bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D-volumetric assessment of response to ivosidenib in IDH-mutant gliomas.
Authors: Puri Sushant , Shi Jessica , Blair Lindsay , Blakeley Jaishri O'Neill , Laterra John , Kamson David 
Published: June 2022

2063 Background: Isocitrate Dehydrogenase (IDH) mutant gliomas represent a distinct class of primary brain tumors. Mutant IDH is a driver mutation implicated in gliomagenesis and a potential therapeutic target. Ivosidenib, an inhibitor of mutant IDH1, is currently being evaluated to treat gliomas. In the present study we assess our single-institutional experience with the off-label use of ivosidenib to reduce tumor growth rate in patients with IDH mutant gliomas. Methods: We have longitudinally analyzed the imaging of patients with histology-proven radio- and chemotherapy-naïve IDH-mutant WHO Grade 2 and 3 astrocytomas (AS) and oligodendrogliomas (OG) treated with off-label ivosidenib between 2019 and 2022. First, each patients’ FLAIR images were anonymized, bias-corrected, co-registered and semi-automatically segmented for volumetric analysis using 3D Slicer 4.11. MR acquisition dates were hidden, and the order of scans was randomized to prevent expectation bias. Volumetric trends and PFS were analyzed. Progressive disease was defined as a ≥40% increase in volume from baseline as per modified RANO criteria. Results: Eleven patients were included in the analysis (median age 46 years [range 26-62], 2F, 8AS/3OG, 7 Grade 2). Mean±SD follow-up time on ivosidenib was 16.1±15.5 months. Tumor volume reduction was noted in 82% of patients at least at one time point. Average volume change at best response was -11.4±12.8%. Mean time to best response was 12.1±9.3 months. PFS-6 and PFS-12 were 91% (n = 11), and 88% (n = 8), respectively. Mean PFS was 24.4 months (CI95% 18.8-29.9). Median PFS was not reached. Patients older than 45 years had significantly higher volume reduction compared to younger patients (18.9±6.3% vs. -2.4±13.2%;-p = 0.047, 2-tailed T-test). Ivosidenib was discontinued in in 2 patients for 2D radiographic changes, and in one for increased seizure frequency. Conclusions: The use of ivosidenib in treatment-naïve gliomas was associated with a high response rate; however, on average it required longer than a year to achieve best response. In this cohort, older patients had higher volume reduction. The drug was well tolerable. Further analysis of an expanded cohort is underway.
Examination of mutation signature and mutation spectrum as predictors of response to immune checkpoint blockade therapy.
Authors: Bowen Danae , Capone Stephen , In Gino Kim , Buisson Rémi 
Published: June 2022

2537 Background: In recent years, there has been promising progress in the use of immune checkpoint blockade (ICB) as a treatment for various cancer types such as lung, kidney, bladder, skin, colon, and breast cancer. In order for this modality to have increased success, more precise selection tools are needed to predict which patients will benefit from treatment. Tumor Mutational burden (TMB) has been implicated as a biomarker for ICB response due to the increased tumor immunogenicity present in high TMB samples. However, we hypothesize that the quality of mutations may also have an impact in determining immune response, rather than just the quantity of mutations alone. Methods: A retrospective analysis of 2041 patients across multiple solid tumor types was conducted using an open-access, open-source cancer genomics database (Gao, Sci Signal, 2013), with the goal of assessing the influence of mutational signature on patient response to ICB (including CTLA-4, PD-1, and PDL-1). Patient demographics, treatment variables/outcomes, and tumor variables, including mutation spectrum, and mutation count, were evaluated. A paired two sample test for means was used to analyze data with p < 0.05 considered statistically significant. Response outcomes were determined per RECIST v 1.1. Results: Our data demonstrate that mutational spectrum profiles show distinct patterns when considering response to ICB, independent of TMB. Patients with breast invasive ductal carcinoma who responded to ICB had less C > A mutations ( p = 0.020) and more C > T mutations ( p = 0.017) compared to non-responders. Lung adenocarcinoma responders had less C > T mutations ( p = 0.003) and more C > A mutations ( p = 0.0003) compared to non-responders. Furthermore, both head and neck squamous cell carcinoma and glioblastoma multiforme responders had more T > A mutations ( p = 0.047 and p = 0.011, respectively) than non-responders. However, in other cancer types studied (urothelial, colon, renal, lung squamous, and melanoma), there were no obvious trends to distinguish responders from non-responders. Preferentially mutated gene targets were also considered for all 10 cancer types (including CARD11, SMARCA4, GLI1, PIK3R1, PTPRT, among others), many of which were also tied to the unique mutational signatures observed and which may be separately identified as novel ICB therapy targets. Conclusions: We found that specific mutation type may impact response to ICB in at least 4 cancer types, including breast, lung adenocarcinoma, head and neck squamous cell carcinoma and glioblastoma multiforme. Of note, this trend was not found in other cancer types which are typically found to have higher TMB. Moving away from solely considering the magnitude of mutations in tumor samples and towards identifying specific mutational signatures may aid in providing necessary specificity for selecting patients for ICB cancer therapy.
Phase 1b study of GS-3583, a novel FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.
Authors: Tolcher Anthony W. , Brody Joshua , Rajakumaraswamy Nishanthan , Lakhani Nehal J. , Kuhne Michelle R. , Trowe Torsten , Jiang Deyuan , Dauki Anees , Kummar Shivaani 
Published: June 2022

2566 Background: We have previously shown that systemic administration of GS-3583, a Fms-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein leads to expansion of conventional dendritic cells (cDC), both subtype 1 (cDC1) and subtype 2 (cDC2), in the periphery of healthy volunteers (Rajakumaraswamy N, et al. J Clin Oncol. 2021;39[suppl_15]:2559.). This mechanism may increase cDC in the tumor microenvironment and promote T cell mediated antitumor activity in patients with solid tumors. Methods: This ongoing, Phase 1b, open label study is investigating the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of escalating multiple doses of GS-3583 monotherapy in adult patients with advanced solid tumors using a standard 3 + 3 design. GS-3583 was administered intravenously on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 52 weeks or until progressive disease or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 therapy at each dose level. Results: At the time of the Dec 3, 2021 data cut-off, 9 patients have enrolled in 3 dose escalation cohorts. Median (range) age was 71 (44-79); 4 (44%) patients were male. Tumor types were pancreatic (n=3), ovarian (n=4), and rectal (n=2). To date, no DLTs or discontinuation due to adverse events (AE) have been observed. Three patients had Grade ≥3 AEs which were also recorded as serious AEs, none of which were considered related to GS-3583. Dose dependent increase in GS-3583 exposure was observed in the evaluated dose range 2 to 12 mg with target-mediated drug disposition appearing to be saturated at doses above Dose Level 2. GS-3583 accumulation was observed at higher dose levels. GS-3583 treatment resulted in expansions of cDC1 and cDC2 at all 3 doses (Table); a dose-dependent trend in the magnitude and the durability of cDC expansion was observed. At the highest dose evaluated, GS-3583 produced ≥100-fold expansion of both cDC1 and cDC2 at multiple time points. Dose escalation on the study is still ongoing. Conclusions: GS-3583 was safe and well tolerated and induced dose-dependent expansion of cDCs in the periphery in patients with advanced solid tumors up to doses of 12 mg. These findings support further dose escalation and clinical development of GS-3583 in combination with agents that would stimulate the expanded cDCs to produce anti-tumor responses. Clinical trial information: NCT04747470. [Table: see text]
Artificial intelligence-powered pathology image analysis merged with spatial transcriptomics reveals distinct TIGIT expression in the immune-excluded tumor-infiltrating lymphocytes.
Authors: Park Gahee , Song Sanghoon , Kim Sukjun , Ahn Sangheon , Kim Hyunjoo , Lee Jaegeun , Ro Juneyoung , Park Woomin , Chung Taiwon , Kang Cholmin , Lee Chunggi , Kim Huijeong , Shin Jisoo , Lee Seungje , Baek Eunji , Lee Sumin , Seo Melody SeungHui , Choi Hyojung , Yoo Donggeun , Ock Chan-Young 
Published: June 2022

2570 Background: TIGIT is a promising emerging immunotherapeutic target. However, the specific sources of TIGIT expression within the tumor microenvironment are largely unknown. Here, we present an AI-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer, Lunit SCOPE IO, to integrate image analysis from whole slide images with single-cell molecular profiling. Methods: We used The Cancer Genome Atlas (TCGA) RNA expression data across 23 cancer types (n=6,930). Lunit SCOPE IO was developed, trained, and validated based on >17k H&E whole-slide images, to segment cancer area (CA) and cancer-associated stroma (CS) and to detect tumor cells and TILs. The intra-tumoral TIL, stromal TIL, and tumor cell purity (TCP) in the CA+CS area were calculated. The public spatial transcriptomics (ST) dataset for breast cancer was downloaded from the 10X Visium web page. Lunit SCOPE IO was applied to the associated H&E WSIs to match distinct TIGIT expression to single cells identified in the WSIs. Results: TIGIT was highly expressed in TGCT (3.45±0.11; median±SEM), LUAD (3.07±0.05), and HNSC (2.89±0.06), and was highly enriched in samples with microsatellite instability-high or tumor mutational burden-high (≥ 10/Mb) compared to those without them (fold change = 1.30, p < 0.001). At a macroscopic, bulk-level in the TCGA dataset, TIGIT expression was positively correlated with intra-tumoral TIL density (R=0.37, p<0.001) and stromal TIL density (R=0.42, p<0.001), but it was negatively correlated with TCP (R=-0.27, p<0.001). Lunit SCOPE IO analyzed the images from ST analysis and calculated intra-tumoral TIL, stromal TIL, and TCP of each region of interest, containing 2 (IQR 0-7) cells. Interestingly, at a microscopic, cell-level, TIGIT expression was still higher in areas of enriched stromal TIL (P < 0.001) and lower in tumor cell-dense areas, but it was not significantly correlated with enriched intra-tumoral TIL areas, meaning that TIGIT expression is likely derived from the excluded TILs in the CS area. Conclusions: Interactive analysis of spatial transcriptomics with AI-powered pathology image analysis revealed that TIGIT expression in the tumor microenvironment is exclusive to confined areas with stromal TIL enrichment, reflecting the exclusion of TIL from the tumor nest. [Table: see text]
Radiotherapy-immunotherapy related pneumonitis prediction from pre-treatment CT using a deep graph-based integrative model.
Authors: Yang Linlin , Cui Hui , Duan Yanan , Yao Yueyuan , Zou Bing , Wang Linlin 
Published: June 2022

2580 Background: Early prediction of symptomatic pneumonitis (grade ≥ 2) could potentially assist the comprehensive management for non-small cell lung cancer (NSCLC) patients who received radiotherapy combined with immunotherapy. A more accurate integrative model for symptomatic pneumonia prediction using CT images is needed. Methods: This retrospective study contains 243 NSCLC patients (62 symptomatic pneumonitis) who underwent radiotherapy combined with immunotherapy between January 2015 and June 2021. Five-fold cross-validation was performed for training and testing. There were 195 cases in the training set (50 symptomatic pneumonitis) and 48 cases in the validation set (12 symptomatic pneumonitis) in each fold. The deep graph integrative model (DG) was composed of two pre-trained 3D UNet encoders to extract deep features from tumor and lung volumes of pre-treatment CT images, respectively, and a graph attention layer (GAT) for integration and classification. The encoders were fine-tuned using manually segmented tumor and lung CT volumetric patches from the training set. Evaluation measures include area under ROC curve (auc), sensitivity (sen), and specificity (spe). Results: Our new DG achieved auc, sen, and spe of 0.823, 0.767, and 0.810, which outperformed conventional CT radiomics model (auc 0.743, sen 0.620, spe 0.752), 3D UNet based deep radiomics model (auc 0.761, sen 0.746, spe 0.737), and our model without GAT (auc 0.796, sen 0.762, spe 0.782). The improvement was statistically significant (p < 0.001). Conclusions: Our DG model improved symptomatic pneumonia prediction using CT images, which can be used as a tool to effectively improve the safety and personalized treatment of combined radiotherapy with immunotherapy for NSCLC patients.
Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study.
Authors: Andre Thierry , Berton Dominique , Curigliano Giuseppe , Jimenez-Rodriguez Begona , Ellard Susan , Gravina Adriano , Miller Rowan , Tinker Anna , Jewell Andrea , Pikiel Joanna , Oaknin Ana , Duan Tao , Zildjian Sybil , Zografos Eleftherios , Veneris Jennifer Taylor , Banerjee Susana N. 
Published: June 2022

2587 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; or dMMR advanced/recurrent (AR) endometrial cancer (EC) that has progressed on or after treatment with a platinum-based chemo; and in the EU as a monotherapy in pts with dMMR/ microsatellite instabilityhigh (MSI-H) AR EC that has progressed on or after treatment with a platinum-based chemo. Here we report on efficacy and safety in 2 expansion cohorts that enrolled pts with dMMR solid tumors. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled pts with dMMR/MSI-H AR EC; cohort F enrolled pts with dMMR/MSI-H/POLε-mut non-EC solid tumors. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until PD, discontinuation, or withdrawal. Primary endpoints were ORR and DOR by BICR per RECIST v1.1. Biomarker status was based on local assessment. Results: For this third interim analysis, 153 pts with dMMR/MSI-H EC and 210 pts with dMMR/MSI-H/POLε-mut non-EC solid tumors (56% colorectal cancer, 11% gastric) were enrolled and treated. Efficacy analysis was performed for 143 dMMR/MSI-H EC and 204 dMMR/MSI-H/POLε-mut non-EC pts who had measurable disease at baseline and ≥6 mo of follow-up. ORRs were 45.5% (dMMR/MSI-H EC) and 43.1% (dMMR/POLε-mut non-EC solid tumors; Table). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 51.8%, 48.1%, and 46.4% in dMMR/MSI-H/POLε-mut non-EC. Median (m) DOR and mOS were not reached for either cohort. A total of 13 pts (8.5%) with dMMR/MSI-H EC and 12 pts (5.7%) with dMMR/MSI-H/POLε-mut non-EC solid tumors discontinued owing to a treatment-related adverse event (TRAE). TRAEs occurring in ≥12% of pts were diarrhea, asthenia, fatigue, nausea, and pruritis (dMMR/MSI-H EC) and diarrhea, asthenia, and pruritus (dMMR/MSI-H/POLε-mut non-EC solid tumors). 2 deaths (1 hepatic ischemia, 1 suicide) were attributed by investigators to dostarlimab in pts with non-EC solid tumors. Conclusions: Dostarlimab demonstrated durable antitumor activity across 16 tumor types in pts with dMMR solid tumors, confirming efficacy in a larger sample size with extended follow-up. The safety profile was acceptable, with manageable toxicities. Clinical trial information: NCT02715284. [Table: see text]
Cisplatin (Cis) combined with sintilimab (Sint) and niraparib (Nir) in advanced solid tumors: Updated results.
Authors: Haitao TAO , Wang Lijie , Liu Zhefeng , Wang Jinliang , Zhang Guoqing , Ma Junxun , Hu Yi 
Published: June 2022

2599 Background: PARP inhibitors or chemotherapy combined with PD1/PDL1 inhibitors resulting in enhanced antitumor activity. We previously reported the part 1 result of a phase Ⅰb study exploring the safety and efficacy of Cis plus Sint and Nir. Here we presented the updated survival and safety data. Methods: Eligible pts will receive Sint and Cis on D1, plus Nir on D1-21, every 21-day for up to 4 cycles, following Sint and Nir until disease progression or intolerable toxicity. Part 1 was dose escalation phase followed 3+3 model, and part 2 was dose expansion phase enrolled more patients based on part 1. The primary objective was to determine maximum tolerated dose (MTD)/ recommended part 2 dose (RP2D). Secondary endpoints include objective response rate (ORR) per RECIST v1.1, and safety based on CTCAE v5.0. Results: PR2D of Cis and Nir were 60 mg/m2 and 100 mg, respectively when combined with sint 200mg. From 7/2019 to 9/2021, 22 pts (13 pts in part2) were enrolled, including 12 small cell lung cancer (SCLC), 7 lung squamous cell carcinoma (LUSC), 2 ovarian cancer (OC) and 1 cervical squamous cell carcinoma (CSCC). Most were male (77.3%, n=17), ECOG=1 (63.6%, n=14), current smoker(68.2%, n=15) and PDL1＜1(50%, n=11). 36.4% (8/22) and 27.3% (6/22) had brain and liver metastasis at baseline, separately. Median follow-up was 6.2 months (range 2.5-10.8). ORR was 27.3% (6/22), DCR was 59.1% (13/22). Median progression-free survival (PFS) was 3.3 months (95%CI 1.9-3.9), and PFS rates at 6 months and 12 months were 28.8% and 10.8%. Median overall survival (OS) was 8.0 months (95%CI 4.9-14.1), 12 months OS rates was 28.5%. Median treatment duration was 4.7 months (range 1.9-15.1). The most common treatment-related adverse events included anemia (90.9%, 20/22, [5 Grade 3/4]), fatigue (77.3%, 17/22, [1 Grade 3/4), γ-glutamyl transpeptidase increased (72.7%, 16/22, [0 Grade 3/4]), leukopenia (68.2%, n=15, [4 Grade 3/4]) and neutropenia (59.1%, n=13, [5 Grade 3/4]). Conclusions: In this updated analysis, Cis combined with Sint and Nir showed clinically meaningful efficacy and an adequate safety profile in previously treated advanced solid tumors. Data need longer follow-up. Clinical trial information: ChiCTR1900024488.
Resistance to anti-PD-1/anti-PD-L1: GB1211 reverses galectin-3 induced blockade of pembrolizumab and atezolizumab binding to PD-1/PD-L1.
Authors: Mabbitt Joseph , Roper James A. , Slack Robert John 
Published: June 2022

2607 Background: Galectin-3 (Gal-3) is a β-galactoside binding lectin highly expressed across many cancers (Li et al. Biomedicines, 2021) with high expression associated with poor response to the PD-1 inhibitor pembrolizumab (Capalbo et al., Int J Mol Sci, 2019). In addition, it has also been shown preclinically in in vivo mouse non-small cell lung carcinoma (NSCLC) models that inhibition of Gal-3 enhances the performance of checkpoint inhibitors targeting the PD-1/PD-L1 axis (Vuong et al., Cancer Res, 2019; Zhang et al., FEBS Open Bio, 2020). The mechanism by which Gal-3 negatively impacts the effect of PD-1/PD-L1 based checkpoint inhibitors is not fully understood. We investigated the hypothesis that anti-PD1/anti-PDL1 is induced by direct binding and blockade of Gal-3 to the PD-1/PD-L1 complex itself. Methods: SPR was used to investigate the effect of recombinant hGal-3 in combination with a Gal-3 inhibitor (GB1211) on the binding of recombinant hPD-L1 to hPD-1 in the absence and presence of either pembrolizumab or atezolizumab. SPR analysis was performed with a BIAcore (Cytiva, USA). hPD-1 was immobilized onto a CM5 Series S sensorchip via amine coupling and proteins, antibodies or small molecules flowed over in various combinations. Observations made at the protein level were further confirmed in cell binding assays using flow cytometry measuring pembrolizumab and atezolizumab binding to cells lines over expressing high levels of either PD-1 (Jurkat cells) or PD-L1 (RAJI-hPD-L1 cells), respectively. Results: Gal-3 potentiated the binding of PD-L1 to PD-1 with a 3-fold increase in its KD observed and the efficiency of pembrolizumab and atezolizumab binding to and blocking the PD-1/PD-L1 axis was reduced. A 6-fold reduction in KD of pembrolizumab for the PD-1/PD-L1 complex was observed in the presence of Gal-3. In addition, atezolizumab PD-L1 blockade was reversed in the presence of Gal-3 and dramatically improved by GB1211. Similarly, in cell systems expressing high levels of PD-1 or PD-L1, Gal-3 reduced the binding of pembrolizumab and atezolizumab to their respective targets on cell surfaces that was also reversed by GB1211. Conclusions: Gal-3 was shown to vastly reduce the binding of the checkpoint inhibitors pembrolizumab and atezolizumab, by potentiating the interaction between PD-1 and PD-L1. GB1211 restored the binding of the anti-PD1/anti-PDL1 therapeutics and may thus reduce tumor resistance to these agents. These findings harmonize excellently with in vivo and clinical data showing an association between Gal-3 expression and lack of efficacy of PD-1/PD-L1 targeted checkpoint inhibitors. Galecto is now investigating the safety and efficacy of GB1211 in combination with atezolizumab in NSCLC.
Safety of dual checkpoint-blockade with PSB205, an anti-PD-1/CTLA4 monoclonal antibody combination, manufactured and dispensed as a single product: A phase 1 study.
Authors: Chugh Rashmi , Wang Judy S. , Olszanski Anthony J. , Wilky Breelyn A. , Algate Paul , Plato Leah , Spira Alexander I. , Korchin Borys , Kylstra Jelle W. 
Published: June 2022

2611 Background: PSB205 is a new biological agent consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) expressed in a fixed ratio (2:1) from a single cell-line, manufactured as one product and dispensed from a single vial. PSB205 was designed to optimally balance efficacy and safety through differential target coverage of PD-1 and CTLA-4: the anti-CTLA-4 antibody was engineered to have a shorter half-life to modulate exposure and lower risk of immune-related adverse events (irAEs). Methods: We report safety data from a first-in-human study, conducted in standard 3+3 Phase 1 dose escalation format, enrolling subjects with refractory solid tumors with mixed histologies, who had exhausted available standard treatments. Primary objectives were safety (including Dose Limiting Toxicities), tolerability and selection of a Phase 2 dose. Secondary objectives were PK and preliminary evaluation of effectiveness. Treatment was Q3 wks. Inclusive the 1st week following the 2nd infusion, the DLT-period was 28 days. Results:Nine US-centers enrolled 27 subjects, representing 19 tumor histologies, in 5 ascending dose cohorts ranging from 0.1 mg/kg to 5 mg/kg; an additional N = 49 pts were dosed in expansion cohorts at 5 mg/kg and 400 mg (fixed dose). Median number of prior systemic treatments for metastatic disease was 4. No DLT was observed at any of dose level evaluated. The most frequent Treatment-Related Adverse Events (TRAE) reported were diarrhea (9%), Infusion-Related Reaction (IRR) (5%) and fatigue (4%). Among the subset (N = 33) who completed at least 4 cycles of treatment, the most common TRAE were diarrhea (21%), IRR (12%), Fatigue (9%), and irAEs, specifically colitis, rash and arthralgia (6% each symptom). Most TRAEs were Grade 1 /2, with just 1 case each of diarrhea and colitis Graded as G 3/4. Tumor responses (all PRs) were observed at dose levels of 3 mg/kg and 5 mg/kg in 4 pts - 1 each with with RCC, SCLC, HNSCC and gastric cancer. Conclusions: PSB205 provides dual checkpoint blockade with a very tolerable side effect profile, with less AEs than typically noted in published studies of anti-PD1 and anti-CTLA-4 combination therapy. Further studies are ongoing to confirm this observation. Dose levels of 5 mg/kg and 400 mg fixed were selected for Phase 2, which has commenced enrollment. Clinical trial information: NCT03986606.