bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world use of a CSF circulating tumor cell assay in the diagnosis and management of leptomeningeal metastasis.
Authors: Blondin Nicholas Alfred , Haberli Nicholas 
Published: June 2024

2029 Background: The diagnosis of leptomeningeal metastasis (LM) can be challenging due to variability in clinical symptoms, radiographic, and cerebrospinal fluid (CSF) findings. The National Comprehensive Cancer Network (NCCN) guidelines recommend assessment of circulating tumor DNA (ctDNA) to increase sensitivity of tumor cell detection and assess the response to treatment. We hypothesize that the real-world use of an assay for the direct detection and enumeration of circulating tumor cells (CTCs) in the CSF is clinically useful for accurate diagnosis of LM, particularly in an early stage of disease. Methods: We report a series of 55 patients treated at our institution with a cancer diagnosis and either neurological symptoms or radiographic findings that suggested LM. All patients underwent a lumbar puncture, assessment for CSF CTCs, and conventional hospital-based cytology testing between 6/1/2020 and 8/1/2023. Survival data cutoff was 12/31/2023. Patient outcomes are reported. Results: 55 patients were tested, and 30 patients were found to be positive for CTCs and diagnosed with LM. Only 10 patients were concurrently positive for CTCs and cytology at our institution, whereas 20 patients with positive CTCs had a negative or ambiguous cytology. No patients with a negative CTC result (25 patients) were subsequently diagnosed with LM, whereas 4 patients with a positive CTC result remained without progressive neurological symptoms. 5 patients diagnosed with LM were alive at the time of data cutoff. The histologic breakdown for LM was: breast (11), non-small cell lung cancer (NSCLC) (16), gastrointestinal (GI) (3). Median overall survival (OS) was longer in patients with a positive CTC and negative cytology result compared to patients with concurrent positive CTC and cytology (172 vs. 63 days, p = 0.06). Median OS was also longer in breast cancer LM compared to NSCLC LM (235 vs. 63 days, p = 0.008). Most patients diagnosed with LM received therapies including Ommaya reservoir placement, intrathecal chemotherapy, and/or radiation. Conclusions: The use of a CSF circulating tumor cell assay aided the diagnosis of LM and led to timely initiation of treatment. A negative result of the CTC assay was associated with ruling out LM. Diagnosis of LM with the CTC assay and negative cytology was associated with longer survival, possibly due to earlier treatment initiation, and not solely a lead time bias. Breast cancer LM patients had improved survival compared to NSCLC and GI cancer patients, possibly due to more effective treatment options.
Intracranial hemorrhage in glioblastoma: Incidence, risk factors, and outcome.
Authors: Lee Seok-Yun , Devos Patrick , Bink Andrea , Regli Luca , Weller Michael , Le Rhun Emilie 
Published: June 2024

2074 Background: The incidence and clinical implications of intracranial hemorrhage (ICH) in patients with glioblastoma have not been well studied. Risk factors for ICH and associations with therapy and outcome remain unknown. It has been speculated that prior radiotherapy, chemotherapy-associated thrombocytopenia, steroid medications as well as age, other comedications and comorbidities contribute to the risk of ICH in this patient population. Methods: We identified consecutive patients with glioblastoma per WHO 2021 definition from the electronic charts of the University Hospital in Zurich, Switzerland and explored the incidence, putative risk factors, management and outcome of ICH in patients with glioblastoma. ICH was identified on central MRI and imaging report review. The study has been approved by Swissethics (2023-00532). Results: Among 387 patients diagnosed between 2010 and 2019, 6 patients presented with ICH, and 22 patients experienced ICH in the further disease course, after a median time of 153 days (IQR 79-323 days). Of the 6 patients with ICH at diagnosis, 2 patients were on anti-platelet agents and 1 was on anticoagulation. ICH occurred in the tumor region in all these patients. There were no specific features in their history compared with patients that did not present with ICH at diagnosis. Among 22 patients with ICH after diagnosis, 9 patients (41%) experienced ICH prior to first progression. ICH were not restricted to the tumor region, but included subdural hematomas in 7 patients and an epidural hematoma in one patient. Fifteen patients (68%) were hospitalized for ICH, and 5 patients (23%) had a craniotomy. Thirteen patients (59%) had no change in management, 4 patients (18%) started a new intervention, and 5 patients (23%) went to palliative care. Compared with patients without any ICH ever documented, the 28 patients with ICH were more often male, but not older, did not have a history of arterial hypertension, diabetes, chronic kidney disease or smoking, and did not have larger tumors at diagnosis. At the timepoint of intracranial hemorrhage, six patients (27%) had been preexposed to bevacizumab, yet, 188 patients (53%) of the reference cohort received bevacizumab across the disease trajectory without experiencing an ICH. Three patients (14%) had platelet counts below 100,000/µl. Overall survival in the 28 patients who experienced an ICH was not inferior to survival in the population of patients without an ICH. Conclusions: ICH at diagnosis is rare in glioblastoma and its etiology remains to be identified. It may be related to intrinsic features of the tumor and its blood vessels since no other patient-related risk factors were identified. Overall, male sex was the only risk factor associated with ICH in this study, but ICH does not signify a poor outcome overall.
IOV-3001, a modified interleukin-2 fusion protein, for potential use in tumor-infiltrating lymphocyte cell therapy regimens.
Authors: Abelson Michelle R. , Johnson Sadie , Poprawski Joanna , Blauvelt Jamie L. , Hall Sean , Yin Hequn 
Published: June 2024

2552 Background: Tumor-infiltrating lymphocyte (TIL) cell therapy has shown promising efficacy in patients with solid tumor malignancies. Interleukin-2 (IL-2) administration after TIL infusion supports persistence and survival of infused TIL. Aldesleukin is a synthetic IL-2 with a short half-life administered every 8–12 hours, to support the expansion and persistence of the TIL in vivo. IOV-3001 is a modified dimeric IL-2 fused to palivizumab that has a longer half-life and potentially better safety profile, compared with aldesleukin. Here, we describe the preclinical activity, pharmacokinetics (PK), pharmacodynamics (PD), and in vivo safety profile of IOV-3001. Methods: Binding of IOV-3001 and aldesleukin to the IL-2 receptor (IL-2R), IL-2R-mediated activation via STAT5 phosphorylation, and T cell proliferation were assessed. Pharmacological activities of IOV-3001 and aldesleukin were evaluated in B16-F10 mice infused with pmel-1 T cells. Safety after a single dose of IOV-3001 (0.01–9.0 mg/kg) was assessed in cynomolgus monkeys across 3 independent studies. PK and PD parameters, clinical pathology, hematology, and histopathology were assessed. Results: Both IOV-3001 and aldesleukin induced comparable STAT5 phosphorylation and proliferation of T-cell subsets. Mice infused with pmel-1 T cells and subsequently treated with IOV-3001 or aldesleukin showed similar reductions in tumor burden. The half-life of IOV-3001 in cynomolgus monkeys ranged from 5–8 hours. IOV-3001 was well tolerated in monkeys across the dose range studied except for 1 animal administered IOV-3001 at the highest tested dose level, with recovery by Day 29. Inflammatory cytokines (IL-12 p40, IL-6, MCP-1) increased from 4 hours to ≤3 days after dosing and returned to baseline by Day 29. Fibrinogen, bilirubin, and triglycerides increased on Day 3 and returned to baseline by Day 29. No signs of capillary leak were observed. Increased numbers of hematopoietic cells were found in the bone marrow, spleen, and lymph nodes 3 days post dosing. During the 4-week recovery, these changes diminished or resolved, while bone marrow showed differential dose-dependent effects. IL-2–induced proinflammatory PD effects were observed, including >10-fold peak CD8+ T cell expansion in peripheral blood mononuclear cells at Day 5 versus preacclimation in most cynomolgus monkeys treated with IOV-3001. Conclusions: IOV-3001 exhibited a similar mechanism of action (MoA) to that of aldesleukin in vitro and has a longer half-life in vivo. PD effects were consistent with the MoA of IL-2. IOV-3001 showed a favorable preclinical safety profile. These results suggest a potentially improved safety profile for IOV-3001 with less frequent dosing compared with aldesleukin. These features of IOV-3001 strongly advocate for its development in TIL cell therapy regimens.
Soluble mesothelin neutralizes mesothelin antibody-based therapies.
Authors: Smith Katherine Emilie Rhoades , Ayers-Ringler Jennifer , Dizona Paul , Lucien Fabrice , Kim Yohan , Orme Jacob , Winters Jeffrey , Moscow Jeffrey , Mansfield Aaron Scott 
Published: June 2024

2565 Background: Mesothelin (MSLN) is overexpressed in mesothelioma and other solid tumors making it the focus of multiple targeted therapies, including antibody drug conjugates (ADCs), T cell receptor (TCR) fusion constructs, and chimeric antigen receptor T-cell (CAR-T) products. However, the clinical efficacy of these treatments remains limited. We hypothesize that soluble MSLN (sMSLN) in the plasma binds to MSLN-targeted therapies before reaching the tumor. Our study aimed to evaluate the effects of sMSLN on a MSLN-targeting antibody, anetumab, and explore methods to reduce sMSLN. Methods: Exploratory analysis in NCT03126630: sMSLN testing was performed on blood samples from participants enrolled in NCT03126630 at the Molecular Targets Core Lab, National Cancer Institute. The median was used to categorize high and low levels of sMSLN. Survival was estimated with the Kaplan-Meier method and compared between groups with the log rank test. Anetumab immunoprecipitation: Anetumab was covalently coupled to Dynabeads at 5 µg per mg of beads to immunoprecipitate MSLN from two plasma samples. Assays were performed in duplicate. Therapeutics plasma exchange (TPE):Whole blood samples were collected before and after one plasma volume of TPE with albumin as the replacement fluid in patients undergoing routine TPE for various medical conditions, such as autoimmune diseases and hyperviscosity syndromes. Plasma levels of sMSLN were measured with an ELISA assay in matched pre- and post-TPE plasma samples. Results: We obtained sMSLN levels from 40 patients enrolled in NCT03126630. For patients treated with both anetumab ravtansine and pembrolizumab, median progression free survival (PFS) was shorter in the high sMSLN group (5 months) vs the low sMSLN group (12 months). For patients treated with pembrolizumab alone, PFS was similar for patients with high and low sMSLN (4 vs 3.4 months). Anetumab significantly reduced the concentration of sMSLN in plasma samples as detected by MSLN ELISA (p<0.05), demonstrating that sMSLN can bind to and sequester anetumab. Next, we evaluated TPE as a mechanism to reduce sMSLN. We obtained pre- and post-TPE plasma samples from 15 patients undergoing routine TPE for various medical conditions. TPE consistently reduced sMSLN (p<0.05) with an average decrease of 43.6% or 15.4 ng/mL. Conclusions: We found that high sMSLN levels are associated with shorter PFS for anetumab ravtansine, but not pembrolizumab. Additionally, anetumab binds to sMSLN in the plasma, which suggests that sMSLN can sequester anti-MSLN antibodies and may limit the efficacy of MSLN-targeted therapies. High levels of sMSLN could potentially be used as a biomarker to select which patients should not receive MSLN-targeting therapies. Furthermore, our results indicate that sMSLN reduction is feasible with TPE. Decreasing sMSLN could restore the activity of MSLN-targeted therapies.
CD4 effector T cell expansion to identify objective responses to the CD40 agonist mitazalimab in combination with modified FOLFIRINOX (mFFX) as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) in the OPTIMIZE-1 study.
Authors: Wattenberg Max Miller , Enell Smith Karin , Pico de Coaña Yago , Gomez Jimenez David , Ambarkhane Sumeet Vijay , Ellmark Peter , Beatty Gregory Lawrence 
Published: June 2024

2569 Background: CD40 agonists have the potential to enhance the efficacy of standard of care chemotherapy and to trigger antitumor immunity. Preclinical models indicate that the success of this approach depends on appropriate sequencing of chemotherapy with a CD40 agonist. Preliminary efficacy results from the OPTIMIZE-1 Phase II study (NCT04888312) combining mitazalimab (anti-CD40) with mFFX chemotherapy in patients with mPDAC have been previously reported. Here, we investigated immunological determinants associated with favorable outcomes with this combination therapy. Methods: Newly diagnosed, chemotherapy-naive patients with mPDAC received mitazalimab (900 µg/kg) on day 1 prior to beginning an every 2-week mFFX regimen on day 8, followed by mitazalimab 48 hours later. Tumor response was determined using RECIST v1.1 criteria. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. Flow cytometric data from evaluable patients were subjected to unsupervised hierarchical clustering to identify immune subsets. A classifier was generated from an interim dataset (n=21) using a random forest model to predict cell populations and their association with tumor response, which were then applied to the full dataset (n=47). Results: Mitazalimab triggered an expected immune response characterized by transient cytokine (IFNg and MCP-1) release and B cell depletion. Chemotherapy caused a reduction in classical monocytes and proliferating CD4+ T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p < 0.0001) at day 8 after receiving mitazalimab. In a blinded analysis based on the classifier, CD4 T cell expansion was linked to an early tumor response to treatment (accuracy 70%, sensitivity 68%, specificity 72%). Conclusions: Mitazalimab and mFFX differentially modulate immune responses in patients with mPDAC. Pharmacological analyses identify mitazalimab-induced expansion of CD4 effector T cells one week after first administration as a correlate of treatment outcomes. These data suggest the contribution of mitazalimab to tumor responses, and further substantiate a priming dose of mitazalimab, prior to administering chemotherapy.
Transcriptome-based response predictor to identify potential responders among patients with negative standard markers for response to immune checkpoint blockers.
Authors: Dinstag Gal , Elis Efrat , Ben-Zvi Doreen S. , Elia Anna , Rajagopal Padma Sheila , Aldape Kenneth D. , Ruppin Eytan , Pikarsky Eli , Popovtzer Aron , Arnon Johnathan , Beker Tuvik , Aharonov Ranit 
Published: June 2024

2666 Background: Immune checkpoint blockers (ICB) are revolutionizing cancer treatment, and are being approved for an increasingly wide range of cancer types. The most common biomarkers currently in use to select patients for ICB are PD-L1 expression on tumor cells, as measured by IHC, and tumor mutational burden (TMB) and microsatellite instability (MSI), both measured by NGS. However, some patients that are negative for these markers still respond to ICB. This calls for complementary biomarkers to better identify responders to ICB, especially in patients that are negative to current biomarkers. Here, we focus on predicting response to anti-PD1 in patients with negative PD-L1, TMB or MSI. Methods: We employ ENLIGHT, our transcriptome-based precision oncology platform, which identifies and utilizes clinically relevant genetic interactions to predict a patient’s response to a wide range of targeted drugs, including ICB. ENLIGHT generates an individual ICB response score calculated from a 10-gene expression signature - the ENLIGHT Matching Score (EMS). Patients with EMS above a predetermined threshold are considered matched by ENLIGHT to anti-PD-1 treatments. We have previously shown, based on more than 1000 cases analyzed retrospectively, that this signature can identify responders to anti-PD-1 with high accuracy. Here, we use ENLIGHT to perform a retrospective analysis of 125 cases from three different datasets, who had low PD-L1 presentation (<1%), low TMB (< 10) or microsatellite stable tumors (MSS), and were treated with anti-PD-1, to specifically assess ENLIGHT’s performance in this biomarker-negative sub-population. Results: Patients who responded to anti-PD-1 treatments had significantly higher EMS in all three datasets. Correspondingly, ENLIGHT is highly predictive of response to anti-PD-1 in patients with negative ICB markers in the three datasets (ROC AUCs of 0.80, 0.84, 0.77, respectively, for low PDL1, low TMB and MSS). It is important to note that ENLIGHT was not trained on any of these datasets, and is applied as-is using previously published parameters. Overall, we find that patients who are ENLIGHT-Matched to anti-PD1 in this biomarker-negative cohort are almost 3 times more likely to respond than patients who are not (31% vs. 11%, p=5e-13). Conclusions: ENLIGHT is a powerful tool for predicting response to anti-PD-1 treatment in patients with negative standard biomarkers for ICB, a currently unmet need with considerable clinical importance.
Phase I trial of talimogene laherparepvec for the treatment of peritoneal surface malignancies (TEMPO).
Authors: Stewart John H. , Lowe Melissa , Chapple Andrew G , Niedzwiecki Donna , Moyer Ashley , Bolch Emily , MacLaughlan Shannon Diane , Levine Edward A. , Moaven Omeed , Nettu Niharika , Strickler John H , Blazer Dan G. 
Published: June 2024

2668 Background: Peritoneal surface malignancies (PSM) constitute a group of difficult-to-treat metastatic diseases that respond poorly to standard chemotherapy. Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus (OV), demonstrates potential in treating various malignancies by effectively initiating crucial immune responses. Yet, the utility of intraperitoneal (ip) T-VEC for unresectable PSM is still unexplored. Methods: TEMPO (NCT03663712) was a nonrandomized, open-label, multicenter phase I trial involving 18 patients with unresectable PSM originating from the appendix (n=14), ovary (n=3), or small bowel (n=1). The trial aimed to determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of ip T-VEC, as well as to evaluate its safety and tolerability. An exploratory endpoint was the Restricted Mean Survival Time (RMST), the estimated non-parametric mean survival time up until the longest patient follow-up time (i.e. maximum of the longest follow-up, and generally an underestimate of the actual mean survival time especially in small samples). Patients received an initial dose of 4x106 plaque-forming units (pfu) of ip T-VEC, followed by their assigned dose every two weeks for up to four additional doses, using a standard ‘3+3’ dose escalation scheme. The doses tested were 4x106, 4x107, and 4x108 pfu of ip T-VEC. Safety assessments were conducted regularly. Results: The RP2D is 4x108 pfu of T-VEC. The trial reported no dose-limiting toxicities, thus the MTD was not reached. Treatment-Related Adverse Events (TRAEs) were recorded and categorized by the maximum dose received (Table).One patient treated with 4x106 pfu had grade 3 abdominal pain and another grade 3 fatigue. No severe TRAEs occurred with 4x107pfu. One patient showed a grade 3 neutrophil count decrease at 4x108 pfu. The RMST, calculated with a truncation time of 5.5 months, varied across the doses. Patients receiving 4x106 pfu had an RMST of 3.1 (95% CI= 1.550-4.733) months, while those treated with 4x107 and 4x108 pfu had RMSTs of 4.2 (95% CI= 2.492-5.884) and 4.6 (95% CI= 3.551-5.722) months, respectively. Conclusions: We conclude that ip T-VEC is safe in patients with unresectable PSM. TEMPO successfully identified 4x108 pfu as the RP2D for TVEC. Notably, the RMST increased with increasing doses of TL. These results are promising, considering the limited benefit of conventional chemotherapy in treating PSM. This study positions T-VEC as a promising candidate for combination immunotherapies for PSM that amplifies the bystander immune response induced by OVs. Clinical trial information: NCT03663712 . [Table: see text]
FU/FA maintenance therapy with or without panitumumab (pmab) in RAS wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses.
Authors: Modest Dominik Paul , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , Fischer von Weikersthal Ludwig , Caca Karel , Goekkurt Eray , Haas Siegfried , Kurreck Annika , Held Swantje , Jarosch Armin , Horst David , Reinacher-Schick Anke C. , Kasper Stefan , Heinemann Volker , Stintzing Sebastian , Trarbach Tanja , Stahler Arndt 
Published: June 2024

3506 Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS), and objective response rates (ORR) were compared by log-rank test / Cox regression and Fisher’s exact test. Results: PFS was significantly (8.8 vs. 5.8 months, HR=0.73 (95%CI 0.56 – 0.94), P=0.015) and OS numerically longer (29.9 vs. 24.7 months, HR=0.85 (95%CI 0.64 – 1.12), P=0.24). PFS re-ind. was significantly shorter after pmab maintenance (4.1 vs. 7.4 months, HR=1.93 (95%CI 1.33 – 2.82), P<0.001). TFS was comparable (17.1 vs. 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), P=0.92). Molecular subgroups are displayed in Table 1. ORR of FU/FA+pmab was comparable to FU/FA during induction (74.4% vs. 76.4%, P=0.77), higher during maintenance (40.8% vs. 29.3%, P=0.06), but lower at re-induction (8.0% vs. 35.9%, P<0.001). Conclusions: PFS remained improved by the addition of pmab to FU/FA maintenance therapy, while OS was not significantly longer. Re-induction of pmab+mFOLFOX6 did not provide benefit following pmab maintenance regarding PFS. Clinical trial information: NCT01991873 . [Table: see text]