tbuckley/cabot-search huggingface dataset:
PD-L1, tumor mutational burden (TMB) and long-term survival in patients with non-small cell lung cancer (NSCLC) and brain metastases.
Authors: Elio Adib, Amin Nassar, David J. Kwiatkowski, Ayal Aizer
Journal: Journal of Clinical Oncology (2024)

2034 Background: Brain metastases (BM) affect up to 50% of patients with NSCLC and are associated with poor prognosis in patients with non-targetable genomic alterations. Radiation forms the typical mainstay of intracranial management in such patients given the historically guarded intracranial efficacy of most systemic options. Immunotherapy-based approaches have shown promise but the extent that patients with BM may display extended survival with combination radiation- and immunotherapy-based approaches remains unclear. Methods: We identified 160 patients harboring non-squamous NSCLC with 486 newly-diagnosed BM between 2015-2023 managed with brain-directed radiation (either stereotactic-based, SRT or whole brain radiation therapy, WBRT) and immune checkpoint inhibition within 3 months of radiation at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (Boston, MA). PD-L1 tumor expression was categorized as &lt;1%, 1-49%, 50-89%, and ≥90% based on immunohistochemistry. TMB was assessed via targeted next-generation sequencing. Cox-proportional hazards regression was used to assess all-cause mortality while Fine-Gray competing risks regression was used to assess other time-to-event based outcomes. Results: The median number of BM was 3 (IQR 1-7). Neurosurgical resection in advance of radiation was performed in 51/160 (32%) pts. SRT was used in 130/160 (81%) versus 30/160 (19%) patients treated with WBRT, respectively. Median follow-up time was 30.1 months (mo). Higher PD-L1 expression was associated with significantly longer overall survival (OS) with a median survival in patients with PD-L1&lt;1%, 1-49%, 50-89% and ≥90% being 11.8, 14.4, 29.5 and 33.1 months, respectively (Table). Similarly, time to systemic death (TTSD) was longer in patients with higher PD-L1 expression, while time to neurologic death (TTND) was not different across categories. Higher TMB (≥10 vs. &lt;10 mutations/megabase) was not associated with significantly longer OS, TTSD or TTND. Conclusions: Higher PD-L1 tumor expression was associated improved all-cause mortality, largely driven by reduction in systemic death. A significant percentage of patients with a very high PD-L1 displayed long-term survival, highlighting the potential importance of multimodality therapy in such patients, and demonstrating that clinicians should be cognizant of treatment-associated long-term toxicities in this population. [Table: see text]
Outcomes and immune response after peptide vaccination targeting human cytomegalovirus antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma.
Authors: Eric Thompson, David M. Ashley, Kathy Ayasoufi, Pamela Norberg, Gerald E. Archer, Evan Buckley, JAMES E HERNDON, Ashley Walter, Bridget Archambault, Charlene Flahiff, Denise Jaggers, Laura Gorski, Elizabeth A. Reap, Kristin Schroeder, Annick Desjardins, Margaret O Johnson, Katherine B. Peters, Mustafa Khasraw, John H. Sampson, Daniel B Landi
Journal: Journal of Clinical Oncology (2024)

2039 Background: The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this first-in-human phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG. Methods: The vaccine is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a single 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV administered intradermally in the groin every two weeks for 3 doses, then monthly. Results: Forty-two patients were enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=21), anaplastic oligodendroglioma (n=3), anaplastic astrocytoma (n=11), and malignant glioma NOS (n=5). The median time from initial diagnosis to treatment was 24 months (range 4-35) and the median number of prior chemotherapy regimens was 4 (range 0-15). The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. Of the 38 patients who received PEP-CMV, the maximum grade adverse event (AE) possibly, probably, or definitely related to PEP-CMV was as follows: 17 (45%) had Grade 1 adverse events (AE), 16 (42%) had Grade 2 AEs, 2 (5%) had Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) had a Grade 4 AE (cerebral edema). One patient developed symptoms and had elevated inflammatory cytokines consistent with cytokine release syndrome (Grade 2). The median progression-free survival was 2.5 months (95% CI:2.2,3.2) and median overall survival was 6.4 months (95% CI:3.4,7.9). The 12-month OS was 26.6% (95% CI:14,41.1%). Of the 22 patients with evaluable immune monitoring data, T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median spot pretreatment vs. prior to vaccine #4: 1 vs 30, P=0.004, Table). Lower percentage of pretreatment regulatory T cells and higher percentage of terminally differentiated effector T cells at vaccine #4 were associated with longer subsequent survival. Conclusions: PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%. A multi-institutional Phase II trial (NCT05096481) of PEP-CMV is opening imminently. Clinical trial information: NCT03299309 . [Table: see text]
Tumor treating fields (TTFields) therapy in patients with glioblastoma: Long-term survival results from TTFields in Germany in routine clinical care (TIGER) study.
Authors: Oliver Bähr, Ghazaleh Tabatabai, Rainer Fietkau, Roland Goldbrunner, Martin Glas
Journal: Journal of Clinical Oncology (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 &gt;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 .
Identification of pharmaceutics with selective activity against melanoma-associated leptomeningeal disease using patient-derived circulating tumor cells.
Authors: Vincent Law, Simon Bayle, Derek R. Duckett, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2024)

2032 Background: Patients with advanced stage of melanoma may develop leptomeningeal disease (LMD), a rare form metastasis in the meninges. Unfortunately, there are currently no rationally designed treatments for melanoma-associated LMD (M-LMD) and the prognosis is dismal; with survival measured in weeks. A major barrier to developing effective therapies for this disease is the absence of model systems, such as patient-derived cerebral spinal fluid-circulating tumor cell (PD-CSF-CTC) models to identify and assess novel therapeutics. Added to this challenge is the difficulty of collecting and analyzing M-LMD specimens in the clinic and at autopsy. To address these hurdles, we have made considerable progress recently in overcoming these barriers via CSF and tissue collection (in clinic and rapid autopsy) and successfully propagating CSF-CTCs from M-LMD patients in vitro and in xenograft mouse models. These valuable resources have allowed us to perform proteomic and transcriptomic analyses of CSF and PD-CSF-CTCs, respectively. By comparing M-LMD -omics data against those from normal brain and extracranial disease, we have found unique LMD-specific biological pathways. In this study, we identified clinical compounds that could target these biological pathways and have efficacy against PD-CSF-CTCs in vitro and in vivo. Methods: PD-CSF-CTCs were propagated from individual M-LMD patients. Next, we have developed a 384-well high throughput cell-based assay and performed a pilot screening of more than 1,400 FDA-approved small molecule compound library using Echo to identify pharmaceutics that inhibit cell proliferation. Clinical compounds with the highest sensitivity were selected for validation of efficacy in vivo via intrathecal (IT) delivery of patient-derived cell lines to establish M-LMD xenografts. Results: Of the 1,436 FDA-approved small molecule compounds, 57 (~3.9%) exerted 95% proliferation inhibition and 20 (~1.4%) had 100% killing effect in PD-CSF-CTCs and murine melanoma cell lines. The compounds with the highest sensitivity include ponatinib (EC50: 1.85 – 4.06e -06 ), sorafenib (EC50: 9.57 – 9.77e -06 ), ceritinib (EC50: 1.84 – 2.05e -06 ) and homoharringtonine (HHT) (3.63 – 4.11e -08 ). In a randomized murine M-LMD preclinical trial, we selected HHT, since it is a cephalotaxine ester compound that can penetrate the brain. Our results show that HHT was well-tolerated in vivogiven systemically or IT via a murine Ommaya. We found M-LMD mice that received 14.5ng HHT (g.d. IT) showed significant prolonged median survival (control vs. HHT, P value: 0.0006; Mantel Cox test). Conclusions: This is the first demonstration of an approach that allows for the rational development of therapeutics in M-LMD. Results will provide crucial new insights into biology and will identify drug candidates that may be suitable for future clinical trials.
Investigating peripheral blood biomarkers of immune checkpoint inhibitor associated fatigue.
Authors: Howard Liu Li, Soren Charmsaz, Stephanie Leigh Alden, Madelena Brancati, Aanika Warner, Kabeer Munjal, Hua-Ling Tsai, Nicole E. Gross, Christopher Thoburn, Evan J. Lipson, Yasser Ged, Rachel Garonce-Hediger, Sanjay Bansal, Laura Tang, Elizabeth M. Jaffee, G Scott Chandler, Rajat Mohindra, Won Jin Ho, Mark Yarchoan, Chester Kao
Journal: Journal of Clinical Oncology (2024)

2571 Background: Fatigue is the most common side effect of immune checkpoint inhibitor (ICI) therapy. Despite its prevalence, the mechanisms underlying ICI-associated fatigue are poorly understood. In this study, we characterized dynamic changes in peripheral immune cell populations and cytokines to identify biomarkers and mechanisms of ICI-associated fatigue. Methods: We prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs between July 2021 and November 2023. Blood samples were collected at baseline, early-on-treatment (month 1-2), and later-on-treatment (month 4-6). Patients were contacted on-treatment to query for worsening of fatigue compared to treatment baseline. We analyzed peripheral lymphocyte populations by Cytometry by Time-of-Flight (CyTOF) and peripheral levels of 39 cytokines with Luminex multiplex assay. Tumor response was characterized by RECIST v1.1. False discovery rate (FDR) was used for multi-testing adjustment. Results: 53 patients received ICI therapy and had fatigue assessment performed. Thirty-one patients (58.5%) reported worsening fatigue, and 22 (41.5%) did not. In patients with worsened fatigue, a cluster of cytotoxic effector CD8+CD28+TIGIT+ T-cells was significantly increased from baseline to early-on-treatment (Wilcoxon Signed-rank Test FDR adjusted p&lt;.05). Early-on-treatment fold changes in Type 1 cytokines (IFN-gamma, IL-2, IL-12) were increased in patients with worsened fatigue compared to patients with no fatigue (Wilcoxon Rank-sum Test unadjusted p&lt;.05; Table). There was no association between increase in fatigue and objective response to ICI therapy, although numerically high rates of fatigue were observed both in patients experiencing disease progression as well as complete responses. After excluding patients with tumor progression to account for tumor-related fatigue, early-on-treatment fold changes in IL-2 and IL-12 were still increased in worsened fatigued compared to non-fatigued patients (unadjusted p&lt;.05). However, in patients with disease progression, changes in Type 1 cytokines were not associated with worsening fatigue. Conclusions: In a pan-tumor cohort treated with ICIs, increases in a cluster of cytotoxic effector CD8+ T cells in parallel with related Type 1 cytokines were associated with fatigue, implicating fatigue as a marker of immune activation in this population. [Table: see text]
Creating a bionic scaffold via light-curing liquid crystal ink to reveal the role of osteoid-like microenvironment in osteogenesis
Authors: Kun Liu, Lin Li, Yizhi Li, Yiting Luo, Zhaoyu Zhang, Wei Wen, Shan Ding, Yadong Huang, Mingxian Liu, Changren Zhou, Binghong Luo
Journal: Bioactive Materials (2024)
Identification of molecular subtypes for integrated multi-omics analysis for use in guiding precision medicine in hepatocellular carcinoma.
Authors: Yihong Chen, Ying Han, Changjing Cai, Yinghui Peng, Jiayao Ma, Hong Shen, Shan Zeng
Journal: Journal of Clinical Oncology (2024)

2576 Background: Tumor microenvironment (TME) heterogeneity leads to the discrepancy of survival prognosis and clinical treatment response for HCC patients. Although the documented molecular subtypes moderately describe the TME heterogeneity and characteristics, their clinical application is constrained by several issues. Methods: We integrated three single-cell datasets from 39 HCC patients to describe the TME landscape and identified prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers (SSMs) was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and Xiangya real-world HCC cohort with patients who received immune checkpoint blockade (ICB) therapy. Cancer stemness was estimated using bioinformatic methods and in vivo and in vitro experiments. The features of TME were further validated using single-cell RNA-seq and immune repertoire sequencing, mass cytometry (CyTOF) and multiplex immunofluorescence (mIF). Ultimately, we constructed prognosis-related score (PRS)based on machine learning algorithm, and identified the potential therapeutic targets and agents for high-PRS patients. Results: The comprehensive single-cell analysis provided a high-resolution depiction of TME heterogeneity in HCC and confirmed 6 cell subclusters of prognostic relevance. Five transcriptomic subtypes were constructed using SSMs, which possessed different clinical prognosis, stemness characteristics, immune landscape and therapeutic responses. Class 1 indicated an inflamed phenotype with better clinical outcomes, while Class 2 and class 4 demonstrated immune-deserted phenotypes lacking T cells infiltration. Class 5 and class 3 indicated inhibitory tumor immune microenvironment enriched regulatory T cells and suppressive immune checkpoints. Multiple therapeutic cohorts suggested that Class 5 and class 3 were sensitive to ICB and targeted therapy, while Class 1 and Class 2 were more responsive to transcatheter arterial chemoembolization treatment (TACE). Class 4 displayed resistant to all conventional HCC therapies. The PRS performed well in prognostic prediction in multiple HCC cohorts. Four potential therapeutic agents and four targets were further identified for high-PRS HCC patients. Conclusions: Our study generated a clinically valid molecular classification, thereby providing guidance for precision medicine in HCC patients.
Phase 1/2 study of the TGF-β-trap-enhanced oncolytic adenovirus, AdAPT-001, plus an immune checkpoint inhibitor for patients with immune refractory cancers.
Authors: Anthony Paul Conley, Vinod Ravi, Christina Lynn Roland, Tony R. Reid, Chris Larson, Scott Caroen, Jeannie Ann Williams, Bryan Oronsky, Meaghan Stirn, Nacer Abrouk, Erica Burbano, Lucy Boyce Kennedy
Journal: Journal of Clinical Oncology (2024)

2506 Background: The benefit of immune checkpoint inhibition is limited to 20-40% of patients. Moreover, acquired resistance often arises. Also, certain tumor types like breast are more CI-refractory. Therefore, the focus is on new combination strategies to increase clinical benefit. This multicenter phase 2 trial evaluated AdAPT-001, an oncolytic adenovirus armed with a “TGF-β trap” that neutralizes the immunosuppressive cytokine, TGF-β, +/- a checkpoint inhibitor (CI) in resistant patients some of whom previously failed a CI. Methods: Eligible patients with refractory tumors, many of them sarcomas, received 1 or more intratumoral injections of AdAPT-001 at dose level 1 x 10 12 viral particles every 2 weeks +/- a CI at Investigator discretion. The CI was administered every 2 nd -3 rd week. Adverse events were recorded and managed. The primary endpoints of this combination therapy were objective response rate (ORR) and progression free survival (PFS). Results: 36 patients (22 males and 14 females) enrolled with a median age of 60.8 years (range 23-86) from Feb 2023-Dec 2023. 24/36 enrolled patients received AdAPT-001 with a CI and 12 patients received AdAPT-001 single agent. The most common treatment related adverse events (TRAE) were transient flu-like symptoms (fever, chills, vomiting, fatigue) 10/36 (27.7%), and injection related events 10/36 (27.7%). Notably, only 1 patient, 1/24 (4.0%), developed an immune-related AE, hypophysitis. All other related AEs were Grade 1/2. 33/36 patients were evaluable for response analysis; monotherapy produced 2/9 (22.2%) favorable responses (complete response (CR): eccrine carcinoma; confirmed partial response (cPR): acral melanoma); and produced a 4/9 (44.4%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. The combination of AdAPT-001 plus a CI produced 7/24 (29.1%) favorable responses (1 clinical CR: angiosarcoma; 6 cPRs: 3 sarcoma, 1 triple negative breast cancer, 1 head and neck cancer, 1 squamous cell carcinoma; and a 15/24 (62.5%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. 21/33 failed a CI before enrollment (16/24 before AdAPT-001 + CI). The PFS was 3.5 months (95% CI: 1.8-NA months). Conclusions: Combination therapy of AdAPT-001 with a CI is well tolerated and demonstrates a high ORR including 1 patient with a CR per RECIST 1.1, 1 patient with a clinical CR and 6 PRs. In several cutaneous sarcomas treated with AdAPT-001 plus a CI, radiologic SD belied how much better they looked visually--not only smaller, but less irregular and more circumscribed. Clinical trial information: NCT04673942 . [Table: see text]
Phase I clinical trial of <sup>64</sup>Cu-ATSM for malignant brain tumors.
Authors: Hiroaki Kurihara, Yoshitaka Narita, Kimiteru Ito, Hidemitsu Sato, Yasuji Miyakita, Masamichi Takahashi, Shunsuke Yanagisawa, Natsuko Tsuda Okita, Ryo Sadachi, Kensuke Tateishi, Yukie Yoshii, Atsuo Waki, Hiroki Hashimoto, Hisashi Suzuki, Ming-Rong Zhang, Kazunori Kawamura, Natsuki Honda, Mitsuyoshi Yoshimoto, Hiroki Matsumoto
Journal: Journal of Clinical Oncology (2024)

2052 Background: Malignant brain tumors such as glioblastoma have poor prognosis. Current standard therapies such as surgery, radiotherapy, and chemotherapy were frequently insufficient. Hypoxic tissue microenvironments induced by rapid cellular growth within tumor lesions lead to treatment resistance. Methods: Eligible patients had a histological diagnosis of grade III/IV glioma, primary central nervous system malignant lymphoma (PCNSL), or grade II/III malignant meningioma based on the most recent pathological diagnosis prior to enrollment, or metastatic brain tumor based on clinical course or imaging. Diacetyl-bis( N 4 -methylthiosemicarbazone) radiolabeled with Cu-64 ( 64 Cu-ATSM) was synthesized as described elsewhere. 64 Cu-ATSM was administered intravenously once a week for 4 weeks. Adverse events were assessed using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The trial had a traditional single arm open-label 3 + 3 design with four 64 Cu-ATSM dose cohorts: 30, 60, 99, and 150 MBq/kg. The primary objective was to assess dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) of 64 Cu-ATSM. Overall survival (OS), progression-free survival (PFS), pharmacokinetics, and 64 Cu-ATSM effective radiation dose were evaluated as secondary endpoints. Results: In total, 20 patients were registered at National Cancer Center Hospital or Kanagawa Cancer Center. Eighteen patients who received 64 Cu-ATSM were included in the primary analysis. None of the 3 patients at 30 MBq/kg, 1 of 6 patients at 60 MBq/kg, and 1 of 6 patients at 99 MBq/kg developed DLT (grade 3 lymphocytopenia). Two of 3 patients at 150 MBq/kg developed DLT (grade 4 lymphocytopenia). Therefore, additional patient recruitment was terminated. The MTD was considered to be 99 MBq/kg. No serious adverse events caused by 64 Cu-ATSM administration were not reported. Median OS was 29.4 months and 1-year OS was 76.6%. Median PFS was 3.8 months and 1-year PFS was 19.0%. 64 Cu-ATSM was rapidly distributed to body organs after intravenous administration and subsequently disappeared gradually. The liver (0.23 mSv/MBq) received relatively high doses, with an estimated effective dose of 0.037 mSv/MBq. Conclusions: Intravenous administration of 64 Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options. Clinical trial information: jRCT2091220362 .