bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ia trial to evaluate the safety and efficacy of HB0030, an anti-TIGIT antibody, in patients with advanced solid tumors: Preliminary results.
Authors: Zhou Huan , Li Wei , Xie Jing , Li Hongtao , Zhu Xiangyang , Yang Yongmin , Yang Yang , Zheng Yang , Wang Qiaofeng , Chen Juan , Li Chao , Xu Ruirui , Wang Jingjing , He Yiran 
Published: June 2023

e14673 Background: HB0030 is an IgG1 type humanized monoclonalanti-TIGIT antibody. Its heavy chain Fc fragment is wild-type that preserves function for inducting CDC and ADCC effects. Nonclinical data showed that HB0030 has a good affinity for TIGIT and anti-tumor activity. Methods: This is an ongoing single-center, open-label, dose escalation Phase Ia study to mainly evaluate HB0030 safety, antitumor activity and immunogenicity in patients (pts) with advanced solid tumor. HB0030 is administered by IV infusion every 21 days. An accelerated titration method combined the standard 3+3 design was utilized for dose escalation, which of contained 8 dose groups (0.1, 0.3, 1.0, 3.0, 10, 20, 30, 40mg/kg). The tumor assessment evaluated by investigator according to RECIST v1.1. Results: As of Jan 9, 2023, 20 pts (4Male/16Female) with advanced malignant solid tumor have been enrolled and dosed at 0.1mg/kg (n = 1), 0.3mg/kg (n = 3), 1mg/kg (n = 3), 3mg/kg (n = 4), 10mg/kg (n = 3) and 20mg/kg (n = 6). The median age was 56.9 years. All pts had stage IV disease and failed from the anti-tumor standard therapy with a median of 3 lines. The main tumor types included lung(n = 6), breast(n = 3), colorectal(n = 3) and cervical (n = 2) cancer. Total 16 pts have completed at least once tumor assessment. The ORR and DCR were 6.3% (1/16) and 62.5% (10/16), respectively. The best response was a PR with 47% tumor regression pt who was diagnosed non-small cell lung cancer (NSCLC) accompanied with TP53 gene mutation. The pt relapsed with multiple metastasis after radical operation and adjuvant chemotherapy, and failed to systemic chemotherapy combined targeting anti-vascular therapy. He achieved PR with 3 cycles of 20mg/kg HB0030 treatment, and PR status continued at present. A NSCLC pt maintained 24 weeks SD after 3mg/kg HB0030 administration. The most common treatment related adverse events (TRAEs) were lymphopenia (9/20, 45%) and shortened activated partial thromboplastin time (APTT) (6/20,30%). Grade 3 TRAEs occurred in 15% of pts (3/20) which included thrombocytopenia, anemia, syncope and hypertension. There were no Grade 4-5 AEs, serious adverse events (SAEs), dose-limiting toxicity (DLT) and death. The anti-drug antibodies (ADAs) were detected in 2 pts in 20 mg/kg dose group, and not caused by HB0030 therapy because it had existed in baseline. Conclusions: HB0030 showed very well safety in the stage of dose escalation from 0.1 to 20 mg/kg, and potential promising anti-tumor activity above 3mg/kg dose in advanced solid tumors pts, especially in NSCLC. Currently, 30mg/kg and 40mg/kg dose escalation are ongoing. Clinical trial information: NCT05706207 .
Adrenal insufficiency in patients on immune checkpoint inhibitors: An All of Us Data study.
Authors: Olusoji Rahman Adesoji , Eun Yong , Mohamed Salih Rajaa , Osei Noah , Ahluwalia Meena 
Published: June 2023

e14675 Background: Immune Checkpoint Inhibitors have revolutionized the management of cancers. Several cases are reported about their adverse effects, which include adrenal insufficiency, a life-threatening irreversible sequela in some patients. Little has been done to evaluate the burden of this adverse effect on cancer patients. This study aimed to measure the incidence rate of adrenal insufficiency in patients on immune checkpoint inhibitors in the United States using the All Of Us database. Methods: In this cross-sectional study, we included participants from the All of Us dataset version 6, which includes data collected between May 6, 2018, and January 1, 2022, who had available Electronic Health Records data (N = 258,188). We defined the cancer cohort as having at least one ICD-9/ICD-10 diagnostic code for cancer. We identified participants in the cancer cohort without or with at least one exposure to immune checkpoint inhibitors nivolumab, pembrolizumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, relatlimab, tremelimumab, pidilizumab. Adrenal insufficiency was defined as having one or more ICD-9/ICD-10 codes for any adrenal insufficiency after treatment with immune checkpoint inhibitors. The calculation for the Relative Risk(RR) was with unconditional maximum likelihood estimation. Results: Among 36,377 individuals diagnosed with cancer, 418 patients had exposure to immune checkpoint inhibitors. 44(10.5%) of the 418 were diagnosed with adrenal insufficiency after exposure to immune checkpoint inhibitors. The relative risk of adrenal insufficiency after the commencement of an immune checkpoint inhibitor is five times that of patients not on immune checkpoint inhibitors. (RR 5.43, 95% CI 4.07-7.25, P < 0.05). Conclusions: Our result suggests a higher incidence of adrenal insufficiency in cancer patients on immune checkpoint inhibitors compared to cancer patients, not on immune checkpoint inhibitors. Future prospective studies will be needed to confirm this finding. Physicians, particularly oncologists and endocrinologists, should have a high index of suspicion for adrenal insufficiency in patients on immune checkpoint inhibitors.
Hemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: A pharmacovigilance study from FDA Database.
Authors: Neupane Niraj , Shikhrakar Shreeja , Thapa Sangharsha , Shrestha Asis 
Published: June 2023

e14684 Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat multiple cancers uncovering varieties of immune-related adverse events (irAEs). ICI-related haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by exaggerated activation of macrophages and cytotoxic T cells resulting in fatal hematological toxicity and multi-organ damage. Methods: We conducted a retrospective analysis of reported cases of HLH in patients treated with checkpoint inhibitors using data from the FDA's Adverse Event Reporting System (FAERS) database from 2018 to 2022. Patients aged 18 or older were included, and cases were classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: Of 2,317 patients with HLH reported in the FAERS, 13.6% (315) of patients were reported to receive commonly used ICIs. With nivolumab being 44.93%%, pembrolizumab 35.87%, Ipilimumab 30.43%, and atezolizumab 15.94%. HLH among these ICI use was most commonly reported in males (65.2%) with a median age of 65. Melanoma was the most common cancer reported in this sample population. Out of the reported cases, 26% died, and 72% were males. Death was observed more in combination ICI therapy (40.73%) than in single-agent use (29.04%). Even though the most commonly reported HLH was with Nivolumab, mortality was highest with Atezolizumab use (29.55%). Conclusions: Nearly half of the patients with a diagnosis of HLH received commonly used ICIs, which points towards ICIs being one of the important risk factors for developing HLH. However, several confounders should be considered, like a cancer diagnosis, infection, and antibiotics. Further studies on ICI-induced HLH are necessary to establish its causal relationship.
Intravenous (IV) infusion of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, as monotherapy in advanced solid tumors: Preliminary results from an ongoing phase 1/2a study.
Authors: Niu Jiaxin , Barve Minal A. , Spira Alexander I. , Edenfield William Jeffery , Pang Weijia , Fu Wenmin , Lu Yingxin , McKean Meredith 
Published: June 2023

e14689 Background: Oncolytic virotherapy has emerged as a promising anticancer treatment. To date, almost all oncolytic viruses (OVs) are delivered via intratumoral (IT) injection, which limits its broad clinical application. Systemic delivery of OVs, a more practical option for patients (pts) without injectable lesions, allows both primary tumor and metastases treated simultaneously. However, due to concerns for immune clearance and the potential cytokine storms, very few studies thus far are conducted using OVs intravenously. T3011 is a genetically modified, next-generation oncolytic HSV-1 expressing IL-12 and PD-1 antibody. Extensive preclinical studies have demonstrated the feasibility, safety and efficacy of T3011 delivered intravenously. Here, we present preliminary results of IV T3011 as a single agent. Methods: In this phase 1/2a, multi-center, open label, dose escalation and expansion study, T3011 was administered intravenously on Days 1, 4, 8 of a 21-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of escalating doses of IV T3011, characterize dose limiting toxicities (DLTs) and identify the MTD and RP2D of IV T3011. Phase 1 portion used a 3+3 design in 4 escalating cohorts (1×106, 1×107, 1×108, 3×108 PFU). Pharmacokinetics, immunogenicities and pharmacodynamic profiles were studied in various samples. Results: As of Jan 2023, 10 pts received IV T3011 therapy: 4 in Cohort 1, 3 in Cohort 2, and 3 in Cohort 3. Median number of doses was 8. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (TRAEs) and no DLTs to date. Nausea and infusion-related reaction (including postdose delayed fever, chills, rigors, etc.) were the most common TRAEs. 7 of 10 pts had ≥ 1 tumor assessment, 4 achieved stable disease (SD) by RECIST 1.1 with a disease control rate of 57.1%, 2 had SD for ≥ 6 months. 1 pt had a postdose tumor biopsy revealing T cell activation via transcriptome profiling and gene ontology analysis. T3011 DNA was detected in blood in 9/10 pts at 0.5 hours after the 1st dose and its level was dose-dependent and increased with repeated doses. T3011 DNA clearance was observed at 4-7 days after dosing. Saliva and urine samples from all pts were tested for T3011 DNA, only one was positive with very low DNA copies in a saliva sample at 0.5 h after the 2nd dose from a pt in Cohort 1. Of note, pre-existing HSV-1 IgG had no impact on T3011 activity. Conclusions: IV T3011 monotherapy was well tolerated and safe at the first 3 dose levels, highly unlikely to be transmissible. Preliminary efficacy was encouraging. Our results also suggest T3011 IV treatment could stimulate anti-tumor immunity in the tumor microenvironment. Clinical trial information: NCT04780217 .
Integrated survival analysis.
Authors: Chiu Vi Kien , Lerolle-Chiu Adele 
Published: June 2023

e14695 Background: Clinical trial efficacy may be determined by the primary endpoint(s) of median progression free survival (mPFS) and/or median overall survival (mOS) from the Kaplan-Meier estimate, and secondary endpoints of overall response rate (ORR) and duration of response (DOR). In the treatment of metastatic cancers, single agent immunotherapy tends to have lower ORR and longer DOR in comparison to chemotherapy or targeted tyrosine kinase inhibitor therapy, which tends to have higher ORR and shorter DOR. This leads to intersecting or crossing Kaplan-Meier survival curves, which are harder to interpret. In immunotherapy trials, mPFS is a poor surrogate for mOS, and both may underrepresent the clinical benefit over time. Methods: We aimed to develop novel metrics that more effectively represent the Kaplan-Meier estimate. The graphical curve of the Kaplan-Meier estimate may be represented by the equation as a function of time. The integration of f ( x), which mathematically represents the area under the curve and clinically the cumulative or integrated survival benefit with time, is: ∫0t f( x) dx = F(t) − F(0). Kaplan-Meier curve equation with constants C and A may be approximated by: ∫0t C e-A x dx = C e-A t ]0 t = C( e-A t – 1). The average integrated clinical benefit with time is: 1/ t ∫0t f( x) dx = [ F( t) − F(0)]/ t. Results: The Phase 3 KeyNote-061 trial of metastatic gastric cancer treated with single agent Pembrolizumab immunotherapy versus Paclitaxel chemotherapy was use for integrated PFS and iOS calculation. The Kaplan-Meier curves intersected or crossed in KeyNote-061 trial. We show the established ORR, mPFS, mOS, DOR. Integrated PFS (iPFS) and iOS were calculated with greater increase in iOS and much less decrease in iPFS for Pembrolizumab than Paclitaxel treatment. Conclusions: Integrated survival is a novel analysis that integrate the Kaplan Meier estimates and better represent the entire median survival and drug DOR may be combined into a single useful metric for overall clinical benefit. [Table: see text]
Influence of CD47 on CD8+ T-cell and tumor prognosis based on pan-cancer analysis.
Authors: Liang Hongxin , Yao Lintong , Xie Daipeng , Qiu Hongrui , Lin Zenan , Li Hao , Leng Jinhang , Wang Huili , Jiao Xiuwei , Qiu Liyun , Zhou HaiYu 
Published: June 2023

e14699 Background: CD47 was an immune checkpoint, constituting the CD47/SIRPα axis, sending the 'Do not eat me' signal to macrophages, hereby promoting immune escape of tumor cells in the tumor immune microenvironment(TIME). The role of CD47 has been proved affected immunotherapy efficacy and patient outcomes. However, how it affects TIME, specifically on CD8+T-cell in pan-cancer, has not been fully illustrated. Therefore, we aimed to identify it, which could help us to gain insights into potential anti-cancer treatment. Methods: We used a lot of R package and computational tools to analysis of differential gene expression, prognosis, immunoinfiltration, pathway enrichment and Correlation. Single-cell sequencing and multiple immunofluorescence staining were uesd to verify our hypothesis. Data was based on 17,382 samples given by 948 healthy individuals from GTEx, 39 cancer types from TCGA, 79 databases and 2045746 cells from tumor patients and healthy donors in TISCH, and our real-world sample. Datasets were normalized for estimation of the TME components at both the single-cell and annotated cluster levels. Our study investigated the role of CD47 in prognosis and TIME, mainly from the view of adaptive immunity. Results: CD47 was expressed in nearly all cancer types, associated with worse prognosis in various cohorts in pan-cancer(p＜0.05) compared to the normal tissues. Then, we found CD47 was better correlated with tumor immune evasion through T-cell infiltration compared with T-cell rejection in multi-cancers. And we detected high CD47 expression with high CD8+T-cell infiltration had a worse prognosis. So we hypothesis high CD47 could linked with T-cell exhausted. Then, we investigated that genetic alterations and oncogenic characteristics of CD47 were concomitant with the CD8+T-cell exhausted by analysis of pathway and gene in mulit-cancer especially squamous-cell carcinomas. Finally, we proved CD47 synergy with CD8+T-cell exhausted genes in LUSC and ESCA by single-cell analysis and multiple immune fluorescence staining. Conclusions: CD47 is highly associated with CD8+T-cell exhausted and may induce cancer immune evasion leading to a worse prognosis. Thus, CD47 and T-cell exhausted correlated genes may serve as dual antigenic targets and provide insights into potential immunotherapy.
Efficacy and safety of penpulimab-containing regimens for advanced malignant solid tumors that have failed immunotherapy: A real-world study.
Authors: Zhou Juying , Xu Chao , Zhang Lu , Ma Chenying 
Published: June 2023

e14700 Background: Immuno-checkpoint inhibitors (ICI) have shown good anti-tumor efficacy and survival benefits in a variety of solid tumors, such lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC). ICI have rewritten the guidelines for multiple tumor types. However, there are still a large number of patients who are ineffective or initially effective after use ICI, and subsequently develop ICI resistance. For these patients, how we choose further treatment is currently uncertain clinically. Some studies suggest that even if the treatment of PD - (L) 1 is ineffective or progresses, it can still bring a certain degree of benefit to re-challenge with other target ICI. This study was to evaluate the efficacy and safety of the patients with advanced malignant solid tumors with the regimen of penpulimab. Methods: This is a non-interventive registration study. Eligible participants must be ≥ 18 years old and have proven malignant tumors that are ineffective, fail for immunotherapy and have no other standard treatment. Patients were treated with penpulimab alone or in combination with chemotherapy or anti-angiogenic agents until progression or unacceptable toxicity. The primary endpoint is objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: Form Sep 2021 to Feb 2023, 28 patients (median age 59.5 years, male 71.4%）were recruited, including 9 pts with NSCLC, 5 pts with HNSCC, 4 pts with Nasopharyngeal carcinoma (NPC), 3 pts with esophageal cancer and 7 with other tumor types. Among all, 1 achieved confirmed PR, 21 achieved SD, the ORR was 3.6% (1/28) and the DCR was 78.6% (22/28). The median treatment duration was 9 months. Among the 9 pts with NSCLC, the median treatment duration was 5.6 months and the DCR was 77.8%. Treatment-related adverse events (TRAEs) of grade 3 were observed in 5 (17.9%) of the 28 patients. The most common TRAEs were decreased lymphocyte count (50%, 14/28), anemia (50%, 14/28), hypoalbuminemia (39.3%, 11/28), hyponatremia (25%, 7/28) and hypercholesterolemia (25%, 7/28). Conclusions: Penpulimab-containing regimens for advanced malignant solid tumors that have failed ICI have shown significant efficacy and a favorable safety profile.
Immune-related hypophysitis: An analysis of a heterogeneous entity.
Authors: Nanah Abdel Rahman , Abdeljaleel Fatima , Ogbue Olisaemeka , Unlu Serhan , Sorathia Sharmeen , Daw Hamed 
Published: June 2023

e14704 Background: Immune-checkpoint inhibitors (ICIs) have led to revolutionary breakthroughs in the management of many malignancies. With the increasing use of ICIs, immune-related adverse events (irAE) have emerged and led to significant challenges and limitations. Immune-related hypophysitis, a potentially life-threatening irAE, has limited data on its diagnosis, clinical findings, and management. This was our incentive to characterize our single-institution experience with immune-related hypophysitis over the past 5 years. Methods: We retrospectively studied a cohort of adult patients who received ICIs at the Cleveland Clinic Foundation between 2017-2022. Our search was done by utilizing an outpatient oncology pharmacy database. Analyzed ICIs included atezolizumab, nivolumab, pembrolizumab, ipilimumab, avelumab, and durvalumab. The occurrence of immune-related hypophysitis was as determined by an endocrinologist or oncologist. Results: 6,615 patients received ICIs from 2017-2022, of which 27 patients were diagnosed with hypophysitis. Immune-related hypophysitis occurred with ICI monotherapy in 44.4% and combined therapy (ipilimumab and nivolumab) in 55.5%. The most commonly implicated agents were ipilimumab (74%), followed by nivolumab (59.3%), pembrolizumab (18.5%), and durvalumab (3.7%). In patients receiving ipilimumab-nivolumab, hypophysitis was detected after a median duration of 65 days (range: 29-163 days) from ICI initiation, compared to 58 days (38-112) with ipilimumab alone and 155 days (8-294) with pembrolizumab. Hypophysitis was grade 1 in 18.5%, grade 2 in 29.6%, grade 3 in 37%, and grade 4 in 14.8% of all patients. No hypophysitis-related deaths occurred. Signs and symptoms included constitutional symptoms (fever, anorexia, myalgia) in 88.89%, severe/intractable headaches in 40.7%, gastrointestinal complaints in 29.6%, dermatologic findings in 7.4%, visual symptoms in 7.4%, and syncope in 3.7% of all patients. Lab findings included abnormalities of TSH in 77.78%, ACTH in 70.60%, FSH and/or LH in 52.63%, and a positive ACTH stimulation test in 69.3%. Imaging findings were present in 62.5% of patients, and most commonly revealed pituitary gland enlargement, enhancement, or stalk thickening on brain/pituitary MRI. Treatment included glucocorticoid replacement in 92.6%, thyroid replacement in 40.7%, and testosterone in 7.4% of patients. All patients remained on glucocorticoid therapy indefinitely after hypophysitis was diagnosed. ICIs were momentarily held in 22.2% and discontinued in 51.86% of patients, while 25.9% of patients did not experience treatment interruptions. Conclusions: Immune-related hypophysitis is an uncommon irAE that presents with variable clinical and diagnostic findings. Nonetheless it is a cause of permanent glucocorticoid dependence. Healthcare professionals should be aware of this entity so treatment can be promptly started.
Safety and tolerability of HLX07 combined with chemotherapy in patients with advanced solid tumors.
Authors: Li Qun , Guo Ye , Xue Junli , Ge Xiaoxiao , Lin Fengjuan , Xue Liqiong , Zhao Wei , Tang Wenbo , Hu Chen , Ni Hongyan , Li Jing , Wang Qingyu , Zhu Jun , Li Jin 
Published: June 2023

e15001 Background: HLX07 is a novel humanized anti-EGFR monoclonal antibody. This study aimed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of HLX07 combined with different chemotherapy regimens (chemo-regimens) in patients with advanced solid tumors. Methods: This was a single-center, open-label, dose-escalation phase 1b/2 study. Three fixed-dose chemo-regimens were given together with HLX07: 1) gemcitabine 1000 mg/m2 (on Days 1 and 8) and cisplatin 75 mg/m2 (on Day 1) in 3-week cycles for 4–6 cycles; 2) paclitaxel 80 mg/m2 and carboplatin AUC = 2 (both on Days 1, 8, and 15) in 3-week cycles for 4–6 cycles; and 3) mFOLFOX6 (on Day 1) in 2-week cycles for 6–12 cycles. Patients with metastatic or recurrent advanced solid tumors suitable to be treated with the above chemo-regimens were given HLX07 IV at escalating doses (400, 600, or 800 mg, QW) combined with chemotherapies following BOIN design. The primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary endpoints included safety and preliminary efficacy. Results: As of August 28, 2022, 56 patients were enrolled; 21 received HLX07 with gemcitabine and cisplatin, 21 received HLX07 with paclitaxel and carboplatin (n = 3 for HLX07 400 and 600 mg, n = 15 for HLX07 800 mg for each chemo-regimen), and 14 received HLX07 with mFOLFOX6 (n = 3 for HLX07 400 and 600 mg, n = 8 for HLX07 800 mg). No DLT related to HLX07 was reported. The MTD was not reached. A summary of treatment-emergent adverse events (TEAEs) in each group is shown in Table 1. All patients experienced TEAEs. Grade ≥3 TEAEs were reported by 17 (81.0%), 20 (95.2%), and 12 (85.7%) patients in each chemo-regimen group, respectively. Only 1 (33.3%) patient in the HLX07 400 mg plus paclitaxel and carboplatin group experienced TEAE leading to death (upper gastrointestinal hemorrhage, possibly unrelated to study drugs). Conclusions: HLX07 was safe and well tolerated when combined with chemotherapy in patients with advance solid tumors. Clinical trial information: NCT03577704 . [Table: see text]