tbuckley/cabot-search huggingface dataset:
Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors.
Authors: Songling Zhang, Xiaoxue Zhu, Lei Gao, Yaling Qi, Xiao Jia, Yongguo Li, Ye Guo, Yanhua Ding
Journal: Journal of Clinical Oncology (2024)

e14627 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. It modulates the tumor immune microenvironment by decreasing tumor Treg and myeloid-derived suppressor cells (MDSC) and improves the immune response to checkpoint inhibitors (CPI) in preclinical models. Methods: The Phase Ib study was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical activity, to determine recommended phase 2 dose (RP2D) of WX390 combined with Toripalimab in patients with advanced solid tumors. WX390 was administered orally daily at escalating doses of 0.7 mg, 0.9mg and 1.1mg, with Toripalimab at 240 mg IV every 3 weeks until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma PK samples were collected up to 24 hours after the first dose at C1D1, and up to 24 hours before and after the morning dose at C1D21. Results: As of December 31, 2023, total 18 patients had been treated in 3 WX390 cohorts: 0.7 mg (n = 3), 0.9 mg (n = 3), and 1.1 mg (n = 12) once daily (QD). No dose limit toxicity (DLT) was observed, and the RP2D of WX390 in combination was 1.1 mg QD, which was consistent with the single agent RP2D. The treatment related adverse events (TRAEs) (≥20%) included hyperglycemia (17/18, 94.4%), creatinine increased (12/18, 66.7%), weight loss (10/18, 55.6%), diarrhea (9/18, 50%), proteinuria (9/18, 50%), nausea (7/18, 38.9%), lymphocytopenia (7/18, 38.9%), vomiting (7/18, 38.9%), rash (7/18, 38.9%), decreased appetite (6/18, 33.3%), hypokalemia (6/18, 33%), fatigue (5/18, 27.8%), hyponatremia (4/18, 22.2%), and thrombocytopenia (4/18, 22.2%). Grade 3 TRAEs included hyperglycemia (5/18), lymphocytopenia (4/18), rash (2/18), weight loss (2/18), leukopenia (1/18), infusion-related reaction (1/18), nausea (1/18), and stomatitis (1/18). There was no TRAE leading to treatment permanent discontinuation and no grade 4/5 TRAE were observed. PK of WX390 in combination showed similar PK profile with the single agent. Among the 16 efficacy-evaluable patients with cervical (N=8), head and neck (N=5), and urothelial cancer (N=3), 5 patients (31.3%) previously received immune checkpoint inhibitors. 3 of 5 (60%) cervical cancer patients at RP2D and 2 of 5 head and neck cancer patient (40%) have achieved confirmed partial response (PR). In addition, 3 cervical patients who were treated with 0.7 or 0.9mg QD and 1of 3 urothelial carcer patients experienced tumor shrinkage (SD). The medium progression free survival (PFS) was 5.49 months (95% CI: 2.53, 6.37). Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and encouraging antitumor effects in patients with advanced solid tumors. An RP2D of 1.1 mg qd of WX390 in combination was selected to be explored in further phase II study, which is ongoing in different tumor types. Clinical trial information: NCT06117566 .
Intracranial hemorrhage in glioblastoma: Incidence, risk factors, and outcome.
Authors: Seok-Yun Lee, Patrick Devos, Andrea Bink, Luca Regli, Michael Weller, Emilie Le Rhun
Journal: Journal of Clinical Oncology (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.
Effect of tobacco use on response to immunotherapy in patients with cancer.
Authors: Hina Zubair, James P Ferrick, Christine A Welch, Elaine A Davis, Amir Shahzad Kamran
Journal: Journal of Clinical Oncology (2024)

e14537 Background: Evidence from existing literature suggests that it remains unclear if tobacco usage affects the efficacy of immune checkpoint inhibitors (ICI). This research aims to evaluate the connection between smoking and the effectiveness of immune checkpoint inhibitor (ICI) therapy in specific cancer types treated at our institution. Methods: This is a retrospective cohort study where cancer patients &gt;18 years old who received immunotherapy from 2017 to 2023 were identified through our center’s Cancer Registry. This study focuses on three major cancer types: lung, head and neck, and melanoma. 458 patients with their demographics, staging, duration of treatment and last contact have been assessed. SAS 9.4 was used for analysis with Chi-square/Fisher’s Exact testing, Student’s T-test, life tests and the Cox proportional hazards model to discern the effects of tobacco use and overall survival. Results: Among 458 patients, 48 (10.48%) are never-smokers, and 410 (89.52%) are smokers (current or former). Overall, 211 (46.06%) have stage 0-IIIA, while 247 (53.93%) have IIIB-IVB tumors. The mean age is 66.08 years. Additionally, 330 patients (72.05%) received chemotherapy as part of their treatment regimen in addition to immunotherapy. Non-tobacco users exhibit a higher survival probability compared to tobacco users. At five years, non-tobacco users showed a survival rate of 41%, whereas tobacco users had a survival rate of 28% (p=0.01) and hazard ratio [HR] of 1.55 (95% confidence interval, 1.00–2.39). The median survival for all patients is 40 months among non-tobacco users and 19 months among tobacco users. Moreover, there is no difference in the survival rates between current and former smokers. Conclusions: The study demonstrates that immunotherapy has better outcomes and increases survival probability in non-tobacco users. Also, there is no difference in survival between current or former tobacco users. However, these findings warrant future prospective studies.
First-line immunochemotherapy modulates peripheral immune landscape in advanced gastric cancer and gastroesophageal junction cancer (GC/GEJC): Prediction of response to combination therapy.
Authors: Hao Wu, Enqing Meng, Ping Li, Rongqi Jiang, Xu Cheng, Chan Zhu, Xing Zhang, Dongsheng Chen
Journal: Journal of Clinical Oncology (2024)

e14540 Background: The use of immunochemotherapy has brought about a change in the treatment of advanced or metastatic GC/GEJC, but only a subset of patients could benefit substantially. Therefore, seeking efficacious biomarkers to identify favorable populations for the regimen is imperative. This study aims to explore predictive markers and potential mechanism of combination therapy for GC/GEJC in real-world settings based on blood proteomic biopsy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after every two treatment cycles for Olink Target 96 IO analysis. CT scans were performed after every two cycles and will be categorized as responding (complete response plus primary response) or non-responding (progress disease plus stable disease) according to RECIST 1.1. Results: As of January 17, 2024, a total of 21 patients were enrolled. Eight of these patients received 16 samples before and after treatment, with 4 each of the 8 patients responding and non-responding. By analyzing the baseline samples comparing the responding and non-responding groups, it was found that patients in the responding group had lower expression of serum PD-L1 (sPD-L1) ( p=0.015). In the post-treatment samples, angiopoietin 1 was found to be poorly expressed in the responding patients ( p&lt;0.001). In contrast, high expression of angiopoietin 2 in post-treatment blood samples was more pronounced in non-responders compared to pre-treatment ( p=0.020). Additionally, we observed that immunotherapy can modify the immune microenvironment by up-regulating the T cell receptor signaling and NK cell-mediated toxic effects pathways. These pathways may be potential targets for treatment. Conclusions: In summary, low sPD-L1 level before treatment may be a predictive biomarker for better efficacy of immuno-combination chemotherapy in advanced GC/GEJC; whereas elevation of angiopoietin after treatment predicts poor efficacy and suggests that antiangiogenic therapy may subsequently be added in non-responding patients. We are further recruiting more patients to obtain more accurate conclusions. Clinical trial information: ChiCTR2300078000 .
First-in-human study of ZGGS15, a dual specific antibody targeting LAG-3 and TIGIT, as monotherapy in patients with advanced solid tumors.
Authors: Ji Zhu, Zhen Wang, Xiaoli Chai, Lihua Wu, Song Qu, Linlin Liu, Yanyan Liu, Yan Sun
Journal: Journal of Clinical Oncology (2024)

e14678 Background: ZGGS15 is a recombinant humanized bispecific antibody composed of a monoclonal antibody against LAG-3 and TIGIT. It can specifically bind LAG-3 and TIGIT. It reverses LAG-3 and TIGIT immune suppression to T and NK cells, relieves suppression of Treg to T and NK cells, promotes the activation and proliferation of T and NK cells, and cytokines release. ZGGS15 restores T and NK cell functions to kill tumor cells. In non-clinical studies, we found that ZGGS15 had significant anti-tumor effects and synergistic anti-tumor effects with Anti-PD-1 antibody. Therefore, we conducted a Phase 1 clinical study to assess the tolerability, safety, and preliminary efficacy of this drug as monotherapy in patients with advanced solid tumors. Methods: During the dose escalation stage, an accelerated titration design (ATD) in the first dose (1 subject if ≤Grade 2 treatment-related adverse event occurred) and the standard "3+3" design in the rest doses were used. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 30 (0.3, 1, 3, 10, 20, 30) mg/kg, intravenous infusion, once every 3 weeks. The first 21-day period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZGGS15 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1 and iRECIST. Pharmacokinetics (PK) and receptor occupancy (RO) profiles were also assessed in this study. Results: A total of 12 patients (4 males and 8 females) completed the DLT observation in the first four dose groups (0.3 to 10 mg), with a median age of 57 years. Eight (66.7%) of them received at least 3 lines of antineoplastic therapies, and five (41.7%) have been exposed to PD-1 or PD-L1 inhibitors. There was no DLT event observed. Thirty-eight treatment-related adverse events (TRAEs) occurred. Up to now, TRAEs were all grade 1 ~ 2. The most frequent TRAEs were proteinuria (33.3%, 4/12), hypokalemia (25%, 3/12), hypoalbuminemia (25%, 3/12), and hypertriglyceridemia (25%, 3/12). The C max and AUC increased from 0.3-1 mg/kg approximately in dose proportion. Nearly complete and sustained RO of T and NK cells in PBMCs was observed at 1 mg/kg dose of ZGGS15 for at least 3 weeks. Conclusions: The first four dose levels of ZGGS15 were very well tolerated. A good PK profile, and a long-lasting RO were observed in this escalation study. It is anticipated that this product could provide an additional benefit only when use in combination with an anti-PD-1 antibody. Clinical trial information: NCT05864573 .
Proteogenomic profiling of clonal hematopoiesis in the solid tumor microenvironment.
Authors: Marco M Buttigieg, Caitlyn Vlasschaert, Michael J Rauh, Robert Vanner
Journal: Journal of Clinical Oncology (2024)

2567 Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in solid tumor patients, and has shown context-dependent associations with survival; however, its contribution to the tumor microenvironment (TME) remains unclear. Here, we employ proteogenomic methods to define CH-associated alterations in the TME. Methods: We tested 1,550 patients across 10 primary, treatment-naïve cancers in the Clinical Proteomic Tumor Analysis Consortium cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival (OS) analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumor type, metastatic status, and smoking. Tumor bulk RNA-sequencing and mass spectrometry proteomics data were processed for differential expression and gene set enrichment analyses. Abundance of immune cell populations was estimated with CibersortX. Results: 349 CH mutations were identified in 283 patients (18.3%). CH was strongly associated with age and mutations were mostly found in the epigenetic regulators DNMT3A(37.8%, n=132) and TET2(20.6%, n=72). CH was most prevalent in ovarian cancer (30%, n=27/90) and colorectal cancer (CRC; 28.3%, n=30/106). 103 blood CH mutations were also detected in tumor WES (CH Tum ), with presence in the tumor associated with higher tumor immune infiltration and peripheral blood VAF ≥10%. CH Tum , but not CH, was associated with worse OS (CH Tum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CH Tum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). We did not identify a pan-cancer proteogenomic signature of CH in the TME. At the tumor-specific level, we consistently observed associations between CH and its subtypes with dysregulated inflammation, with high transcriptomic-proteomic concordance. In CRC, TET2-mutant CH was associated with greater infiltration of CD4+ T cells, monocyte/macrophages, NK cells, and B cells, alongside an inflammatory response characterized by IL6/JAK/STAT3 signalling, TNF signalling via NFκB, and IL2/STAT5 signalling. Conclusions: CH is common, even prior to therapy, in solid tumor patients and the infiltration of CH-mutant immune clones into the TME is linked with poor outcomes. Beyond confounding molecular tumor diagnostics, CH in the TME also dysregulates the anti-tumor immune response, highlighting the value of a blood reference in precision oncology. The lack of a pan-cancer CH signature in the TME supports a tumor-specific influence of CH. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.
A novel co-receptor with mutated TIGIT to enhance PSCA CAR-T therapy for bladder cancer.
Authors: Junjie Shen, Depeng Dai, Wenxu Zhao, Tongcan Liu, Yongchun Zhao, Yanmin Xu, Yanan Qi, Juan Hong, Xianxun Shi, Zhi Yang, Xia Huang, Lei Qin, Jun Chen, Cheng Qian
Journal: Journal of Clinical Oncology (2024)

e14574 Background: TIGIT plays a crucial role in immune regulation, particularly in tumor environments, by acting as an inhibitory receptor. Leveraging its interaction with ligands like CD155 on tumor cells, we developed an innovative CAR-T cell therapy using a mutated TIGIT co-receptor to overcome inhibitory effect induced by CD155, together with targeting Prostate Stem Cell Antigen (PSCA) CAR, chosen for its high expression in bladder and other cancers versus its minimal presence in normal tissues. Methods: We initiated our approach by inducing strategic mutations in TIGIT, selecting a variant with heightened affinity for CD155. Bio-Layer Interferometry (BLI) analysis confirmed the variant's high binding affinity (KD = 1.635 nM). This mutated TIGIT, combined with CD28's signaling components, was integrated as a co-receptor in our CAR construct. For PSCA targeting, we isolated a high-affinity ScFv against PSCA from a fully human phage display library. The specificity of this ScFv for PSCA was rigorously validated using Cell Membrane Protein Targeting Catcher (CMPTC) technology, covering over 6000 human cell membrane proteins. Results: In our comparative analyses, CAR-T cells featuring a mutated TIGIT co-receptor (T-PSCA-CAR-T) matched the cytotoxicity of traditional second-generation BBz-structured CAR-T cells (PSCA-CAR-T) against PSCA-expressing HT-1376 bladder cancer cells. However, T-PSCA-CAR-T cells distinguished themselves by producing significantly higher IFN-γ levels (3805.683±65.506 vs 1271.712±39.768 pg/mL). Our in vivo tumor model, utilizing luciferase-expressing HT-1376 cells, demonstrated T-PSCA-CAR-T's enhanced anti-tumor efficacy, as evidenced by a more significant reduction in bioluminescence signal intensity (average decreasing ratio: 0.02 for T-PSCA-CAR-T vs 0.35 for PSCA-CAR-T; p &lt; 0.05). These results underscore the efficacy of the mutated TIGIT co-receptor in improving CAR-T cell therapy. Conclusions: Our study signifies a transformative advancement in CAR-T cell therapy by incorporating a mutated TIGIT co-receptor, markedly improving therapeutic outcomes in bladder cancer treatment. Utilizing PSCA as a model target not only validates the efficacy of this novel approach but also paves the way for its application in a broader range of cancers, representing a significant leap in the field of immunotherapy.
Global, national, and regional burden of brain and central nervous system cancer in youth under 20 from 1990-2019: A benchmarking analysis.
Authors: Priyatha Vemparala, Mohit Lakkimsetti, Dhruval Pinalkumar Patel, Kushagrita Singh, Shrey Goel, Ibrahim Reyaz, Pinank Bathvar, Prashantkumar Savaliya, Danish Ahmed, Yassmeen Sharafeldin Mohammed, Shivani B Sonani, Juhi Patel, Himanshu Bharatkumar Koyani, Vishrant Amin, Dhruvkumar Gadhiya, Hardik Dineshbhai Desai
Journal: Journal of Clinical Oncology (2024)

2084 Background: Brain and central nervous system (CNS) cancer ranks as the second leading cause of death among all cancer-related fatalities globally in individuals under 20 years old. Despite its significance, there is a notable dearth of data on brain and CNS cancer in this age group, necessitating a comprehensive cross-country comparison. Methods: Utilizing the Global Burden of Disease study framework, we estimated the prevalence, incidence, deaths, and disability-adjusted life years (DALYs) attributable to brain and CNS cancer by age, sex, year, and location across 204 countries and territories from 1990-2019. Results: The total prevalence increased from 153,334 (95%UI: 111,452-233,819) in 1990 to 212,459 (164,908-245,556) in 2019, with incidence rising from 47,373 (32,635-74,710) in 1990 to 47,600 (36,572-55,194) in 2019. Notably, the annual percentage change (APC) in deaths decreased by 21% (56-15), and DALYs by 22% (57-15) from 1990-2019. Sub-Saharan Africa and the African Union exhibited the highest APC increase in deaths, while Southeast Asia, East Asia, and Oceania experienced the most significant decrease. The highest APC in incidence occurred in the 10-14 years age group at 27%, with a slight increase of 1% in deaths observed in the 10-19 years age group. Females bore a higher burden compared to males, with APC in prevalence at 29% versus 51%, and incidence at -4% versus 7%. Conclusions: Brain and CNS cancer accounted for 9.55% of deaths among individuals under 20 globally in 2019. While the overall global trend has shown an increase over the last three decades, females exhibit a higher burden. Despite a decrease in deaths over the same period, strategies must be implemented to combat this burden, emphasizing the importance of early investigation and management, particularly in resource-limited settings worldwide. [Table: see text]