bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel method that leverages existing data to conduct comparative analyses of competing assets: Sugemalimab and agents targeting the PD-L1/PD-1 axis as an example.
Authors: Fojo Antonio Tito , Zhou Mengxi , LaRose Meredith , Bates Susan Elaine , Schwartz Lawrence Howard 
Published: June 2023

2609 Background: Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Numerous immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) axis have garnered regulatory approvals. A novel method of comparative analysis that discerns differences/similarities amongst such agents could reduce redundancy and hopefully enhance true competition. Methods: We’ve described an approach for assessing efficacy that assumes changes in tumor quantity result from two simultaneous processes – exponential decay of the treatment-sensitive fraction of tumor at rate d, and exponential growth of the resistant fraction at rate g. Using this method, the USFDA analyzed data from 9934 patients with NSCLC enrolled in registration trials treated with chemotherapy, targeted therapies, and immunotherapies concluding g is inversely associated with survival across treatment types and encouraging prospective studies to evaluate whether g derived from early tumor measurements might serve as an earlier clinical trial endpoint (Gong ASCO 2020). Using data provided by EQRx and CStone we analyzed the GEMSTONE-302 trial comparing chemotherapy +/- the PD-L1 inhibitor sugemalimab in first line NSCLC. Results: 88% of the data could be analyzed. Regression without growth was seen in 10-12% of both arms with indistinguishable d values. Evidence of tumor growth was estimable as a g value in 68-71% with statistically slower g values and longer tumor doubling times (TDT) seen with sugemalimab + chemotherapy [0.0012/day (0.0005-0.0022); TDT 578d] than placebo + chemotherapy [0.0025/day (0.0013-0.0035); TDT 277d] p<0.0001. A comparative analysis with FDA data from 1521 patients who received Combo ICI in front line, finds comparable/slightly slower g values for sugemalimab + chemotherapy using all or a fraction of the data. Conclusions: We used a method of analysis that estimates rates of tumor growth ( g) to analyze the efficacy of the PD-L1 antagonist, sugemalimab, in NSCLC. Because time is included in our equations the intervals of assessment are rendered inconsequential, making this method of analysis ideal for virtual comparisons. We confirmed the value of sugemalimab in the first-line setting by demonstrating its data track very closely with data aggregated from randomized trials reported by the USFDA in patients treated with Combo ICI in front line. Because g values can be estimated with fewer data it can be leveraged for early decisions. [Table: see text]
Incorporating long non-coding RNA (lncRNA) into genome-wide biomarker screening for prognostic gene signatures of immunotherapy outcomes.
Authors: Wang Xuefeng , Li Tingyi , Sukrithan Vineeth , Ratan Aakrosh , McCarter Martin , Carpten John D. , Colman Howard , Ikeguchi Alexandra , Puzanov Igor , Arnold Susanne M. , Churchman Michelle L. , Hwu Patrick , Dalton William S. , Weiner George J. , Tarhini Ahmad A. 
Published: June 2023

2617 Background: Emerging data have shown that long non-coding RNA (lncRNAs) have the potential to become biomarkers in cancers with potential roles in regulating cell proliferation, apoptosis, migration, invasion and maintenance of stemness during cancer development. In this research, we aimed for a genome-wide biomarker screening approach incorporating lncRNA in order to identify key molecules and pathways involved in ICI response and resistance. Methods: We utilized clinical and transcriptomic data collected under the Total Cancer Care Protocol (NCT03977402) and Avatar project within the Oncology Research Information Exchange Network (ORIEN). We analyzed RNA-seq data from a total of 875 ICI treated pts. A novel resampling-based technique with elastic net regression was utilized for genome-wide biomarker screening, in which Cox regression was used for survival outcomes and logistic regression for a 2-year-based dichotomized outcome. All search was done through 200 resampling steps, each consisting of randomly selecting 80% of pts and 80% of all gene signatures. Moreover, we searched the genes that are most complementary to the established immune cell scores (i.e., Ecotyper and xCell) by incorporating these scores into the regression adjustment. Finally, we applied the same approach to identify prognostic long non-coding RNA (lncRNA) signatures. All analyses were carried out on all ICI pts, as well as on subgroups stratified by cancer type. Results: Of 875 pts treated with ICI, 125 had melanoma, 143 had kidney cancer, 126 had non-small lung cancer, and 110 had head and neck cancer. The genome-wide selection method successfully identified a panel of top prognostic genes and pathways for all cancer types included. In melanoma, the top five prognostic genes were ZDHHC2, CBX4, MET, NTN4, and HLA-DQA1, with 80%, 78%, 77.5%, 77.5%, 76.5% resampling-based selection probability respectively; the top five lncRNAs were AC073655.3, AC116348.3, PITPNA-AS1, AC011447.3, and AL021978.1. When adjusting for the immune scores in the selection model, the top five prognostic protein-coding genes in melanoma were TENM3, POLR2J3, SCCPDH, MET and SIAH1, and the top five lncRNAs were AC007620.2, PITPNA-AS1, HCG11, SLC25A5-AS1, and LINC02258, respectively. Conclusions: Our analysis has successfully identified gene panels of mRNA and lncRNA molecules with potential roles related to ICI mechanisms of action. Ongoing analyses are further investigating the potential mechanisms and pathways linking these molecules and will be presented at the meeting. [Table: see text]
Tracking plasticity along with proliferation and immune evasion using FOXC1, MKI67 and PDL1 for prediction of therapeutic response and risk for hyperprogressive disease with PD1/PDL1 inhibitors in advanced/metastatic cancers: Pan-tumor validation in clinical trial and real-world cohorts.
Authors: Ray Partha S , Ray Tania , Taylor Clive R , Hussa Robert 
Published: June 2023

2627 Background: Accurate prediction of therapeutic response (TR) to treatment with immune checkpoint blockade (ICB) as well as any resultant durable clinical benefit in terms of improved progression-free survival (PFS) and overall survival (OS) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden (TMB). We hypothesized that a multi-marker predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1, respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD). Methods: Pre-treatment tumor RNA-Seq data obtained from training/validation clinical trial cohorts and real-world patients diagnosed with advanced/metastatic non-small cell lung cancer (NSCLC, n=82/28) and melanoma (n=154/121) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure <=2 months post-treatment initiation. Optimized biomarker cutoff values based on model area-under-curve were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets. Results: ORR prediction accuracy was confirmed in validation datasets with high accuracy: NSCLC AUC=0.96, OR=9.63 (0.98-94.54, 95%CI) p=0.03 and melanoma AUC=0.91, OR=3.85 (1.73-8.58, 95%CI), p=0.0005. Predicted Responders consistently displayed superior PFS and OS compared to predicted Non-Responders: NSCLC PFS HR=0.51 (0.32-0.82, 95%CI) p=0.007, OS HR=0.44 (0.27-0.73, 95%CI) p=0.003; melanoma PFS HR=0.45 (0.30-0.68, 95%CI) p=0.002, OS HR=0.43 (0.26-0.71, 95%CI) p=0.002. Patients at risk for HPD were identified with high accuracy: NSCLC AUC=0.96, OR=9.67 (2.95-31.73) p<0.0001; melanoma AUC=0.98, OR=44.36 (11.73-167.74, 95%CI) p<0.0001. Conclusions: Tracking multiple dimensions of cancer biology including plasticity (using FOXC1), as opposed to tracking immune evasion alone, proved to be a superior and accurate pan-cancer, tissue-agnostic predictor of TR to ICB therapy in advanced/metastatic tumors in terms of ORR, PFS, OS as well as HPD risk prediction. This approach merits further testing in prospective clinical trials.
Effect of personalized immunization with GNOS-PV02 of patients with hepatocellular carcinoma on TCR clonal expansion, tumor infiltration, and vaccine-specific reactivity.
Authors: Perales Renzo , Cooch Neil , Yarchoan Mark , Sardesai Niranjan Y. , Yan Jian 
Published: June 2023

2629 Background: Tumor-specific neoantigens can be identified from cancer biopsies and used to develop personalized therapeutic cancer vaccines (PTCV) to prime neoantigen-specific T cell responses. Here, we characterized the antitumor neoantigen-specific reactivity of tumor-infiltrating, high-frequency TCR clones in a patient treated with personalized therapeutic DNA cancer vaccine GNOS-PV02 in the ongoing GT-30 advanced hepatocellular carcinoma single-arm open-label multi-center phase Ib/IIa trial (NCT04251117). Methods: Paired blood and tumor biopsy samples from patient #8 enrolled in the GT-30 study were collected before and after treatment with GNOS-PV02 (1mg) + plasmid-encoded IL-12 (0.3mg) + Pembrolizumab (200mg). GNOS-PV02 and IL-12 were administered at Q3W for the first 4 doses, then, at Q9W. Pembrolizumab was administered Q3W. Neoantigen positivity was evaluated by IFNγ-ELISpot. TCRβ sequencing was performed on all 4 samples and single-cell TCR and transcriptome sequencing was performed from T cells isolated from the post-treatment blood sample. After vaccination, three newly identified TCRs in blood and tumor were inserted into a pMXs-IRES-GFP retroviral plasmid vector and used to generate engineered TCR T cells. Engineered T cells were tested against the neoantigens included in PTCV by flow cytometry. Results: The treatment resulted in a partial response with a decrease in tumor size of 44% by RECIST1.1. Five vaccine-encoded responding neoantigens were identified. Differential abundance frame network analysis revealed that 27 of 42 (64.28%) significantly expanded peripheral TCR clones were also found enriched in the tumors post-treatment. Importantly, we observed an increase in cumulative frequency (from 0.4 to 7.7%), and absolute numbers (from 3 to 14) of significantly expanded vaccine-specific TCR clones in the tumor. Increased TCR clonality confirmed a focused tumor repertoire response. Single-cell sequencing data analysis revealed that the 6 most expanded clones in blood were activated CD8+CD69+ T cells (81.82%). Three full TCR sequences from T cell clones newly present in the tumor post-vaccination were selected, synthesized and cloned. TCR-engineered patient-specific T cells showed a dose-dependent CD8+ and CD4+ T cell activation (CD69+) upon stimulation with a pool of epitopes covering all the neoantigens in the patient’s PTCV. Conclusions: PTCV treatment resulted in neoantigen-specific T cell responses, clonal expansion in the periphery and primary lesion, and tumor infiltration of T cells with an activated phenotype. TCR-engineered high-frequency T cells found in the tumor are reactive to PTCV-encoded neoantigens post-treatment. These results may account for the observed objective decrease in the primary tumor size.
Multisystem immune-related adverse events from dual agent immunotherapy use.
Authors: Li Yuchen , Pond Gregory Russell , McWhirter Elaine 
Published: June 2023

2635 Background: Immune-related adverse events (irAEs) are commonly seen in cancer patients who undergo immunotherapy treatment. Increasingly, there has been recognition that multiple different irAEs can occur during or/and after a single course of immunotherapy treatment, known as multisystem irAEs, though much remains unknown. The primary objective of this study was to assess for rate of multisystem irAEs in patients who received dual agent ipilimumab and nivolumab for cancer treatment. Methods: A retrospective cohort review was completed that included all cancer patients seen at Juravinski Cancer Centre who received at least one dose of ipilimumab and nivolumab from January 1, 2018 to May 31, 2022. Patient characteristics, cancer types, and number and types of irAEs were recorded. Multivariate logistic regressions were also completed comparing those who developed multisystem irAEs, single irAE, and no irAE. Results: A total of 123 patients were included in this study. Median age was 59 years old, with 69% male. 72 out of 123 patients (59%) had melanoma, 50/123 (41%) had renal cell carcinoma (RCC), and 1/123 (1%) had breast cancer. At least one irAE was seen in 72% of patients who were treated with ipilimumab and nivolumab, and most irAEs occurred during the combination phase (89% of first irAE, 59% of second irAE, 75% of third irAE, and 50% of fourth irAE). Multisystem irAEs were seen in 40% of the overall cohort. The most common irAE type was dermatitis (22%), followed by colitis (19%), hepatitis (17%), and thyroiditis (15%). 30 out of 89 patients (34%) who experienced irAE(s) required hospital admission for inpatient treatment of irAE(s). Patients who experienced multisystem irAEs had significantly higher rates of response to immunotherapy irAE (p < 0.001) and improved overall survival (OS) than those who experienced single or no irAE. Conclusions: From our single-centre cohort study, there appeared to be a higher than previously quoted number of patients who experienced irAEs after receiving ipilimumab and nivolumab, with majority of them developing multisystem irAEs. Many patients experienced debilitating associated symptoms and hospital admission relating to irAEs. It is important for both the counselling and consent of patients, and for patient education, to discuss the possibility of multiple irAEs prior to dual immunotherapy initiation.
Comparing the impact of steroid sparing immunosuppression vs. steroid monotherapy for immune-related adverse events in non–small cell lung cancer and melanoma.
Authors: Syed Sharjeel , Hines Jacobi , Baccile Rachel , Rouhani Sherin Juliet , Reid Pankti 
Published: June 2023

2637 Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.
A phase I/IIa study to assess the safety, tolerability, PK, and PD of T3011, a genetically modified oncolytic virus (OVs) administered intravenously (IV) in patients with advanced solid tumors.
Authors: Li Ziming , Zhang Jian , Zhang Shuang , Zheng Li , Zhang Zhiye , Wang Junbin , Hu Ying , Luo Su-xia , Pang Weijia , Fu Wenmin , Qin Yanmei , Lu Shun 
Published: June 2023

2640 Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human IL-12 and the Fab fragment of an anti-human PD-1 antibody. T3011 intratumoral injection (IT) was reported to be well tolerated in patients (pts). IV therapy of OVs is rare and provides an attractive option to many pts with advanced cancers that are not candidates for IT therapy. Methods: It is a phase I/IIa multi-center, open label, single ascending dose (SAD) /multiple ascending dose (MAD) study to evaluate T3011 IV therapy. The primary objective is to evaluate the safety and tolerability. Dose cohort and regimen are shown in Table. PK and PD profiles are tested in samples of blood, saliva, urine, and tumor tissue. Results: As of 16 Dec 2022, 15 pts with stage IV disease were enrolled, 9 pts had received at least 3 lines of prior therapy. The median follow-up time is 1.58 months. Treatment-emergent adverse event (TEAE) occurred in 15 (100%) pts and treatment-related adverse event (TRAE) occurred in 10 (66.7%) pts. G3 TEAE in 3 (20%) pts (hypertriglyceridemia, dyspnea, lymphopenia) and G3 TRAE in 1 (6.7%) pt (lymphopenia), no≥ G4 AE reported. Dyspnea, the only reported SAE (1, 6.7%), is drug-unrelated. TRAEs were lymphopenia (5, 33.3%), anemia (1, 6.7%), diarrhea (1, 6.7%), malaise (1, 6.7%), urticaria (1,6.7%), rash (1, 6.7%), constipation (1, 6.7%), flu like symptoms (1, 6.7%), headache (1, 6.7%) and abnormal laboratory test results (incidence were all 6.7%), most of them are mild and manageable. No AEs led to drug withdrawal. No DLT occurred; MTD was not reached. 11/15 pts achieved stable disease (SD) by RECIST v 1.1. DCR was 73.3%. 1 pt with colorectal cancer who experienced irinotecan-based chemotherapy, anti-VEGF and radiotherapy in Cohort 1 had a long-term SD for over 4 months. In SAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 0% (0/4), 66.7% (2/3) and 100% (2/2) pts in Cohort 1, 2, 3 and 4 respectively. The DNA copies in pts of Cohort 4 are significantly higher than those of Cohort 3 (Mean viral DNA copies/ul 49.6 vs. 5.7). In cohort 2 of MAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 66.7% (2/3) and 100% (3/3) pts at C1D1, C1D4 and C1D8 respectively. T3011 DNA was not detected in saliva or urine samples. Pre-existing HSV-1 IgG was shown to hardly affect T3011 activity. Conclusions: T3011 IV is safe and well tolerated, and unlikely to spread to close contacts. Preliminary efficacy is encouraging. T3011 DNA in blood is in a dose-dependent manner with additive effect from repeated doses supporting continued recruitment of pts to higher dose cohorts. Clinical trial information: NCT05598268 . [Table: see text]
The incidence of thyroid-related adverse events in solid tumors receiving immune checkpoint blockade with curative intent: A meta-analysis.
Authors: Zhou Susu , Horita Nobuyuki , Shao Theresa , Harrington Matthew , Fujiwara Yu 
Published: June 2023

2641 Background: Adjuvant/neoadjuvant treatments with immune checkpoint blockade (ICB) improve survival outcomes in patients with several types of cancer. However, immune-related adverse events (irAEs) which frequently involve the thyroid gland may lead to delays in curative treatments such as surgery and radiotherapy. Thus, it is essential to report the incidence of thyroid-related adverse events (AEs) associated with the addition of ICB to conventional therapy with curative intent through a meta-analysis of randomized controls trials (RCTs). Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for RCTs evaluating ICB-containing treatment of solid tumors with curative intent. We calculated the odds ratio (OR) of all-grade and grade 3-5 thyroid-related AEs including thyroiditis, hyperthyroidism, and hypothyroidism. We performed a meta-analysis using the random-effect model to compare the incidence of thyroid-related AEs in patients who received therapy with and without the addition of ICB. Subgroup analysis based on the type of ICB (anti-PD-1, anti-PD-L1, and anti-CTLA-4) was conducted. Results: 24 RCTs comprising 12,199 patients were analyzed. The addition of ICB was associated with higher incidence of all-grade thyroiditis (OR=3.53, 95%CI:1.88-6.64, p<0.0001), hyperthyroidism (OR=7.18, 95%CI:4.30-12.01, p<0.00001), and hypothyroidism (OR=5.39, 95%CI:3.68-7.90, p<0.00001). In subgroup analysis, PD-1 and PD-L1 inhibitors were particularly associated with higher incidence of hyperthyroidism and hypothyroidism. The incidence of grade 3-5 thyroid-related AEs in patients who received therapy with the addition of ICB was 0.13% (thyroiditis, N=4/3135), 0.20% (hyperthyroidism, N=12/5877), and 0.19% (hypothyroidism, N=12/6369). Conclusions: The addition of ICB to conventional therapy with curative intent was associated with an increased risk of all-grade thyroid-related AEs, but the incidence of grade 3-5 AEs was low. These results suggest ICB may be added safely as an adjunct to curative treatments such as surgery and radiotherapy. Clinicians should monitor patients’ thyroid function and maintain vigilance for symptoms and signs of thyroid disease. OR (95% CI) and number of studies (N) for thyroid-related AEs with subgroup analysis. [Table: see text]