bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of murine PVSRIPO plus anti-PD-1 immune checkpoint inhibitor (ICI) in a melanoma tumor model.
Authors: Neighbours Lauren , McKay Zachary P , Gromeier Matthias , Nichols Garrett , Kelly Andrea True , Corum Daniel , Brown Michael 
Published: June 2021

2560 Background: Most patients with advanced melanoma (mel) fail/acquire resistance to ICI, including anti-(α) PD-1. PVSRIPO is a novel intratumoral immunotherapy derived from the Sabin type 1 attenuated poliovirus (PV) that targets CD155, widely expressed on solid tumors and antigen-presenting cells (APCs) of the tumor microenvironment. Therapy leads to direct tumor cell death and type I/III interferon-dominant innate inflammation, mediating priming and recruitment of tumor antigen-specific T cells. Inflammation-mediated upregulation of the PD-1/L1 IC suggests greater anti-tumor response could be achieved with PVSRIPO + αPD-1. The aim of this preclinical study was to evaluate the efficacy and safety of murine PVSRIPO (mRIPO) + αPD-1 in an aggressive mel tumor model (B16-F10.9-OVA in human-CD155 transgenic mice [C56BI/6]). Methods: Mice were randomized to 4 groups (G) of 12: (G1 [control]: vehicle [v] + IgG; G2: v + αPD-1; G3: mRIPO + IgG; G4: mRIPO + αPD-1). Tumor cells (5 x 105) were implanted into the right (R) and left (L) flanks. When tumor volume (vol) was ̃25 mm3, 15 µL v or 1 x 107 TCID50 mRIPO was injected into R (Day 1) and L (Day 4) tumors; αPD-1 or IgG (250 µg, 100 µL ip) was given on Days 1 and 4 and q 3 days until termination (Day 13). Weight, hematology, chemistry, and inflammatory cytokines were assessed pre/post-tumor implantation. Tumor vol was assessed every other day, with gross/histologic exam at termination. Results: 47 mice without health issues were euthanized as planned; 1 G1 animal required early euthanasia for tumor ulceration. Microscopic findings: increased mononuclear cell tumor infiltrates (G2 and G4); less severe L tumor growth necrosis in G2, G3, and G4 vs G1. There were no specific treatment-related changes in serum cytokines in G4. See the table below for summary of total tumor vol changes vs control; the most significant reduction was observed in G4. No tumor cells were observed via histopathology at Day 13 in R flanks of 1 mouse in G2; 3 in G3; and 8 in G4; and only G3 (n=1) and G4 (n=5) mice had no evidence of L flank tumor cells, with regression evident before L tumor mRIPO injection (ie, abscopal response). Conclusions: mRIPO + αPD-1 had the greatest overall anti-tumor response, and the combination was well tolerated. These results suggest combination therapy is not associated with untoward immune-mediated toxicity and highlight the potential for enhanced efficacy in injected and uninjected tumors. A phase 2 clinical trial of PVSRIPO ± αPD-1 in unresectable αPD-1 refractory mel is enrolling (LUMINOS-102, NCT04577807).[Table: see text]
Mega- and meta-analyses of fecal metagenomic studies in predicting response to immune checkpoint inhibitors.
Authors: Heirali Alya , Chen Bo , Wong Matthew , Schneeberger Pierre H.H. , Rey Victor , Spreafico Anna , Xu Wei , Coburn Bryan 
Published: June 2021

2570 Background: A number of studies have demonstrated that the gut microbiome of responders to immune checkpoint inhibitors (ICI) is compositionally different compared to that of non-responders. However, differences in study design, patient cohorts and bioinformatic analyses make it challenging to identify bacterial species consistently associated with response to ICI across different cohorts and cancer types. Methods: We leveraged the statistical power of mega- and meta-analyses to identify bacterial species consistently associated with response to ICI using data from three published fecal metagenomic studies (Gopalakrishnan et al., Science 2018; Matson et al., Science 2018; Routy et al., Science 2018). Metagenomic data was uniformly processed and analyzed using Metaphlan v2.0. We conducted a two-part modelling approach of bacterial species present in at least 20% of samples to account for both prevalence and relative abundance differences between responders/non-responders. Results: A total of 190 patients (n = 103 responders; n = 87 non-responders) were included from the three studies. Data from Routy et al., was analyzed as subsets based on tumor type for a total of 4 analyzed cohorts. We identified five species including Bacteroides thetaiotaomicron, Clostridium bolteae, Holdemania filiformis, Clostridiaceae bacterium JC118 and Escherichia coli that were concordantly significantly different between responders and non-responders using both meta- and mega-analyses. B. thetaiotaomicron and Clostridium bolteae relative abundance (RA) were independently predictive of non-response to immunotherapy when data sets were combined and analyzed using mega-analyses (AUC 0.59 95% CI 0.51-0.68 and AUC 0.61 95% CI 0.52-0.69, respectively). Conclusions: Despite inter-cohort heterogeneity in tumor type, treatment regimens, and sequencing modalities, meta- and mega analysis of published metagenomic studies identified generalizable bacterial species associated with ICI response or lack thereof. B. thetaiotaomicron and C. bolteae were predictors of non-response to ICI suggesting the clinical potential of narrow spectrum anti-biotics targeting non-response associated bacterial species to improve outcomes in ICI recipients.
A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb) in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Ganju Vinod , Cooper Adam , Gao Bo , Wilkinson Kate 
Published: June 2021

2577 Background: YH001 is a humanized anti -hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard “3+3” design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2020 data cut-off, 10 pts were enrolled and treated at 0.05 mg/kg (n = 2), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3) and 1 mg/kg (n = 2). The median age was 62 years (range 46-74). Baseline ECOG scores were 0 (n = 8), 1(n = 2) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-4) including 1 pt progressed after immunotherapy of pembrolizumab. There were no dose limiting toxicities (DLT) observed. No severe adverse events (SAEs), Grade (G) 3 or above adverse events (AEs) and AEs leading to treatment discontinuation were reported. Twelve drug related AEs were all G1/2 events including 2 G2 AEs (1 rash maculopapular at 0.05mg/kg, 1 hypothyroidism at 0.1mg/kg), 10 G1 AEs (1 hypotension, 1 dry skin, 1 pruritus at 0.05mg/kg; 1 rash, 1 rash macular, 1 hyperthyroidism, 2 rash pruritus at 0.1mg/kg, 2 fatigues at 0.3mg/kg). Among 7 patients having imaging tumor assessment by RECIST v1.1, there were 4 SD, including 1 at 0.05 mg/kg with tongue carcinoma at week 8 assessment, 1 at 0.1 mg/kg with nasopharyngeal carcinoma at week 8 and 15 assessment, 2 at 0.3 mg/kg with gastroesophageal junction cancer and uterus leiomyosarcoma at week 8. Conclusions: YH001 combined with Toripalimab is safe and tolerable up to 1 mg/kg dose level. Updated safety and preliminary efficacy data will be presented. Clinical trial information: NCT04481009.
Relationship between DICER1 mutations and immunotherapy biomarkers in solid tumors.
Authors: Gao Jie , You Xia , Guo Taiyan , Zhang Qin , Duan Qianqian , Qi Chuang 
Published: June 2021

2603 Background: Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. DICER1 is the core caner-intrinsic CTL-evasion gene, especially positive correlate with innate anti-PD-1 resistance signature or IPRES signature and hERV expression which involved in sensitivity and resistance to ICIs. Nevertheless, the association between mutations in DICER1 and the Chinese patients, the relationship between DICER1 mutations with immunotherapy biomarkers are unknown. Methods: NGS and clinical data were collected from 10953 Western pan-cancer patients (TCGA cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 3514 Chinese pan-cancer patients (Chinese cohort). Both DICER1 mutation ratio and TMB were calculated on the two cohorts following the same criteria.DNA NGS testing (MSI-high vs low/stable (MSS)) in Chinese cohort were included. NGS data of 3514 patients who also detected PD-L1 expression from Chinese clinical dataset were analyzed to explore the association with mutation and PD-L1. The survival information was collected from 1661 pan-cancer patients to analyze the association between DICER1 mutation and efficacy of immunotherapy (MSKCC cohort). Results: In total, 2.91% (319/10953) patients in TCGA harbored DICER1 mutation; in the Chinese cohort, the DICER1 mutation ratio (2.67%, 94/3514) was similar to TCGA. The top 5 mutant DICER1-associated cancer types in Chinese cohort were lung cancer, colon adenocarcinoma, liver cancer, uterine corpus endometrial carcinoma, melanoma. In both cohorts, TMB level of mutation group was significantly higher than wild-type group (p < 0.001). The ration of mutation group in MSI-H (50%) and MSI-L (23.53%) was significantly higher than wild-type group in Chinese cohort (2.17%) (p < 0.001). In addition, the ratio of PD-L1 positive expression (≥1%) in mutation group (48.94%, 46/48) was significantly higher than wild-type in Chinese cohort (38.48%,1316/2104) (p < 0.05). The survival probability of mutation group was significantly longer than wild-type group in immunotherapy. Conclusions: The results indicated that DICER1 mutation was associated with a higher TMB, MSI-H and PD-L1 expression level in Chinese patients. Patients with DICER1 mutations may benefit more from ICIs.
Awareness and utilization of tumor mutation burden (TMB) as a biomarker for administration of immuno-oncology (I-O) therapeutics by practicing community oncologists in the United States (U.S.).
Authors: Savill Kristin M. Zimmerman , Zettler Marjorie E. , Feinberg Bruce A. , Jeune-Smith Yolaine , Gajra Ajeet 
Published: June 2021

2608 Background: TMB, a measurement of the number of mutations carried by tumor cells, is emerging as a biomarker for the identification of patients who may benefit from certain I-O-based therapies. TMB-high (TMB-H) tumors, defined by the detection of ≥10 mutations/megabase (mut/Mb) in tumor cells using a tissue-based assay such as the FoundationOneCDx (F1CDx) assay (Foundation Medicine, Inc.), may be more likely to respond to some I-O therapies. Higher neoantigen loads of TMB-H tumors have been proposed to contribute to increased responsiveness of TMB-H tumors to certain I-O therapeutics. Pembrolizumab was approved by the FDA on June 16, 2020 for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H tumors, as determined by F1CDx, based on results from the KEYNOTE-158 trial (NCT02628067), which demonstrated that 50% of patients with TMB-H tumors had response durations of ≥24 months, with objective response rates in TMB-H vs. non-TMB-H patients of 29% and 6%, respectively (Marabelle et al, The Lancet Oncology, 2020). This survey-based study aimed to evaluate awareness and utilization of TMB as a biomarker for I-O therapeutics among practicing community oncologists in the U.S. Methods: Questions related to awareness and utilization of TMB as a biomarker for I-O therapeutics were developed by two medical oncologists (AG and BF) and presented to community oncologists in a web-based survey prior to virtual meetings held between October and November 2020. Descriptive statistics were used to analyze the results. Results: Of the 193 participating providers geographically distributed across the U.S., 15% reported being unaware of either the concept of TMB in I-O therapy or how to use the information clinically. 39% of these providers reported testing ≤25% of patients with advanced cancer for TMB, including 8% who do not test for TMB at all. Misconceptions regarding TMB identified among participating providers included the belief that high TMB is considered to be > 5 mut/Mb among 20% of providers, that TMB is essentially the same as MSI-high among 8% of providers, and that there are no therapies with FDA approval based on TMB among 15% of providers. Further, 37% of the participants did not identify pembrolizumab as an agent approved for the treatment of solid tumors based on TMB-H status. Conclusions: These findings demonstrate that there is a knowledge gap regarding the definition of TMB, testing for TMB, as well as implementation of TMB status in clinical decision making. Education directed towards community oncology providers regarding TMB and its use as a predictive biomarker for I-O therapy may improve its utilization and adoption in solid tumors to improve patient outcomes.
Comprehensive genomic and transcriptomic profiling (CGTP) to predict pembrolizumab (P) benefit in patients (pts) with advanced solid tumors (STs).
Authors: Rhodes Dan , Hovelson Daniel H , Safa Malek M. , Burkard Mark E. , Yang Eddy Shih-Hsin , Edenfield William Jeffery , Reeder Travis , Vakil Hana , Kwiatkowski Kat , Mitchell Khalis , Johnson Bryan , Tomlins Scott A. 
Published: June 2021

2609 Background: P is approved in many ST types, however predictive biomarkers and the proportion of pts who benefit vary widely. Biomarkers beyond PD-L1 immunohistochemistry and comprehensive genomic profiling (CGP) based tumor mutation burden (TMB) may improve benefit prediction. We determined if treatment data and CGTP collected in an ongoing observational trial (NCT03061305) could predict pan-ST P benefit. Methods: Eligible advanced ST pts had QC-passing TMB and expression data from multiplex PCR based tissue CGTP on FFPE tissue (StrataNGS and an investigational test) and documented P treatment > 1 month. Real-world time to next treatment (TTNT) was defined as time in months from therapy start to new therapy start (after stopping initial therapy) or death. TMB and gene expression biomarker association with P TTNT was evaluated. Backward stepwise regression was performed to fit a multivariate Cox proportional hazards model; pts were assigned to four score groups (IRS 1-4) based on overlapping TTNT curves from 8 equal bins. P TTNT were compared between IRS groups by log-rank test. A chemotherapy (C) comparator cohort was established from C TTNT for pts in this cohort. Results were stratified by ST type, P mono vs. C combo, and TMB status. Results: 610 pts (254 [41.6%] NSCLC; 356 [58.4%] from 23 other ST types) with CGTP and P treatment were identified; P TTNT was highly correlated to overall survival (n=146; Pearsons r2=0.75). By univariate analysis of TMB and 9 expression biomarkers, TMB, two independent PD-L1 expression amplicons, and PD-L2 expression were significantly associated with P TTNT (all p ≤ 0.002). The most significant multivariate model included 5 variables, with 1) increasing TMB, PD-L1, and PD-L2, and 2) decreasing TOP2A (proliferation) and GZMA as P TTNT predictors. Median P TTNT, but not C TTNT (345 courses from 254 pts), differed significantly by IRS group (Table). Median P TTNT by IRS group did not significantly differ by non-small cell lung vs. other ST type or P mono vs. C combo (both p > 0.05); excluding TMB-high patients, median P TTNT was still significantly longer in IRS groups 3/4 vs. 1/2 (p = 5.0e-4). Across 19,623 total evaluable pts in NCT03061305, 12.2% were in IRS groups 3/4 and outside of P approved ST types/TMB-low. Conclusions: CGTP in an observational trial cohort demonstrated that TMB, PD-L1 and PD-L2 independently predicted pan-ST P benefit as assessed by OS-validated TTNT. A multivariate CGTP signature predicted P benefit relative to C across ST types. If further validated, such a signature may enable improved P benefit prediction. P versus C TTNT by IRS group. Clinical trial information: NCT03061305. [Table: see text]
Adverse effects of COVID-19 vaccination among cancer patients: Results from an Internet-based survey.
Authors: Loew Brian , Tsai Richard , Hervey John , Hoffman Kathleen D. , Novack John , Johnson Jennifer , Dizon Don S. , Goldberg Stuart L. 
Published: June 2021

2621 Background: The rapid development of safe and effective vaccines against SARS-CoV-2 may stem the global COVID-19 pandemic. However, since individuals with cancer were under-represented during clinical vaccine trials, experience with COVID-19 vaccines among cancer patients is limited. Methods: An internet-based survey was conducted January 15 - February 10, 2021 among members of the Inspire online health community. The 63-item survey was emailed to members of the Inspire community who had opted-in for research. Results: Out of 19,152 respondents, 4895 (25%) self-reported a cancer diagnosis. Of these, 1337 (27%) were receiving active therapy. Cancer respondents were 66% female, 77% white, 44% college educated, with a median age range 55-65 years. 88% had solid tumors and 12% hematologic malignancies. 241 (5%) had prior COVID-19 and 148 (3%) thought they had had it but were not tested. Among cancer patients with COVID-19 approximately 30% reported ongoing late symptoms. At the time of survey, 1335 (27%) cancer patients had received a COVID-19 vaccine (Moderna 51% Pfizer-BioNTech 46%, Astra-Zeneca 3%, Other/unknown >1%). Following the first injection, 63% had local adverse events (AEs): injection site pain (51%), swelling (8%), redness (6%), and itching (4%). 34% reported systemic AEs including myalgia (32%), fatigue (18%), headache (12%), joint pain (5%), and chills (5%). 199 (15%) had received the second (booster) vaccination. 76% reported local AEs including pain (69%), swelling (14%), itching (8%), and redness (7%). 67% reported systemic AEs including fatigue (49%), myalgia (30%), headache (29%), chills (23%), fever (16%), joint pain (15%), and nausea (12%). AEs were comparable to the clinical trial results obtained from the general population (fda.gov/media/144245/download & 144434/download). Conclusions: In this internet-based survey drawn from the Inspire online health community 1335 cancer patients reported receiving COVID-19 vaccinations. By self-report the vaccines were well tolerated with AEs patterns mimicking clinical trial results conducted in the general population. These safety results should be reassuring to cancer patients although attention to COVID-19 vaccine efficacy is required (and will be studied during follow-up surveys).[Table: see text]
Risk factors for immune mediated adverse events with immune checkpoint inhibitors.
Authors: Pelcovits Ari , Mistry Hetal , Chudasama Rani , Andrea Sarah , Khurshid Humera 
Published: June 2021

2622 Background: Immune checkpoint inhibitors (ICIs) are associated with unique toxicity - immune-related adverse events (irAEs). irAEs are common, occurring in nearly 30 % of patients (pts) in clinical trials. Risk factors for irAEs remain largely unknown, with limited evidence to guide risk stratification for these pts. Methods: In this historical cohort study, we identified 400 pts receiving ICIs at our institution between 1/1/2015 - 12/31/2019 and followed them until progression, death, or study end date. Using modified Poisson and multinomial logistic regression we assessed irAEs (yes/no; none/grade 1-2/grade 3-4) as a function of independent risk factors in separate models. These included age, PDL-1%, steroid use in the 2 weeks (S2wks) prior to ICI, concurrent chemotherapy, combination ICI use, and pre-ICI creatinine (Cr) and absolute lymphocyte count. We constructed sample weights using sociodemographic and clinical factors to account for confounding by indication and mortality-related censoring. Results: 367 pts (median age: 68 yrs) had complete data for analysis comprising 55% men and 89% white. 111 (31%) experienced an irAE during the study period (median time to first event: 81 days). Risk was greatest for the youngest and oldest pts on ICI. In weighted models, Pts ≤59 yrs were 3 times as likely to experience an irAE relative to those aged 60-68 (95% CI: 1.18,7.41; Table). Additionally, for each 1 unit increase in Cr, risk of irAE increased by 19% (95% CI: 1.08,1.28). Precision of weighted estimates was impacted by limited pt comparability across factors of interest and overall sample size. While not statistically significant (RR: 2.04;95% CI:0.92,4.53) 70.6% of pts on combination ICIs experienced an irAE compared with 20.3% on one ICI. Similarly, while not statistically significant, 15.4% of pts with PDL-1 >49% experienced a grade 3/4 irAE compared with 7.7% of pts with PDL-1<1%. Conclusions: In this real-world analysis of irAEs, younger age and elevated creatinine were risk factors for development of irAEs. Further research leveraging larger data sources is needed to examine PDL-1% as a potential risk factor of irAE.[Table: see text]