to the viable tumor cells. Results: At the Jan 2022, a total of 193 patients have been enrolled to the study. In the completed cohorts, 138 patients have received 1-21 doses (median 3) of Bexmarilimab Q3W. Bexmarilimab was well tolerated, and no new safety signals were detected. Part I and Part II fully enrolled 11 cancer cohorts, the median PFS was 2.0 months (95% CI 1.9 – 2.0) and the median OS was 5.2 months (95% CI 4.3 – 6.4). CBR for Part II was 17.3% (19/110) at cycle 4 of treatment (by RECIST v.1.1). Notably, 30-40% CBR at cycle 4 was seen in cutaneous melanoma (30%), gastric cancer (30%), cholangiocarcinoma (30%), hepatocellular cancer (40%), and ER+ breast cancer (40%). Six-month survival rates (landmark analysis) were 70.1% for CBR compared to 34.7% for non-CBR patients, with a similar duration of prior therapy in both groups. Preliminary biomarker analysis (n = 77) demonstrated positive trend (p = 0.038) between CBR and higher intratumoral Clever-1 positivity (median of 15% positivity (range 0-25) in CBR and 3% (range 0-85) in non-CBR patients) Conclusions: Bexmarilimab continues to demonstrate promising anti-tumour activity as a monotherapy in several refractory solid tumours. Furthermore, preliminary biomarker analysis suggests a possibility for patient selection based on tumour Clever-1 expression. Further expansion of the study will investigate optimal dosing and biomarkers of efficacy. Clinical trial information: NCT03733990.
Landscape of tumor mutation burden and correlation to clinical outcomes in 1,744 solid cancers.
Authors: Jung Jaeyun , Park Sehhoon , Lee Jeeyun , KIM Seung 
Published: June 2022

2667 Background: Tumor mutation burden (TMB) has proven clinical utility and efficacy related to immune checkpoint inhibitor (ICI) treatment in different tumor types. However, limited data were available to understand the landscape and matched clinical outcomes to a pan-cancer extent. Methods: Target sequencing results, using TruSight Oncology 500, from 1,744 solid cancer between 2019 and 2021 as a part of real-world clinical practice were collected. Matched clinical and histological outcomes, including PD-L1 expression ( n= 798) and immunotherapy treatment ( n= 400), were analyzed. Results: Among the 33 different cancer types, high TMB was observed in 257 patients (14.7%) with a significantly higher incidence observed in carcinoma of unknown origin (33.3%), bladder cancer (32.3%), and small bowel cancer (30.0%). TMB was positively correlated with the degree of mutation in homologous recombination genes (HRD, 0.76) and microsatellite instability (MSI, 0.51). The predictive value of high TMB to ICI treatment seemed to be enhanced when it was combined with PD-L1 expression, showing higher response rates in the PD-L1 high group (63.3%) than in the low group (22.2%). In the patients with high TMB, both longer overall survival ( p = 0.015) and progression-free survival ( p = 0.020) were observed compared to the patients with low TMB. Conclusions: We examined the landscape of TMB in a different type of cancer using clinical-level target sequencing outcomes. High TMB seems to be a promising predictive biomarker of ICI, showing a positive correlation with alteration in other DNA damage response and repair-related genes and additive value to PD-L1, which needs to be validated through further prospective trials.