bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive associations of active immune therapy OBI-833/OBI-821 induced immune responses with clinical outcomes in patients with non-small cell lung cancer.
Authors: Ou Chien-Chih , Tsao Chun-Yen , Yu Chung-Yun , Yang Cheuh-hao , Tang Wei-Chien , Yang Ming-Chen , Ho Ching-Liang , Lai Ming-Tain
Published: June 2024

e14671

Background: OBI-833/OBI-821 (OBI-833) is a novel active immune therapy (cancer vaccine) targeting a tumor-associated carbohydrate antigen, Globo H. Previous reports have shown that OBI-833 can elicit a beneficial immune response in Non-Small Cell Lung Cancer (NSCLC) patients and rendered durable stable disease with some TKI-treated patients. In this study, we further evaluated the effect of OBI-833-induced immune responses on the in-study progression-free survivals (isPFS) during the treatment. Methods: Sera were collected for the evaluations of maximum concentration (Cmax) and exposure (area under the curve: AUC) of anti-Globo H IgM (GH IgM) and IgG (GH IgG), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and ex-vivo GH IgM induction with PBMC from each subject at baseline. The correlations of OBI-833-induced immune responses with isPFS and best overall response (BOR) were also evaluated. Pearson correlation coefficient analysis was used for all correlation evaluations. Results: Among the 14 OBI-833-treated subjects, 93% and 64% of subjects had significant increase in GH IgM and GH IgG, respectively. Median Cmax GH IgM and Cmax GH IgG were 13.8 µg/mL and 12.4 µg/mL, respectively. While the increase in CDC activities was not significantly correlated with the increase of GH IgM, a weak association between GH IgG and ADCC was observed (r=0.3380, p<0.0001). In addition, a strong association (r=0.84) was observed between Ex-vivo IFN-γ secreting and their Cmax IgM concentration in the OBI-833 Ex-vivo stimulation study. In contrast, weak association (r=0.26) was observed between Ex-vivo GH IgM induction and their Cmax of IgM. Correlations of the immune responses on isPFS were further analyzed. Significant positive correlations were observed for the Cmax and AUC of GH IgM with isPFS (Cmax: r=0.6345, p=0.0148; AUC: r=0.8212, p=0.0003) and the Cmax and AUC of GH IgG with isPFS (Cmax: r=0.7192, p=0.0037; AUC: r=0.6306, p=0.0062). Furthermore, distinct features of GH IgG responses from 2 subjects were identified based on the ADCC-GH IgG scatter plot. Samples from subject 034-006 showed high ADCC activity with relatively low GH IgG concentration, whereas the BOR was at -27%, which has significant negative correlation of tumor response (TR) with GH IgG (r=-0.7381, p=0.0148) and ADCC (r=-0.8565, p=0.0016). In contrast, samples from subject 034-004 showed average ADCC activity and relatively high GH IgG concentration with BOR at -12%, showing a negative correlation of TR with GH IgG (r=-0.8352, p=0.0001) and ADCC (r=-0.5690, p=0.0269). Conclusions: OBI-833 can elicit beneficial immune responses in NSCLC patients. Both GH IgM and GH IgG may contribute to the isPFS and TR of the subjects. Further development of OBI-833 in EGFR-mutated NSCLC patients phase II trial is ongoing.
Intravesical local administration of pembrolizumab for treatment of bladder cancer: A novel strategy to minimize toxicity.
Authors: Tyagi Pradeep , Ganguly Anirban B. , Hafron Jason , Kaufman Jonathan , Chancellor Michael
Published: June 2024

e14687

Background: A major hallmark of bladder cancer (BCa) is a higher treatment success rate than prostate cancer following stimulation of innate anti-tumor immune response either by intravesical BCG or to FDA approved intravenous anti-PD1 checkpoint antibody (pembrolizumab) approved for BCG resistant BCa since 2021. However, injected pembrolizumab is characterized by a markedly higher incidence (66%) of serious adverse events than the median duration of complete response of ~40% for non-muscle invasive BCa (NMIBC) and 15-20% for invasive BCa. Since the toxicity (fatigue, Pneumonitis and diarrhea) of injected pembrolizumab is linked to systemic breakdown of T-cell mediated immune surveillance we enquired whether analogous to BCG, pembrolizumab can be administered intravesically to safely induce a localized anti-tumor response in mouse model of BCa. Methods: Six weeks old female mice of B6D2F1 strain (n=10) were ad libitum fed carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) in drinking water (0.05% w/v) for 12 weeks. The presence of BBN evoked tumor was ascertained by unenhanced T2 weighted MRI at week 11 prior to single intravesical dosing by 24G transurethral catheter under isoflurane anesthesia of 0.1mL vehicle (sterile water) with or without 0.3mg of Pembrolizumab (Lipella Pharmaceuticals). 6 weeks later, T2 weighted MRI was repeated together with T1 mapping by ICE-MRI prior to organ harvest. Results: BBN feeding evoked multiclonal tumors (red*) of comparable size on T2 weighted MRI at week 11 but repeat MRI 7 weeks after treatment revealed that tumor progression and perivesical invasion noted in vehicle group was arrested in pembrolizumab group. Longest dimension of BBN tumor in vehicle treated mice was ≥ 1mm longer (p<0.05) than in pembrolizumab treated mice. T1 mapping revealed thickened bladder wall missed by T2 MRI. Conclusions: These findings on single intravesical dose of pembrolizumab (10mg/kg) in mice are consistent with human study on multiple intravesical dosing of BCG plus pembrolizumab (1-2mg/kg) in BCG resistant NMIBC patients. Intravesical pembrolizumab mirrors the limited systemic uptake of radiolabelled antibodies together with substantially higher ingress into tumor foci. The tumor selective ingress for BCa immunotherapy without any toxicity will be enhanced with Lipella Pharmaceutical’s liposomal delivery of Pembrolizumab.
Phase I safety and preliminary efficacy of PM1009, a bispecific antibody targeting TIGIT and PVRIG, in patients with advanced solid tumors.
Authors: Xue Liqiong , Wu Lihua , Tang Wenbo , Wang Zhuoyi , Xue Junli , Li Qun , Ge Xiaoxiao , Lin Fengjuan , Zhao Wei , Zhou Jiuli , Guo Ye
Published: June 2024

e14695

Background: PM1009 is an anti-TIGIT x PVRIG bispecific antibody containing a fully human anti-TIGIT IgG1 fused with a fully human anti-PVRIG scFv at the C terminus. PM1009 can potently block the TIGIT/CD155/CD112 and PVRIG/CD112 signaling pathways, and supports the depletion of TIGIT-positive Treg cells in the tumor microenvironment through FcγR engagement. This leads to the enhancement of T cell and NK cell activity towards the killing of tumor cells. PM1009 showed robust in vitro and in vivo efficacy with good safety in preclinical studies. Methods: This is the first-in-human study of PM1009, which includes a dose escalation stage (accelerated titration & 3+3 design) followed by dose expansion. In the dose escalation stage, PM1009 was administered as flat doses of 120, 300, 600 and 1200 mg for DLT evaluation after 3 weeks followed by administration Q2W. Primary endpoints were safety and tolerability, and the secondary endpoints were PK, ORR and DCR (per RECIST 1.1). Results: As of February 1, 2024, a total of 12 patients were enrolled for dose escalation and received at least one dose of PM1009, with 3 patients in each of the 120, 300, 600 and 1200 mg dose-levels. Median number of prior therapies was 5 lines (range 1- 9). No DLTs were observed up to 1200 mg. Any-grade TRAEs occurred in 11 patients (91.7%), and ≥ Grade 3 TRAEs occurred in 2 patients (16.7%). Any-Grade irAEs occurred in 7 patients (58.3%), and ≥ Grade 3 irAEs occurred in 1 patient (8.3%). Treatment interruption due to TRAE occurred in 2 patients (16.7%), with infusion related reaction (the main symptom was nausea, and the single infusion was eventually completed), and neutrophil count decrease respectively. Treatment discontinuation due to TRAE occurred in 2 patients (16.7%), with acute myocardial infarction, and neutrophil count decrease respectively. The most common TRAEs were ALP elevation (33.3%) and AST elevation (25.0%). 12 patients completed at least one tumor evaluation. The DCR per RECIST 1.1 by investigator was 33.3% (4/12; 95% CI: 9.92 - 65.11), best overall response was SD. Pharmacokinetics were dose-proportional with a terminal half-life of 5.2-7.4 days across the dose range of 120-1200 mg. Conclusions: PM1009 was well-tolerated up to 1200 mg with signs of anti-tumor activity. These findings support further clinical investigation of PM1009 especially for the combination with chemotherapy or PD-1/L1-based checkpoint inhibitors. Clinical trial information: NCT05607563 .
Prediction of immune-related adverse events in urological cancer during checkpoint inhibitor immunotherapy through immunohistochemical analysis of tumorous LCP1/ADPGK.
Authors: Xu Liqing , Ying Yicen , Yang Kaiwei , Tang Qi , Li Xuesong
Published: June 2024

e14699

Background: The expanded utilization of immune checkpoint inhibitors (ICIs) have successfully improved the outcome of cancer patients, yet the concomitant immune-related adverse events (irAEs) can lead to fulminant unfavorable consequences. Currently, a comprehensive approach to predict irAEs is lacking. Some relevant biomarkers derived from database analyses are still in the early stages of investigation and lack robust validation in clinical samples, including LCP1/ADPGK. Herein, we validated the performance of LCP1 and ADPGK in a retrospective patient cohort with advanced urological cancers undergoing ICIs treatment, while comparing the predictive efficacy between different algorithmic models. Methods: We retrospectively collected clinical data of patients with renal cell carcinoma (RCC), upper urinary tract epithelial carcinoma (UTUC), bladder cancer (BC) receiving anti-PD-1/PD-L1 treatment from 2020 to 2023 in Peking University First Hospital. Patients were categorized into irAEs and non-irAEs groups, with irAE assessments conducted by two expert urological oncologists. Immunohistochemistry (IHC) was performed on 5-µm-thick pre-treated FFPE tumor tissue sections. Results: A total of 112 patients were included in the study, comprising 60 with RCC, 21 with UTUC, and 31 with BC. Among them, 51 (45.5%) patients experienced irAEs, with 9 exhibiting severe irAEs of grade III-IV. Immunohistochemical analysis revealed higher expression levels of LCP1 and ADPGK in patients with irAEs compared to those without irAEs. The area under the receiver-operating characteristic curve (AUC) for predicting irAEs using LCP1 and ADPGK individually was 0.82 (p < 0.0001, 95%CI = 0.74-0.90) and 0.86 (p < 0.0001, 95%CI = 0.80-0.93), respectively. The combination of LCP1 and ADPGK demonstrated an improved AUC of 0.89 (p < 0.0001, 95%CI = 0.83-0.95). Among different algorithms, the bivariate linear-regression and the geometric mean model show similar prediction effects. Notably, the combined LCP1+ADPGK model successfully predicted irAEs in RCC (AUC = 0.89, p < 0.0001, 95%CI = 0.81-0.98), UTUC (AUC = 0.81, p = 0.0063, 95%CI = 0.63-0.99), and BC (AUC = 0.88, p = 0.0004, 95%CI = 0.75-1.00). The expression of LCP1/ADPGK was not associated with the type of cancers. Conclusions: The bivariate linear-regression model of LCP1 and ADPGK could accurately predict irAEs in patients with urological cancers, which may allow us to improve the risk-benefit balance for individuals considered for ICIs therapy.
Comparative efficacy of six programmed cell death protein-1 inhibitors in first-line treatment for advanced non-small cell lung cancer: A retrospective cohort study.
Authors: Chen Siyuan , Qin Yuhui , Du Zhijuan , Qiao Yu , Hu Yi , Liu Zhefeng
Published: June 2024

e14702

Background: All six programmed cell death-1 (PD-1) inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) have been used as first-line therapy in Chinese patients with advanced non-small cell lung cancer (NSCLC), but the comparative efficacy of these different drugs remains unclear. Methods: Retrospective collection of patient data from the First, Third, and Fifth Medical Centers of the Chinese PLA General Hospital who received PD-1 inhibitors (monotherapy or combination therapy) from June 2015 to April 2023. Analysis of patient clinical characteristics, treatment response, and survival outcomes was conducted, with the primary endpoints being overall survival (OS) and progression-free survival (PFS). Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Results: 913 patients were included and divided into 6 groups: nivolumab (123, 13.5%), pembrolizumab (421, 46.1%), sintilimab (239, 26.1%), tislelizumab (64, 7.0%), toripalimab (39, 4.3%), and camrelizumab (27, 3.0%). Median PFS was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and median OS was 33.7, 36.1, 32.5, not reached, 30.9, and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. PFS and OS did not differ among the different PD-1 inhibitor groups (all P>0.05). There were differences in ORR among the different PD-1 inhibitors (P<0.05), but no differences in DCR (P>0.05). Conclusions: Nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab exhibit similar efficacy in first-line treatment for patients with advanced NSCLC.
Effect of common medications on immune checkpoint inhibitor efficacy.
Authors: Falvello Virginia , Brinzevich Daria , Bryant Alex , Green Michael D
Published: June 2024

e14710

Background: Previous studies have suggested that certain common medications could impact immune checkpoint inhibitor (ICI) efficacy and survival. These studies lacked non-ICI control groups, raising the possibility that survival differences could be explained by confounding. Methods: We developed a pan-cancer cohort of 27,998 patients who received ICIs in the national Veterans Health Administration (VHA) from 2010 to 2023. ICI patients were matched to 66,488 historical control patients treated with chemotherapy or targeted therapy before initial ICI regulatory approval in each cancer. We ascertained baseline use of drugs from 15 common medication classes within 1 year before therapy start and performed propensity-weighted Cox regression analyses to assess the impact of each medication class on overall survival (OS) and time to next treatment (TTNT). Interaction tests measured whether the impact of each medication class was significantly different in ICI versus historical control patients. Results: In the ICI cohort, the most common cancer types were NSCLC (46%) and melanoma (10%). After adjustment for multiple comparisons, only statins (adjusted hazard ratio [aHR] 0.93), PPIs (aHR 1.06), and loop diuretics (aHR 1.19) were associated with overall survival differences among ICI patients; nearly identical associations were observed in historical control patients (interaction p-values > 0.4 for all; Table). Similar results were seen for TTNT and in sensitivity analyses limiting to more recent medication users. Conclusions: Common medications do not appear to impact ICI efficacy. Previously described survival effects are likely the result of confounding. [Table: see text]
Predictors of endocrine immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICI) in routine clinical practice.
Authors: Kozhevnikov Alexander , Mkrtumyan Ashot , Feoktistova Polina Serrgeevna , Filonenko Daria , Polshina Natalya , Volkova Ekaterina , Grechukhina Katerina , Bykonya Irina , Zhukova Lyudmila
Published: June 2024

e14713

Background: Endocrine irAEs have been reported in association with various ICI and are characterized by their correlation with improved survival outcomes. A growing clinical comprehension of endocrine irAEs has facilitated the development of effective treatment strategies involving hormone replacement, which has been shown to enhance patients' quality of life. This study aims to evaluate outcomes in patients (pts) experiencing endocrine irAEs and identify predictive factors for their occurrence. Methods: This retrospective cohort study comprised 214 adult pts with solid malignant tumors who underwent ICI, either as monotherapy or in combination with other chemotherapeutic agents, at the SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM. Results: Between June 2016 and January 2023, 214 pts were included in the study (46.3% female, 53.7% male). The median age was 62.6 years (range 32–91). At the data cut-off (1 February 2024) the median overall survival (OS) for the analyzed population was 34,5 months (95%CI 21,15-43,91). No significant difference in median OS was observed between pts with overall endocrine irAEs and those exhibiting specific manifestations, such as hypocortisolism and destructive diabetes mellitus. However, thyroid irAEs were associated with improved median OS: 27.5 months compared to 22.6 months in those without (p=0.037); RR=1.39 (95%CI 1.025-1.89; p=0.036). The grade of endocrine irAEs did not impact the survival benefit. A significant association was observed between age group and endocrine irAEs (Pearson’s χ2=9.92, p=0.019), with a left-skewed age distribution due to a higher proportion of participants aged 32–44 years among those developing endocrine irAEs. Pts with nodular goiter had a 2.91 times higher risk of developing thyroiditis (95%CI 1.03–8.25), although this did not reach statistical significance (p=0.067). Calcium channel blockers were associated with an increased risk of developing thyroid irAEs (RR=1.54, 95%CI 1.09–2.19; p=0.036). Antihistamine use was a robust predictor of hypothyroidism with a RR=1.68 (95%CI 1.05–2.7, p=0.04). Initial derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 predict the development of endocrine irAEs (Pearson χ2=4.02; p=0.045) as well as dNLR>2.2 (Pearson χ2=4.22, p=0.04). Conclusions: Thyroid irAEs are correlated with improved OS. Predictors of endocrine irAEs may include young age (32-44 years), calcium channel blocker or antihistamine use, dNLR ≥3, or dNLR >2.2. Prospective trials are warranted to validate these findings.
Enhancing liquid biopsy potential: The impact of the R3CE 3D culture platform.
Authors: Wu Yi-Chun , Pegram Mark D. , Kuo Wen-Hung , Chou Hsu-Huan , Huang Yen-Jang , Chen Jia-Yang , Han Hao-Wei , Zong Yu , Chen Chia-Chun , Chang Ying-Chih
Published: June 2024

e15032

Background: The ability to expand and preserve tumor cells ex vivo has been an important aspect of cancer research, offering insights into tumor biology and the advancement of personalized therapies. However, expanding rare tumor cells, such as circulating tumor cells (CTCs) and needle biopsies, remains challenging. Methods: We present the R3CE (Reproducible, Rapid, Rare Cell Expansion) 3D culture platform, a novel system that enhances the conventional tissue culture plate with a coating of polyelectrolyte multilayer. This approach can reliably cultivate various tumor specimens, including CTCs, needle biopsies, and surgical tissues, into tumor spheroids. Results: Our platform achieved over a 90% success rate (n = 305) in producing tumor spheroids with uniform size and preserved mutational profiles across diverse cancer types such as breast, lung, and colorectal cancers. In comparison to traditional tissue biopsies, liquid biopsies are less invasive and contain CTCs that offer a more comprehensive representation of heterogeneous tumor cell populations. We show that the proliferative capacity of cultured CTCs, rather than the initial CTC counts, have a strong correlation with lung adenocarcinoma prognosis (n = 124), highlighting the clinical potential of the R3CE platform (1). Furthermore, we have successfully employed cultured CTCs for drug screening for various cancers (breast cancer, cholangiocarcinoma, colon cancer, EMPD, gastric cancer, hepatoma, lung cancer, mucosal melanoma, pancreatic cancer, and urinary bladder cancer, n = 80), resulting in measurement of ex vivo response to chemotherapy and targeted drugs. For instance, R3CE-cultured CTCs have been used in predicting response to neoadjuvant chemotherapeutic drugs in breast cancer, as evidenced by an ROC curve analysis with an AUC of 0.963, 100% sensitivity, 87.5% specificity, P=0.02. Also in an exploratory analysis of immunotherapy efficacy, involving co-culture of R3CE-cultured CTCs (n = 6) and tumor tissue-derived organoids (n = 6) with immune cells such as CAR-T and autologous NK cells, has shown promising outcomes for selected cancers. Conclusions: The R3CE 3D culture platform represents a potentially transformative tool above and beyond CTC enumeration, significantly enhancing 1) the expansion of tumor cells ex vivo and, more importantly, informing phenotypic and genotypic characterization of CTCs, thereby holding promise for advancing cancer care and treatment efficacy. 1. Che et al., Lung Cancer, 2023; 178:198-205.
Development of a prediction model for lung metastasis by using postoperative circulating tumor DNA binding clinicopathological risk factors in patients with colorectal cancer.
Authors: Han Bohan , Li Weiyao , Li Jianxia , Hu Huabin , Zhang Jianwei , Xie Xiaoyu , Mo Qinli , Deng Yanhong
Published: June 2024

e15035

Background: Lung metastasis is common in patients with colorectal cancer (CRC). However, diagnosing lung metastasis in CRC is challenging due to slow-growing pulmonary lesions. Circulating tumor DNA (ctDNA) testing provides a direct indication of the presence of minimal residual disease (MRD) which contributing to cancer recurrence. Yet, there are no reports on the potential indications of ctDNA for the site of metastasis. The objective of this study is to develop a predictive model for lung metastasis in CRC patients who have received adjuvant therapy by integrating ctDNA with clinicopathological factors. Methods: Two independent cohorts' series were evaluated including 299 patients from China as training cohort and 134 patients from Spain as validation cohort from 2012-2020. We specifically focused on the detection of ctDNA in these patients. We employed LASSO regression for optimal feature selection and built a predictive model by multivariable logistic regression. Results: In training cohort, 59/299(19.7%) patients have detectable ctDNA. In validation cohort, 24/134 (18.6%) patients have detectable ctDNA. Patients who tested ctDNA-positive had a significantly higher incidence of lung metastasis (33.9% vs. 11.2%, P<0.001) compared to ctDNA-negative patients. A predictive model for lung metastasis was developed by multivariable logistic regression analysis. The model incorporated factors such as ctDNA status, preoperative carcinoembryonic antigen (CEA) level, presence of cancerous nodes, and the mutation status of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) in plasma. The lung metastasis prediction nomogram demonstrated a favorable ability to distinguish with a concordance index of 0.775 (95% CI: 0.706-0.775) during internal validation. The Hosmer-Lemeshow test, with p-value of 0.967, indicated that prediction nomogram model had a good fit. In addition, the prediction model of validation cohort demonstrated a discriminative performance with a concordance index of 0.724(95% CI: 0.698-0.724). Furthermore, the DCA (Decision Curve Analysis) and CIC (Clinical Impact Curve) in both cohorts indicated that the lung metastasis nomogram exhibited a favorable clinical net benefit. Finally, through multi-model comparison, it was found that the predictive performance of the model, which includes ctDNA and blood PIK3CA mutation status, was significantly superior to all clinical prediction models. Conclusions: A lung metastasis prediction nomogram was developed by integrating postoperative ctDNA and clinicopathological risk factors. The purpose of this nomogram is to assist clinicians in predicting the probability of lung metastasis in patients who have undergone surgery for CRC, with the aim to facilitate prompt intervention.
The NAVigate-HPV Registry: A comprehensive biomarker evidence base for HPV-driven cancers.
Authors: Roof Scott , Hanna Glenn J. , Rettig Eleni M. , Routman David M. , Holsinger Floyd Christopher , Kalman Noah , Bhatia Aarti K. , Patel Mihir R. , Jabalee Jamie , Yom Sue S. , Baliga Sujith , Raben Adam , Sims John , Kaczmar John M. , Bhayani Mihir K , Berger Barry , Del Vecchio Fitz Catherine
Published: June 2024

e15045

Background: Human papillomavirus (HPV) is an oncogenic driver of several human cancers, including those of the anal canal, uterine cervix, and head and neck (predominantly oropharynx). Despite advancements in our understanding of HPV-related cancers, there remains an unmet need for a comprehensive biomarker-driven registry to establish correlations between biomarker detectability and clinicopathologic features in patients diagnosed and treated for HPV-driven cancers. To address this need, the NAVigate-HPV Registry has been established to systematically collect and analyze integrated biomarker and clinical data from many U.S. cancer centers. Methods: NavDx (Naveris, Inc.) is a clinically validated blood-based assay detecting circulating cell-free tumor tissue modified viral (TTMV)-HPV DNA. The NAVigate-HPV Registry is a web-based data platform based on a centrally IRB approved protocol. Participating investigators will include providers that order NavDx tests in the routine clinical care of their patients and agree to the terms and conditions for use of the registry. Eligible subjects will have or have had an HPV-driven cancer (with an initial focus on HPV-driven oropharynx cancer with confirmatory tissue testing) and have received one or more NavDx blood tests during routine clinical care. Clinical data and TTMV-HPV DNA scores will be collected at enrollment and defined intervals over five years or until death. Results: In the initial phase, the registry has enlisted participation and established a steering committee composed of a representative from each of 14 institutions. These institutions are geographically diverse centers ranging from community hospitals to clinics and academic medical facilities. An IRB protocol governing the registry will maintain ethical standards, ensuring compliance and ethical conduct throughout the registry process. Data extraction methods have been previously established to evaluate an initial cohort of 543 patients (Hanna GJ, Roof SA, et. al 2023). Conclusions: Naveris and collaborators have together successfully launched the NAVigate-HPV registry with the aim of creating a robust database linking tumor biomarker results from NavDx with clinical outcomes data for HPV-related cancers. The NAVigate-HPV database is expected to encompass more than 1,000 patients within 1 year and grow to > 5,000 patients within 5 years, serving as a powerful tool for precision cancer medicine in this patient cancer population. Establishing this registry will deepen insights into HPV-related cancers and advance diagnostic and therapeutic approaches to improve patient outcomes.
MSK-ACCESS powered with SOPHiA DDM: Performance analysis of a decentralized MSK-ACCESS solution.
Authors: Klemm Florian , De Martino Fabio , Mohammad Fuad , Wenger Yvan , Casanova-Murphy Jacklyn , Bowman Anita S. , Houck-Loomis Brian , Brannon Angela Rose , Berger Michael F. , Xu Zhenyu
Published: June 2024

e15063

Background: Blood plasma cell-free DNA (cfDNA) testing of cancer patients allows for genomic profiling when tissue sampling is too invasive or of insufficient quality. This approach has demonstrated clinical utility to identify treatment targets, screen for resistance and monitor disease burden. MSK-ACCESS (Memorial Sloan Kettering – Analysis of Circulating cfDNA to Evaluate Somatic Status) is a validated, high sensitivity cfDNA assay employed at MSK to identify biologically actionable tumor alterations in clinical care. SOPHiA GENETICS is developing a decentralized solution of this assay that incorporates major features of MSK-ACCESS such as molecular barcoding, duplex-based variant calling, the inclusion of tumor-informed prior knowledge and identification of somatic alterations through the removal of both germline and clonal hematopoiesis (CH) variants. Here, we present the results of a performance study obtained during product development. Methods: A cohort of 24 plasma cfDNA and matched white blood cell (WBC) DNA samples were collected from patients with solid tumors and processed at MSK according to the validated standard operating procedures and bioinformatic analyses. In parallel, for the same set of materials libraries were constructed at SOPHiA GENETICS using the proprietary CUMIN molecular identifiers, captured with probes targeting the updated MSK-ACCESS v2 set of 146 genes and sequenced on an Illumina NovaSeq 6000. Variants were called using a duplex-aware approach by SOPHiA GENETICS and germline and CH variants were identified and filtered by paired cfDNA – WBC DNA analysis. Accuracy of the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution was assessed through concordance to the orthogonal results obtained by MSK. Results: A total of 104 somatic SNV/Indels were detected with variant allele fractions (VAF) ranging from 0.1% to 97.0% with a median of 5 variants per sample. The positive percent agreement (PPA) for all variants above the limit of detection of the original MSK-ACCESS assay was 98.9% with 99.98% specificity. For the subset of prior-knowledge variants PPA was 95.6% down to 0.1% VAF. A total of additional 59 variants with ≤ 15% VAF were found both in cfDNA and WBC and assigned as CH-derived. Importantly, these occurred not only in CH-associated genes but also in common oncogenes such as BRCA1/2 and ERBB2, highlighting the utility of matched WBC analysis to correctly identify somatic variants. Conclusions: The results demonstrate that the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution exhibits a high degree of agreement to the results achieved by MSK. Further studies will be conducted to expand the analytical performance evaluation.
Reporting an Indian multicentric community oncology practice’s observation on patterns of homologous recombinant deficiency across various solid cancers evaluated through tumor-DNA-based NGS.
Authors: Bose Chirantan , Maheshwari Udip , Morzaria Dr Disha , Joshi Ashish , Maniar Vashishth , Jobanputra Kunal Naishadh , Pawar Akash , Joshi Kshitij Chandrakant , Kalaskar Pritam , Mekha Mangesh , Chaudhari Krushna , Sethjiwala Taha , Pal Devendra , Sheth Smit , Khandare Pravin
Published: June 2024

e15066

Background: Homologous recombinant deficiency(HRD) is being evaluated across various solid organ malignancies to assess not just the underlying biological behavior of the cancer but also for potential response to PARP inhibitors. HRD status is assessed by measuring mutations in genes involved in the HRR (Homologous Recombinant Repair) pathway along with other genomic aberrations across the tumor genome like Loss of Heterozygosity (LOH), Telomeric Allelic Instability (TAI) and Large Scale Transitions (LST).We compare here overall HRD scores and their sensitivity and specificity to HRR v/s HRR + LOH, TAI, and LST in an attempt to study the prevalence and pattern of HRD scoring and response to PARPi. Methods: The retrospective data of cancer patients who have undertaken the aforementioned test were evaluated to analyze the patterns of HRD. Responses of a limited subset of patients who received PARP inhibitors were also assessed. Results: A total of 101 patients were evaluated from a community oncology practice over the last 1 year who underwent HRD testing of which 58.4% were female and 41.5% were male. 27.7% of patients were therapy-naive of which 67.8% were stage IV, 28.5% were stage III, and 3.5% were stage I/II while 72.2% were pre-treated and mostly ( > 90%) of advanced stage. The most common cancer types that were tested were Gynaecological cancers (20.7%), followed by Pancreatobiliary (18.8%), Lung (13.8%), Genitourinary (13.8%), and other solid cancers (32.4%). Limited-HRD testing based on small panel HRR genes was performed on 9.9% (10/101) while Comprehensive-HRD (including HRR genes, LOH, TAI, and LST) was performed on 90% (91/101). The sensitivity and specificity of Limited-HRD were 43.75% (with 95% CI 26.36% to 62.34%) and 69.46% (with 95% CI 56.13% to 80.81%) showing an accuracy of 60.44% (with 95% CI 49.64% to 70.54%). Comprehensive-HRD analysis showed a sensitivity of 78.12% (60.03% to 90.72%) and specificity of 67.80% (54.36% to 79.38%) with increased accuracy of 71.43% (with 95% CI 49.64% to 7.54%) as compared to Limited-HRD. PARPi were used in 8.9% (9/101) of patients for organ types- Ovary (44.4%), Prostate (33.3%), Stomach (11.1%), and Lung (11.1%) with a clinical benefit rate of 66.6%. It is also reported that in 3% of cases, BRCA1 mutation was detected however, the comprehensive-HRD score was found low. Conclusions: Predictive sensitivity and accuracy improved with Comprehensive-HRD analysis, thereby reflecting the power of LOH, TAI, and LST in the true identification of both positive and negative cases thus expanding the usage of PARPi in deserving patients.
Patient-derived 3D bioprinting pan-cancer drug screening platform for personalized medicine.
Authors: Yang Huiyu , Zhang Jiangang , Shan Ying , Wang Yanan , Cao Yaning , Sun Yuning , Jin Ying , Pan Lingya , Ke Chunhai , Cui Wei , Yang Mian , Zhou Bo , Jia Ziqi , Cao Heng , Wang Yu , Ma Wenbin , Xu Xiao , Zhao Hai-Tao , Yang Huayu , Mao Yilei
Published: June 2024

e15088

Background: Patient-derived tumor model offers an individualized approach to overcome interpatient heterogeneity in cancer therapy. 3D bioprinting (3DB) enables construction of in vitro model with high-throughput, high-fidelity, and high efficacy. We hereby report a pipeline of establishing pan-cancer patient-derived 3DB (PT-3DB) models with personalized drug sensitivity results in 148 patients from multiple medical centers. Methods: Tumor tissues of 148 patients were collected with informed consent at 4 medical centers in Beijing, Hangzhou and Ningbo from 2022-12 to 2023-12. Tumors were digested into cell suspension and mixed with GelMA, and PT-3DB was fabricated by extrusion-based bioprinter. A panel of chemotherapies and targeted therapies was selected based on first-line treatment of corresponding cancer type. PT-3DB was treated with drugs in dose gradient at DIV 5. Cell viability was measured by ATP quantification at DIV 8 and dose-response curve and IC50 of each drug was calculated. Results: We have established PT-3DB in 148 patients with success rate of > 95% and turnaround time of only 8 days. 137 were surgically resected samples and 11 were biopsy samples. Cancer types included ovarian cancer (OC, n = 52), colorectal cancer (CRC, n = 51), hepatobiliary cancer (HBC, n = 17), breast cancer (BC, n = 10), high-grade glioma (HGG, n = 10), cervical cancer (CC, n = 4), pancreatic cancer (PC, n = 2), and gastric cancer (GC, n = 2). A total of 27 drugs were screened, of which 15 were chemotherapies and 12 were targeted therapies. The median number of drugs tested for each patient was 5 (4-6) (Q25-Q75). Significant interpatient heterogeneous drug response was observed within each cancer type and between tumors with the same treatment regime. Representative data were presented in the attached table. Conclusions: We have successfully constructed pan-cancer PT-3DB platform for personalized drug screening in 148 cases, with outstanding stability across multiple centers. The timeline of 8 days preceded pathological diagnosis, which is the earliest start of systematic treatment, underscoring its high translational potential. PT-3DB has demonstrated interpatient heterogeneous response to systematic treatment, providing a strong foundation for precision medicine. Our ongoing research aims to correlate PT-3DB drug responses with clinical outcomes. [Table: see text]
Study on the mechanism of ginsenoside Rg5 attenuating radiation myocarditis through GDF11-SIRT1 pathway.
Authors: Bai Hansong , Li Tao
Published: June 2024

e15098

Background: Radiation-induced Heart Disease (RIHD) refers to the damage caused by the radiation dose to the heart during radiotherapy for malignant tumors (especially chest tumors), generally including myocardial disease, pericardial disease, coronary artery disease, etc. It generally occurs during radiotherapy or within months to years after radiotherapy. It is reported that the incidence within 5-10 years after the end of radiotherapy is about 10%-30%. With the advancement of equipment and technology, radiotherapy has become increasingly involved in malignant tumors and has become one of the most important treatments for thoracic tumors. Radiation heart disease will significantly reduce the quality of life of patients with malignant tumors after radiotherapy. and survival rate. Although the incidence of RIHD can be reduced by optimizing radiotherapy technology, current technology cannot eliminate the risk of RIHD4. Therefore, it is of great clinical significance to explore how to reduce the incidence and severity of radiation heart disease. Methods: In vitro cultured cardiomyocyte model: used to analyze the impact of Rg5 on cardiomyocytes at the molecular level. Animal model: Construct an animal model of radiation heart disease to evaluate the protective effect of Rg5. Construction of iPCS organoid model to verify that Rg5 attenuates radiation heart disease mediated through Sirt1. Results: Immunohistochemistry, HE staining and Masson staining in early animal experiments showed that Rg5 can slow down radiation heart disease caused by radiotherapy. Immunohistochemistry results showed that SIRT1, HDAC3, PINK1, PARKIN, MFN2 and GDF11 showed obvious differences in expression, while SIRT6 and DRP1 did not. There were obvious differences. At the same time, immunofluorescence double staining of DRP1+SIRT1, MFN2+SIRT1, and HDAC3+SIRT1 was further performed to clarify their intracellular spatial relationship. After using iPSCs to induce cardiac endothelial cells, double immunofluorescence staining of mitochondrial markers and endothelial marker CD31 was performed. The results showed that radiotherapy can cause damage to vascular endothelial cells, reduce vascular integrity, reduce mitochondrial length, and impair function. Ginsenoside Rg5 can reduce this trend. From the common database of single-cell myocardial tissue, it was found that markers such as SIRT1, HDAC3, PINK1, MFN2, GDF11, and GPX4 have similar expression profiles in cardiomyocytes and are more likely to regulate each other. Conclusions: Ginsenoside Rg5 can regulate cardiac radiation injury through the HSP90α-HDAC3-GDF11-SIRT1 axis.It is expected to provide new therapeutic targets for the prevention and treatment of radiation heart disease, making ginsenoside Rg5 of great value in radiotherapy sensitization and radiation heart protection.
Pharmacogenomic diversity of clinically significant cancer treatment biomarkers in ancestrally diverse US population.
Authors: Fonkem Ekokobe , Aminkeng Folefac , Hay Chuck , Al-Gizawiy Mona M , Pettit Jaimy , Connelly Jennifer M , Schmainda Kathleen M
Published: June 2024

e15099

Background: Cancer Health Disparities (CHD), in the US is well documented. The is significant evidence of CHD treatment related outcomes along ancestry lines. Africans and Hispanics generally have higher rates of adverse drug reactions (ADR), and poorer survival and response rates when compared to Europeans and Asians. The causes of CHD treatment related outcomes are poorly understood but it is plausible to believe that CHD has a genetic basis, given that human genomic variations underlie both disease susceptibility and treatment outcomes. Our goal is to determine the genetic basis of CHD treatment related outcome, with a particular focus on under-represented and underserved populations. Methods: We will deploy pharmacogenomic (PGx) differentiation analyses using a comprehensive patient database and correlative banked tissue (~ 2,000 patients) from MCW, together with 3 international cohorts as comparators (Africans = 372, Asians = 1,250 and Europeans = 958) to: Interrogate clinically significant cancer treatment PGx biomarkers and characterize the variation across different populations. Assess the implications of genetic admixture on CHD treatment related outcomes. Evaluate the intersection of genetic diversity with pharmacogenomic diversity. Explore the distribution of age, gender, diagnosis, treatments, response, ADRs, survival, comorbidities, and concomitant medication. Results: Our initial results point to a significant genetic contribution to CHD treatment related outcomes. The enrichment of genetic risk factors for therapeutic failure, ADRs or poorer survival in patients of African vs European descent, explains the increased sensitivity to ADRs, poorer response rates, and decreased survival in patients of African vs European descent. We will extend this analysis to a multi-ethnic US cohort including Africans, Hispanics, Europeans, Asians, and First Nations. Conclusions: There is extensive PGx diversity within the US population, hence, coupling preemptive PGx testing with genetic testing is imperative for a truly equitable delivery of healthcare. There is a need for diversified representation of all population in cancer research to level the gaps in CHD. The identification of the genetic basis of CHD treatment related outcomes is imperative for predicting outcomes, and the implementation of preemptive PGx and precision medicine. [Table: see text]
Phase 1 study of ERK inhibitor JSI-1187 for patients with advanced solid tumors with MAPK pathway mutations.
Authors: Xi Yuqin , Wang Zhenghang , Shen Lin , Wu Lin , Chen Yu , Fang Meiyu , Li Mei , Ye Feng , Paradiso Linda J. , Myers Thomas J. , He Junqiang , Zhang Jintao , Xu Wen , Zhang Lei , Li Ao
Published: June 2024

e15111

Background: Mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation and survival, it is highly correlated with the occurrence of many cancers, JSI-1187 is a potent and reversible small molecule inhibitor of ERK1/2. This study is designed to assess the safety and efficacy of ERK Inhibitor JSI-1187 for advanced MAPK-mutant tumors patients. Methods: This is a phase 1 study included dose escalation and expansion (NCT06239623). The dose escalation study was conducted using a 3+3 escalation design to assess JSI-1187 16, 24, 32, 48,72, 80 and 96 mg BID, and 80, 128 and 152mg QD, repeated q 28 days. Dose limiting toxicities (DLTs) were predefined in the protocol. MAPK-mutant tumor patients whose disease progressed after existing standard treatment were treated. RAS and BRAF-mutated solid malignant tumors were explored in the dose-escalation phase. Results: As of December 23, 2023, 26 patients were enrolled, including 23 from the BID group and 3 from the 80mg QD group. No DLT was observed in QD group, 1 DLT (1 macular edema) and 2 DLTs (1 macular edema and 1 pneumonia) were observed at 96 and 80 mg BID, respectively. The most common JSI-1187 16-96mg BID related AEs were hypoalbuminemia (69.6%), rash (62.5%), and anemia (43.5%), while the most common JSI-1187 80mg QD related AEs were rash (100%), leukopenia (100%) and neutropenia (66.7%). The most common Grade 3 JSI-1187 16-96mg BID treatment-related AEs were anemia (17.4%) and thrombocytopenia (8.7%). Tumor response was evaluated in 18 of the total 26 patients. SD was noted as best response at doses of 16 – 96 mg BID and 80 mg QD including 29.8% tumor shrinkage in 1 NRAS-mutant melanoma patient treated at 32mg BID and 21.6% tumor shrinkage in 1 MEK1 K57N-mutant lung cancer patient treated at 72mg BID. Conclusions: JSI-1187 monotherapy is well-tolerated in advanced solid tumor patients and demonstrated preliminary antitumor effect. Current evidence supports future exploration of JSI-1187 as monotherapy, and in combination, in patients with MAPK-mutant tumors. Research Sponsor: JS Innopharm Clinical trial information: NCT06239623 .
Phase I clinical study of FC084CSA, a high selective AXL kinase inhibitor that ameliorates tumor microenvironment and augments the effectivity of immunotherapy.
Authors: Li Wei , Wang Lei , Wang Jing , Song Zhengbo , Zhang Qingyuan , Zhou Caicun
Published: June 2024

e15116

Background: NSCLC patients with STK11 gene mutations could not benefit from immunotherapy, according to the data of multiple clinical trials. This is associated with immunosuppressive tumor microenvironment (TME) due to elevated AXL expression, and deficiency in pro-inflammatory cytokines and effector T cells. AXL inhibitor bemcentinib (formerly BGB324) has been found to improve the effectiveness of immunotherapy of immune checkpoint inhibitors. FC084CSA is a high selective AXL inhibitor. Methods: This is an ongoing first-in-human, phase I study of FC084CSA in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of FC084CSA. The secondary objectives include preliminary efficacy and pharmacokinetics. Results: As of January 10th, 2024, 9 patients with a median age of 60 years (44-73) were enrolled in 4 different dose levels: 100mg QD, 200mg QD, 400mg QD and 600mg QD. All patients had ≥ 2 prior lines of prior therapy. No dosing-limiting toxicities were observed. 8 (88.9%) patients experienced treatment-related adverse events (TRAEs). Most TRAEs were grade 1 or 2 and only one grade 3 TRAE was observed. The most common TRAEs (≥20%) included increased blood lactate dehydrogenase (44.4%), elevated gamma-glutamyl transferase (33.3%), proteinuria (33.3%), anemia (33.3%), increased aspartate aminotransferase (22.2%), weight loss (22.2%), increased blood creatinine (22.2%) and vomiting (22.2%). A total of 8 patients had at least 1 post-baseline tumor assessment. Objective response rate (ORR) was 0% and disease control rate (DCR) was 62.5% (5/8). Conclusions: FC084CSA was well tolerated in patients with previously heavily treated solid tumors. Clinical trial information: NCT06231550 .