bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct oral anticoagulant versus low molecular weight heparin for venous thromboembolism in patients receiving immune checkpoint inhibitors.
Authors: Chiang Cho Han , Chang Yu-Cheng , Tang Zhiting , See Xin Ya , Chi Kuan-Yu , Chang Yu , Chiang Cho Hung , Gong Jingyi , Curtis Lauren Mary , Neilan Tomas G. 
Published: June 2024

12127 Background: The two most common therapies for the treatment of cancer-associated venous thromboembolism (VTE) are low molecular weight heparin (LMWHs) and direct oral anticoagulants (DOACs). However, there is a paucity of data on the optimal anticoagulation strategy specifically among patients receiving immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the comparable safety and efficacy of DOACs versus LMWHs in the treatment of VTE among patients receiving ICIs. Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network, which contains de-identified data from over 120 healthcare institutions and 250 million patients. We included adult cancer patients who have received ICI therapy including nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, dostarlimab and who also received a diagnosis of VTE. Patients treated with DOACs were matched in a 1:1 ratio to patients treated with LMWHs based on the variables: age, sex, metastatic disease, cancer therapy, underlying comorbidities, Khorana score, and history of intracranial and gastrointestinal bleeding. The primary outcome was the occurrence of a new VTE, a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT). The safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding within 2 years following the start of anticoagulation therapy. Results: We matched 4608 ICI-treated patients on a DOAC to 4608 ICI-treated patients on a LMWH. In a Cox proportional hazard analysis, patients receiving DOACs or LMWH had a similar risk of a subsequent VTE event (Hazard ratio (HR), 1.13 [95% CI: 0.84-1.50]). When comparing different types of VTEs, the DOAC group was associated with a lower risk of PE (HR, 0.72 [95% CI: 0.54-0.96]) and a similar risk of DVT (HR, 0.87 [95% CI: 0.70-1.09]) compared to LMWHs. Furthermore, DOACs were associated with a lower risk of intracranial hemorrhage and all-cause mortality. There were no detectable differences in the risk of gastrointestinal bleeding between the two groups. Conclusions: DOACs were associated with a similar risk for subsequent VTE events but a lower risk of intracranial bleeding as well as an improvement in mortality compared to LMWHs among ICI-treated patients with a diagnosis of VTE. Prospective trials are needed to validate these findings. [Table: see text]
Efficacy of intrathecal delivery of peptide-pulsed type 1 conventional dendritic cell vaccine for the treatment of breast cancer-associated leptomeningeal disease in preclinical models.
Authors: Law Vincent , Snyder Colin , Chen Zhihua , Kalinski Pawel , Czerniecki Brian J. , Forsyth Peter A. J. 
Published: June 2024

2030 Background: Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease, a rare form of metastasis in the meninges, a membrane surrounding the brain and spinal cord. The prognosis for BC-LMD is dismal and currently available treatments are ineffective. For example, intrathecal (IT) therapy such as trastuzumab, and proton cranial spinal radiotherapy have only showed modest success. Dendritic cells are a master regulator of the immune system and play a critical role in bridging the innate and adaptive immune response. Here, we used a novel preclinical model to administer MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) intrathecally in mice that harbor either HER2+ or triple negative breast cancer (TBNC) LMD. Our murine BC-LMD murine data lead us to open a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress). Methods: Our lab developed a “murine Ommaya” which mimics the clinically used Ommaya reservoir and allows for repeated intrathecal (IT) injections of novel drugs at 3 – 7µl volume directly into the CSF. We next developed a pipeline for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets to generate tumor-targeting cDC1s. We tested the resulting vaccines in a preclinical model that IT delivers peptide-pulsed cDC1 cell therapy directly into the BC-LMD microenvironment. Results: We tested the efficacy of treatment in HER2+ LMD and TNBC-LMD models and found effective responses; LMD mice that received IT cDC1 therapy exhibited reduced tumor burden and prolonged survival that was significantly better than systemic therapy. Approximately 70% of mice from HER2+ LMD and 30% from TNBC LMD demonstrated complete responses. This was CD4+ T cell dependent. Notably, cured mice also showed signs of resistance against LMD recurrence upon rechallenge. Subsequent single cell RNA-seq (scRNA-seq) analyses of the CSF showed a shift in the innate immune landscape found in untreated LMD to an adaptive immune landscape. In addition, we noted the elevated secretion of Th1 proinflammatory cytokines such as IFN-γ in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 triggered a high concentration of several proinflammatory cytokines. Conclusions: Our preclinical data suggest IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. We are currently investigating the mechanism(s) by which IT cDC1-initiates the CD4 Th1 adaptive immune response against LMD. By employing an scRNA-seq approach, we hope to further determine the roles of different immune cells and their subtypes in the CSF to IT cDC1s in mice and in patients. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
Tumor treating fields (TTFields) therapy in patients with glioblastoma: Long-term survival results from TTFields in Germany in routine clinical care (TIGER) study.
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin 
Published: June 2024

2036 Background: Tumor Treating Fields (TTFields) therapy has demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) when applied with adjuvant temozolomide (TMZ) compared to TMZ alone in newly diagnosed glioblastoma (ndGBM). TTFields therapy delivers electric fields, through scalp-placed arrays, that disrupt cellular processes critical for cancer cell viability, is CE marked for WHO grade 4 glioma, and is a recommended treatment regimen for ndGBM. TTFields therapy was administered to >25,000 patients, showing no systemic toxicities and mild to moderate skin reactions being the main therapy-related adverse event. Here, we report survival and safety data from the TIGER study, the largest prospective study investigating real-world use of TTFields therapy during routine clinical care in patients with ndGBM in Germany. Methods: TIGER (NCT03258021), a prospective, non-interventional, multicenter, medical device study, screened patients ≥18 years of age with histologically confirmed ndGMB from August 2017 to November 2019 in 81 participating centers in Germany who had clinical indication for TTFields therapy and were within the first 3 cycles of maintenance chemotherapy treatment. The analysis presented here focuses on patients that accepted TTFields therapy. Endpoints included OS, PFS, safety, and quality of life. Results: In this study, 710 assessed patients agreed to participate, with 583 (82%) opting for TTFields therapy, and 429 actually commencing the treatment. This patient population represents typical GBM patients, with a median age of 58 (range 19–82) and 64.1% being male. After a total follow-up of 56.2 months, the median OS and PFS were 19.6 months (95% CI, 17.9–22.4) and 10.2 months (95% CI, 9.4–11.4), respectively. The corresponding 1, 2, 3, and 4-year OS rates stood at 79.2%, 42.4%, 31.5%, and 27.7%, while the PFS rates were 42.0%, 23.2%, 19.9%, and 17.6%, respectively. Serious AEs were observed in 68% of patients, with only 0.5% being attributed to TTFields therapy. Conclusions: TIGER is the largest prospective study to date on routine clinical practice in ndGBM. It reaffirms TTFields therapy’s positive safety profile, and its OS and PFS survival benefits are consistent with prior reports. It also reveals promising long-term survival rates. Clinical trial information: NCT03258021 .
Phase 1 study (DRAGON) of SRK-181 (linavonkibart), a latent TGFβ1 inhibitor, combined with pembrolizumab in patients with anti-PD1 resistant advanced solid tumors: Updated results of expansion part.
Authors: Vaishampayan Ulka N. , Sweis Randy F. , Kilari Deepak , Tarhini Ahmad A. , Gainor Justin F. , Barve Minal A. , Sonpavde Guru P. , McKean Meredith , Park David J. , Babu Sunil , Ju Yawen , Liu Lan , Henry Susan , Gan Lu , Yap Timothy A. 
Published: June 2024

2507 Background: Linavonkibart (LKT), also known as SRK-181, a fully human IgG4 monoclonal antibody, selectively inhibits latent transforming growth factor-beta isoform 1 (TGFβ1). TGFβ1 drives tumor immune escape by promoting an immunosuppressive pro-tumor microenvironment, including reducing antigen presentation, impairing T-cell infiltration, and tumor-killing activity. Previously, results from the dose escalation phase (3+3 design) of the ongoing open-label, phase 1 DRAGON study (NCT04291079) have showed antitumor activity with LKT + pembrolizumab (P). The combination was well tolerated with no dose limiting toxicity and the recommended dose for LKT is 1500mg q3W. Methods: In the Part B (expansion phase), LKT (1500mg q3w) + P were administered in melanoma (MEL), urothelial carcinoma (UC), and non-small cell lung cancer (NSCLC) pts, who were non-responders to prior anti-PD-1; and in ccRCC and HNSCC pts, with disease progression on the most recent prior anti-PD-1.Biomarker analyses include immunohistochemistry and flow cytometry. Results: As of 12 Jan 2024, 72 pts (29% females, median age of 65 years) were enrolled in Part B. All pts received at least one anti-PD-1 therapy with median prior lines of therapies of 3 (range 1-9). All ccRCC and all but 2 HNSCC pts had a best response of SD or PD on prior anti-PD-1. All these patients had progressed on the most recent anti-PD-1. None of the MEL, UC and NSCLC pts had a response to prior anti-PD-1. The most common treatment-related AEs (TRAE, ≥10%) of any grade were rash (23.6%), pruritus (20.8%), fatigue (19.4%) and diarrhea (12.5%). Grade 3 TRAE (≥5%) were rash (8.3%). Only 1 grade 4 TRAE (dermatitis exfoliative generalised) occurred. No grade 5 TRAE and no treatment-related SAE (≥2% [1 pt]) was observed. Efficacy results are presented in the table below. Tumor assessments were based on RECIST 1.1 criteria by PI assessment. Biomarker results showed decreased circulatory myeloid derived suppressor cell levels and increased CD8+ infiltration into tumors across multiple tumor types, indicating enhanced proinflammatory microenvironment. Conclusions: Combination treatment with LKT+P is associated with enhanced proinflammatory microenvironment with promising efficacy in anti-PD-1 resistant pts across multiple tumor types with manageable safety profile. The result supports LKT as a potential treatment to overcome immune checkpoint inhibitor-associated resistance. Clinical trial information: NCT04291079 . [Table: see text]
Examining response to immunotherapy in clear-cell renal cell carcinoma using baseline serum metabolic signatures.
Authors: Pirhaji Leila , Morris Matthew , Eaton Jonah , Zhang Min 
Published: June 2024

2604 Background: Clear cell renal cell carcinoma (ccRCC) accounts for 80% of kidney cancer cases. While immune checkpoint blockade (ICB) is a front-line treatment, most patients do not have durable clinical benefit, and current biomarkers fail to predict response. Previous studies reported metabolic alterations in response to ICB based on profiling of 202 targeted metabolites. To identify metabolic signatures predicting response to ICB at baseline, we have developed mzLearn, a data-driven algorithm that overcomes obstacles in liquid chromatography/mass spectrometry (LC/MS) measurements of untargeted metabolomics at scale. Methods: We used baseline and post-treatment raw LC/MS data (n=1,650) from ccRCC patients in Phase I (n=91) and Phase III (n=741) trials (Workbench IDs ST001236 and ST001237), where anti-PD-1 treatment yielded a significant increase in overall survival compared to mTOR inhibitor. mzLearn detected 4,018 signals present in >60% of all samples. The identified signals have 90% accuracy in detecting targeted metabolites with 10% false positives while effectively overcoming signal drifts and batch effects. We then performed unsupervised K-means clustering of baseline metabolomic features and supervised linear and Cox proportional hazard models to find minimal subsets of those features associated with clinical benefit after adjusting for clinical variables, e.g., age and prognostic scores. We then developed logistic regression models to predict clinical benefit (CB), i.e., tumor shrinkage with ≥6 months progression-free survival (PFS). Finally, we used PIUMet (1), a network-based tool for untargeted metabolomic analysis, to identify linked mechanisms. Results: We identified three main metabolomic subtypes with distinct PFS in response to treatments. We identified a cluster of anti-PD-1 responders (n=279) with significantly higher PFS (p=2e-5, HR=0.56) and a non-responder cluster (n=261) who showed no significant effect from anti-PD-1 relative to mTOR inhibition (p=0.874, HR=1.02). Importantly, one subtype (n=201) tended to have higher PFS after mTOR inhibition (p=0.11, HR=1.27). Next, using supervised methods, we identified 97 baseline metabolite features associated with clinical benefit in the ICB arm. A smaller subset of top-scoring features predicts CB with a cross-validated AUC of 78% and the AUC=71% when tested in the independent Phase I cohort. PIUMet analysis of these features predicted their association with sphingolipid metabolism and arginine/proline metabolism. Conclusions: We showed baseline metabolic stratification of ccRCC patients can predict treatment response and discovered novel blood-based metabolic signatures of predicting response to ICB at baseline. These results establish a solid foundation for predictive biomarker discovery and potentially therapeutic recommendations after further validation. 1. Pirhaji et al. Nat. Met. 2016.
Lung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.
Authors: Wrangle John M. , Redman Mary Weber , Husain Hatim , Reckamp Karen L. , Stinchcombe Tom , Edelman Martin Joseph , Leal Ticiana , Faller Bryan A. , Minichiello Katherine , Borghaei Hossein , Kelly Karen , Herbst Roy S. , Gray Jhanelle E. 
Published: June 2024

2619 Background: IL-15 is a member of the IL-2 common gamma chain family of cytokines. N-803 is IL-15 administered in complex with IL-15 receptor alpha. Lung cancer, despite advances in targeted therapies and immunotherapy, remains the leading cause of cancer related death in the United States. Strategies to improve the performance of immunotherapy in advanced NSCLC is a clinical unmet need. Methods: Lung-MAP S1800D was a randomized study comparing N-803 plus pembrolizumab (NP) to investigators’ choice standard-of-care chemotherapy (SoC) for previously treated advanced NSCLC. Patients were enrolled into an Acquired Resistance Cohort (ARC) if disease progression on prior anti-PD-(L)1 occurred > 84 days from start of treatment and otherwise into a Primary Resistance Cohort (PRC). The ARC was a phase II/III study with a sample size goal of 334 patients. The PRC was a phase II with sample size of 134 patients. The first interim analysis (IA1) in the ARC evaluated futility among the first 25 patients treated with NP which required ≥1 response and ≥50% with disease control at 12 weeks to continue accrual. The primary endpoint in both cohorts was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response, and toxicity. Results: Accrual in the ARC and PRC were closed at the IA1 in the ARC with 74 pts in the ARC and 8 in the PRC. Of the 74 ARC patients, 71 met eligibility (36 SoC, 35 NP), and 32 pts on each arm received treatment. With 44 events, OS was not significantly different between the two arms (HR (95%CI: 0.73(0.40-1.36), p=0.32) with a 12-month OS rate of 25% with SoC and 44% with NP. With 61 events, PFS was not significantly different but numerically worse (HR (95% CI): 1.29 (0.78-2.13, 95% CI), p=0.33). There were 3 unconfirmed partial responses and 1 confirmed complete response with NP and 3 unconfirmed partial responses and 2 confirmed partial responses with SoC. On the NP arm, there were 10 Grade 3 (1 hematologic) and 1 Grade 5 treatment-related adverse events reported as Disease Progression (34% Grade 3+ TRAE). The Grade 3+ TRAE rate on the SoC arm was 53% with 10 Grade 3+ hematologic toxicities. Conclusions: While the study failed to continue accrual past IA1, there is an indication of a subgroup that might benefit from NP with a potential OS difference at 12 months. NP was safe when compared to SoC, and responses were seen in both treatment arms, including partial and complete responses in the NP group. Evaluation of tumor and patient characteristics will be critical to define if there are those who may benefit from N-803 plus pembrolizumab. Clinical trial information: NCT05096663 .
The efficacy of immune checkpoint inhibitors in patients with cancer with pseudoprogression.
Authors: Lyadova Marina , Fedorinov Denis , Pardabekova Olesya , Nosova Margarita , Tuleiko Veronika , Lyadov Vladimir , Kuzmina Evgenia , Antonova Tatiana , Lyadov Konstantin , Galkin Vsevolod , Poddubnaya Irina 
Published: June 2024

2620 Background: Pseudoprogression (PsP) is quite a common phenomenon in cancer patients undergoing therapy with immune checkpoint inhibitors (ICI). It could be defined as temporary increase of tumor volume or the number of tumor lesions after beginning of ICI treatment (immune unconfirmed progressive disease - iUPD) followed by clinical response. However, many specialists in real clinical practice are hesitant to continue ICI therapy in patients with iUPD because of medical or financial constraints. We aimed to evaluate the efficacy of ICI in patients with clinical evidence of PsP. Methods: We retrospectively analyzed 1001 cases of ICI treatment (male 58,4%, age 28-90 years) in patients with various solid malignancies: melanoma – 316, lung – 280, kidney – 247, GI cancer – 96, cervix of the uteri – 62. The patients were treated in 2 regional referral centers in Moscow and Moscow Region between June 2018 and Dec. 2022. Unconfirmed progressive disease (iUPD) according to iRECIST criteria was diagnosed in 316 patients at the first imaging control after the beginning of ICI treatment (31,6%). Results: Among 316 patients with iUPD the presence of progression (immune confirmed progressive disease – iCPD) was verified in 105 (33,2%): melanoma – 109 (34,5%), lung – 86 (30,7%), kidney – 75 (30,4%), GI cancer – 42 (43,8%), cervix of the uteri – 4 (6,5%). Stable disease was found in 144 (45,6%), partial response in 50 (15,8% - iPR), complete response in 17 patients (5,4% - iCR). Altogether, PsP was diagnosed in 211 of 1001 patients (21,1%). Overall objective response rate in 316 patients with iUPD reached 21,2%, control over disease was achieved in 66,8% of cases. Severe immune-mediated adverse events (3-4 st. according to CTC AE 5.0) were diagnosed in 9 patients (2,8%). Median overall survival in patients with iUPD and ORR was 16,85 mon (95% CI 15,1–18,5), in patients without iUPD and ORR – 14,93 mon (95% CI 13,78–16,0). Conclusions: PsP was diagnosed in 21,1% of patients getting ICI treatment in real clinical practice with median survival in PsP patients with objective response of about 17 months. Only 10,5% of patients had iCPD after their second follow-up. We feel that close adherence to iRECIST criteria to verify true progression is mandatory in patients under ICI treatment to exclude unnecessary cessation of treatment.
PD-L1 immunohistochemistry in gastric cancer: Comparison of combined positive score and tumor area positivity across 28-8, 22C3, and SP263 assays.
Authors: Klempner Samuel J. , Cowden Eric S , Cytryn Samuel Louis , Fassan Matteo , Kawakami Hisato , Shimada Hideaki , Tang Laura H. , Wagner Daniel-Christoph , Yatabe Yasushi , Savchenko Alexander , Salcius Jennifer , Johng Dorhyun , Fairchild Lauren , Chen Jing , Montenegro Giuliana , Moehler Markus H. 
Published: June 2024

2625 Background: The clinical application of programmed death-ligand 1 (PD-L1) immunohistochemistry is complicated by multiple available assays and different testing platforms, scoring algorithms, and cut-offs applied. This study assessed the analytical comparability of three commercially available PD-L1 assays (28-8, 22C3, and SP263) and two scoring algorithms used in gastric cancer (GC). Methods: Serial sections of 100 commercially procured GC samples, selected by the 28-8 assay to represent the dynamic range of PD-L1 expression, were stained with the three in vitrodiagnostic (IVD)-grade PD-L1 assays. Stained slides were blindly and independently evaluated by three trained pathologists for intra- and inter-reader assessment. Scoring was performed using the combined positive score (CPS) and tumor area positivity (TAP) methods, followed by statistical analysis. Digital image analysis (DIA) was used to objectively assess the technical performance of each assay by simulating CPS and TAP scoring methods using the HALO platform. Results: Comparable, specific, staining patterns were observed with the three PD-L1 assays. Pathologist assessment of PD-L1 positivity was reproducible in GC sample cohorts despite discernible variability in the observed staining intensity. When the same PD-L1 cut-offs were applied, inter- and intra-assay assessments of all three assays, using either CPS or TAP scoring methods, demonstrated moderate to almost-perfect (inter-assay Cohen’s kappa [κ] ranged from 0.47 to 0.83) and substantial to almost-perfect (intra-assay κ ranged from 0.77 to 1.00) agreement, respectively. Moreover, inter-pathologist evaluation showed a significant level of reproducibility (intraclass correlation coefficient (ICC) ≥0.92). DIA confirmed no difference in technical performance when specific digital algorithms were applied. Conclusions: This GC study highlights analytical concordance in PD-L1 testing among three major PD-L1 assays when TAP and CPS scoring algorithms are prospectively applied. Independently, DIA further supports the comparability of the technical performance of the assays. These observations support flexibility in cross-application of the different PD-L1 assays and scoring algorithms currently used to characterize PD-L1–positive GC samples.