bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot trial of personalized neoantigen pulsed autologous dendritic cell vaccine as adjuvant treatment in hepatocellular carcinoma.
Authors: Wu Qiuji , Li Qiu , Yang Li , Xu Heng 
Published: June 2023

e14658 Background: The primary means of treating hepatocellular carcinoma (HCC) is radical surgery. However, HCC has a high propensity to recur post-operatively, and no standard adjuvant therapies have been approved. Tumor neoantigens, which are epitopes derived from tumor-specific mutations, may be utilized in personalized vaccines to activate T cell responses. This trial aims to assess the safety and efficacy of personalized neoantigen pulsed autologous dendritic cell vaccine (Neo-DCVac-02) in patients with HCC. Methods: Eligible patients had histologically confirmed high-risk HCC after radical surgery. Upon obtaining the baseline biopsy specimens and PBMCs of appropriate quality for DNA and RNA sequencing, neoantigen prediction, screening, and synthesis were performed. Subsequently, autologous dendritic cells (DCs) were generated and pulsed with neoantigen peptides to produce Neo-DCVac-02.On day 0, patients were treated with cyclophosphamide at a dose of 250 mg/m2. The prepared Neo-DCVac-02 vaccine was administered subcutaneously on day 1, followed by GM-CSF administered daily for 5 days. The primary objectives of this study were to evaluate the feasibility and safety/tolerability. Secondary objectives included assessment of immune responses (via vaccine response: IFNγ ELISpot), recurrence-free survival (RFS), and overall survival (OS). Results: A total of 32 patients provided informed consent to initiate the process of personalized neoantigen discovery, of which 26 (81%) met the requirements for successful product selection for clinical manufacturing. And feasibility was shown with 13 patients receiving Neo-DCVac-02. Thirteen patients did not receive neoantigen vaccines (7 for progressive disease,6 for withdrawal of informed consent because of COVID-19). Treatment was well-tolerated with no grade 2+ treatment-related adverse events (TRAEs). The common grade 1TRAEs were neutropenia (8.3%), injection site reactions (75%), rash (16.7%), fatigue (8.3%), and headache (8.3%). The median follow-up to date is 19.30 (14.4-31.9) months, with median RFS and OS not yet reached and a 1-year RFS of 83%. Five of 13 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot for more than 50% of neoantigen peptides in Neo-DCVac-02, and persistent cellular responses were noted out to 1 year. Increases in activation/co-stimulatory of T cells seen after treatment with Neo-DCVac-02 revealed by Flow-cytometric analyses, suggest immune priming. Conclusions: These data demonstrate that Neo-DCVac-02 is safe, well tolerated, and able to generate durable antigen-specific lymphocyte immune responses. Early signs of clinical efficacy were observed in HCC patients. Clinical trial information: NCT04147078 .
An exploratory trial of a novel R-ISV-RO technique in the treatment of advanced solid tumors.
Authors: Li Rutian , Min Limei , Wang Xiaolu , Chen Anni , Chang Xiaofeng , Cen Lanqi , Chen Jun , Sun Wu , Yan Jing , Zhou Xia , Shen Jie , Liu Baorui 
Published: June 2023

e14666 Background: The immunotherapy of bone and soft tissue sarcomas remains a challenge. Our pre-clinical trial confirmed that the combination of Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and OX-40 agonist had prominent synergistic effects. Immunoradiotherapy, especially Stereotactic Body Radiotherapy (SBRT) could further activate specific immune response. We hypothesized that intratumoral injection of “RO” (R837+αOX40) combined with SBRT will realize tumor control and reduce adverse reactions. Meanwhile, the synergetic application of PD-1 mAb systematically will improve the effectiveness of immunotherapy. Methods: This is a single-arm, single-center, open-label, exploratory trial that explore intratumoral injection of an emulsion of “RO” in combination with SBRT as “in situ vaccination” for advanced solid tumor (Ethics number: 2021-133-02). The inclusion criteria included: 1) advanced solid tumors which progress after standard therapies, 2) presence of one or more injectable lesions. SBRT to injected lesions was at a dose of 5-8Gy per fraction at a total dose of 20-32Gy. Imiquimod (0.75mg/ml) and αOX40 (2.5mg/ml) were prepared as emulsion and intratumoral injected into the target lesion for 4 times. Patients were also systematically administrated with PD-1 mAb (serplulimab). The primary endpoint was objective response rate (ORR) of target lesions. The secondary endpoint mainly included disease control rate (DCR) of target lesions, progression free survival (PFS), overall survival (OS), and clinical benefit rate (CBR), etc. Results: From May 2021 to October 2022, 30 patients were eligible for this trial (60% were sarcomas). 46.7% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb respectively before. The ORR, DCR and CBR of target lesions were 29.2%, 91.7% and 41.7%, while these of systemic efficacy were 21.7%, 82.6% and 17.4%, respectively. In sarcomas, the ORR, DCR and CBR of target lesions were 25.0%, 93.8% and 50.0%, while these of systemic efficacy were 20.0%, 93.3% and 26.7%, respectively. Systemic median PFS were 3.67 months. The median event-free survival (EFS) of target lesions and median OS were not reached. Among the evaluable target lesions, 6-month EFS was 85.7% in sarcomas (6/7) and 76.9% in all patients (10/13). The most common TRAEs were leukopenia (50%), hypoproteinemia (30%) and anemia (20%), demonstrating that treatment is tolerable. Grade≥3 treatment-related adverse events (TRAE) occurred in 3 patients, including myocarditis (6.7%) and thyroiditis (3.3%). Conclusions: In situ vaccination with “RO” emulsion, along with SBRT was tolerable and induced anti-tumor immunity, which would also trigger systemic response when synergized with PD-1 mAb. This in situ vaccination has been proved to be a promising option for advanced solid tumors especially for sarcomas. Clinical trial information: ChiCTR2100053870 .
Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.
Authors: Kovalenko Iuliia , Ng Wern Lynn , Geng Yimin , Benkhadra Raed , Msaouel Pavlos , Alhalabi Omar 
Published: June 2023

e14667 Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. [Table: see text]
Relationship between ICOS and ICOS ligand RNA expression patterns with tumor type, tumor mutational burden, and clinically relevant immune checkpoints.
Authors: Nikanjam Mina , Kato Shumei , Nishizaki Daisuke , Barkauskas Donald A. , Pabla Sarabjot , Nesline Mary K. , Conroy Jeffrey M. , Naing Aung , Kurzrock Razelle 
Published: June 2023

e14669 Background: ICOS (inducible T-cell co-stimulator) has a unique ligand (ICOSL). Together they contribute to both antitumor responses/immune stimulation and potentiating immunosuppression. The interaction of ICOS and ICOSL can stimulate CD4 and CD8 ICOS-positive T-cell populations, but also can increase immunosuppressive regulator T-cells. ICOS agonists and antagonists are both under development as novel therapies. We aimed to quantify ICOS and ICOSL expression relationships with tumor type and other clinically relevant checkpoint inhibitors along with evaluating relationships between ICOS and ICOSL expression patterns. Methods: Data from 514 patients with advanced solid tumors at the University of California San Diego were used in the analysis. RNA expression levels of ICOS, ICOS ligand, PD-1, PD-L1, LAG-3, and CTLA-4 from tumor specimens were analyzed at OmniSeq. Tumor mutational burden (TMB) was also evaluated. Univariate analyses (Fischer’s exact tests) and multivariate analysis (logistic regression) were conducted in SAS v 9.4 to determine relationships between high (>=75 percentile RNA rank) and low (0-24 percentile RNA rank) ICOS and ICOSL expression with age, gender, cancer type, high LAG-3, high TMB, high CTLA4, high PD-1, and high PD-L1. The relationship between ICOS and ICOSL high or low expression were also assessed. Results: Seventy patients had high ICOS (14%) and 192 had high ICOSL (37%) while low ICOS was seen in 226 (44%) and low ICOSL was seen in 76 (15%). High ICOS RNA levels were independently associated with patients not having colorectal cancer (p=0.0009), tumors with high PD-1 expression (p=0.025), tumors with high PD-L1 expression (p<0.0001), and tumors with high CTLA-4 expression (p<0.0001). Low ICOS RNA levels were independently associated with patients whose tumors did not have high PD-1 (p=0.0006), tumors that did not have high PD-L1 (p=0.01), tumors that did not have high CTLA-4 expression (p<0.0001), and those with low ICOSL expression (p=0.0007). High ICOSL was independently associated with a diagnosis of colorectal cancer (p=0.0015), tumors that did not have high PD-L1 expression (p=0.003), and tumors with high CTLA4 (p=0.0001). Low ICOSL was independently associated with patients who did not have colorectal cancer (p=0.0001) and tumors with low ICOS expression (p=0.0032). Conclusions: ICOS and ICOSL RNA expression patterns can provide insight into the complicated ICOS/ICOSL immune checkpoint signaling pathway and help support rational immunotherapy combinations as part of a precision medicine approach. Both stimulators and inhibitors of the ICOS/ICOSL axis are being developed, and their proper application may require interrogation of the individual patient’s tumor/environment.
Factors associated with myocarditis in patients with cancer treated with immune checkpoint inhibitors.
Authors: Izadi Zara , Zhang Yan , Lou Youbei , Dreyfus Brian , Plautz Greg , Wolf Robert , Cooper Leslie 
Published: June 2023

e14674 Background: Myocarditis is an uncommon but serious adverse event (AE) of immune checkpoint inhibitor (ICI) therapy. We aimed to identify factors associated with ICI-related myocarditis in cancer patients using pooled data from multiple clinical trials. Methods: Data on 25,965 adults receiving at least one dose of an ICI (nivolumab [NIVO] or ipilimumab [IPI])-containing regimen were extracted from corporate safety and clinical trial databases. Patients missing documentation of AEs, indication, or trial ID were excluded. Myocarditis events were identified using MedDRA preferred terms. A nested case-control study design with controls who had no myocarditis selected at random from the risk sets and matched 1:5 on ICI regimen, duration of exposure to ICI regimen, and trial ID was used. Descriptive statistics were used to derive time to onset of myocarditis and to investigate patterns of myositis and rhabdomyolysis relative to myocarditis. A multivariable conditional logistic regression model was used to identify factors associated with myocarditis. Covariates included age, sex, race/ethnicity, medical history (cardiovascular disease, diabetes, sleep apnea), smoking, cancer type, medication use (within the prior 6 months), and co-occurrences of other AEs (pneumonitis, colitis, and hepatitis). Results: Myocarditis was documented in 122/24,106 (0.5%) patients meeting study eligibility criteria. A total of 732 patients (122 cases and 610 matched controls) from 46 trials were included in the analyses. Mean (SD) age was 63 (12) years; 65% of patients were male, 76% Caucasian, and 52% had a history of cardiovascular disease. NIVO + IPI was the most commonly used regimen (36%), followed by NIVO + relatlimab (25%) and NIVO + chemotherapy (14%). Median (Q1-Q3) time to onset of myocarditis was 38 (26-77) days from first dose of ICI. Myositis was reported in 18/122 (15%) cases and in 2/610 (0.3%) controls (p<0.001). Among the 18 cases, a majority (83%) developed myositis within 3 days before the onset of myocarditis. Rhabdomyolysis was reported in 4/122 (3%) cases, all within a month before myocarditis, and in none of the controls (p=0.001). In adjusted analyses, older age (odds ratio 1.38 per 10-year increase, 95% CI 1.12-1.70) and hepatitis (5.69, 2.24-14.44) were significantly associated with the development of myocarditis. Conclusions: In this large cohort of ICI-treated cancer patients, myocarditis had an early onset and was associated with older age and co-occurrences of hepatitis. Due to a low incidence among controls, rhabdomyolysis and myositis could not be included as covariates in adjusted analyses; however bivariate results showed strong associations between myocarditis and rhabdomyolysis or myositis. These findings suggest that co-occurrences of myositis, rhabdomyolysis, or hepatitis are associated with myocarditis and may originate from a more generalized ICI myopathy.
Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.
Authors: Li Lin , Zhang Ping , Gao Jiayi , Tang Min , Nie Xin , Ma Di , Zhao Zhe , Yuan Yue , Ding Li , Li Chao 
Published: June 2023

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .
Incidence of venous thromboembolism with immune checkpoint inhibitors in a community setting: A single-center retrospective study.
Authors: Kumar Madhan Srinivasan , Majmundar Vidit , Arun Kumar Sumukh , Ramasamy Chidambaram , Seetharaman Kala 
Published: June 2023

e14681 Background: Immune activation and inflammation caused by immune checkpoint inhibitors (ICIs) are critical pathobiological drivers for venous thromboembolism (VTE). There is a paucity of data about VTE risk in cancer patients receiving ICI. We aimed to describe the incidence of VTE in cancer patients receiving ICI in a community setting. Methods: We conducted a single center, retrospective cohort study at Saint Vincent Hospital. The study cohort was created using our center's pharmacy database of patients who received any of the five ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab) between Jan 2017 and Dec 2022. VTE events including deep venous thrombosis, splanchnic vein thrombosis, and pulmonary embolism, were identified by chart review. We used a self-controlled risk-interval design, with "control period" and "at-risk period" being 6 months before and after the initiation of ICI treatment respectively. VTE events were also analyzed for subgroups: Single-agent ICI therapy (IA), Dual ICI therapy (IB), and ICI + chemotherapy (IC). Descriptive statistics and cox regression were used for statistical analysis. Results: Study population included 170 patients, with 75, 14, and 81 patients in subgroups IA, IB, and IC respectively. The mean age of the patients was 69.51 ± 10.05 years with a majority being males (62.4%). The most common cancer observed was non-small cell lung cancer (43.5%) followed by small cell lung cancer (6.9%), and malignant melanoma (5.7%). Pembrolizumab (55.3%) was the most common ICI used and nivolumab + ipilimumab (7.64%) was the most common dual ICI used. We noted a 1.25-fold higher incidence of VTE post-ICI use (Incidence rate ratio [IRR]: 11.76 per 100 person-year) compared to pre-ICI use (IRR: 9.41 per 100 person-year) at 6 months. On subgroup analysis, Group IB had the highest risk for VTE at 6 months (IRR: 28.57 per 100 person-year), followed by group IC and IA (IRR: 14.12 and 8.0 per 100 person-year respectively). IRR decreased to 6.62 per 100 person-year at 12-month interval indicating increased VTE risk in the first 6 months of ICI exposure. Type of ICI, adjuvant chemotherapy or type of cancer was not able to predict VTE risk on multivariate analysis. Conclusions: ICI treatment was associated with an increased incidence of VTE in our study cohort with the highest risk among patients on dual ICI followed by ICI + chemotherapy and ICI monotherapy. Future prospective studies are needed to identify risk factors and biomarkers to improve risk stratification and risk-adapted thromboprophylaxis.[Table: see text]
Efficacy of checkpoint inhibitors in hospitalized patients with cancer.
Authors: Medik Yusra B. , Singh Vinit , Alsabaawy Marina , Gerbino Gabriella , Khalid Farhan , Kata Priyaranjan , Divanna Mariela , Yosry Nashwa , Meghal Trishala , Nookala Vinod 
Published: June 2023

e14687 Background: Pembrolizumab is approved by FDA in 2014 to treat metastatic melanoma. Use of immune check point inhibitors (ICI) has been expanding in multiple cancer types including non-small cell lung cancer since then. In this mini case series, we will evaluate the benefits and risks of immunotherapy in hospitalized patients. Use of immunotherapy agents in inpatient unit has been associated with poor clinical outcome and higher cost. Byrne et. al have recently shown that more than 45% of hospitalized patients receiving PD1 or PD-L1 antibodies have either died or discharged to hospice care. A large retrospective chart review in Dana Farber Cancer Institute reveals 86% mortality rate in hospitalized immunotherapy recipients within the study period. Understanding the safety and advantages of using immune checkpoint inhibitors in inpatient unit has a pivotal role in decreasing the healthcare associated costs and setting the appropriate goals of care with patients and families. Methods: This is a retrospective observational cohort study conducted by review of electronic health records in last 5 years (from January 1st 2017- January 1st 2022) in Rutgers Health Community Medical Center and Monmouth Medical Center. Adult patients admitted to inpatient unit who received Pembrolizumab, Atezolizumab, or Nivolumab were included. Results: A total of 61 patients has received ICI therapy while in hospital with 57% males and 42% female. All patients had solid tumors, with most common malignancy being lung cancer (55%) followed by colon cancer (14%). Most common ICI given was pembrolizumab (62%) followed by atezolizumab (18%) and Nivolumab (16%). 26% of patients that were treated died in the hospital, 35% were transferred to another care facility and 29% were discharged home. No immune-related adverse events were reported. Age groups, cancer types were comparable with regard to discharge status. Conclusions: Poor mortality and survival outcome from this case series should prompt clinicians to consider benefit and risks of ICI therapy when prescribed to patients who were hospitalized for non-oncological acute conditions.