bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pan-cancer analysis of P21 activated kinase (PAK) family genes as potential biomarkers for immune checkpoint therapy.
Authors: Gang Sun , Guo Wenjia , Qiao Lei , Sun Tonghui , Tan Yuan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang 
Published: June 2022

2614 Background: PAK (P21 activated kinase) is a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. Recent studies have found relationship between mutations of some PAK family genes and antitumor immunity. Here, we explored the associations of PAK family gene mutations with ICI response based on multidimensional data from multiple solid tumors. Methods: An immunotherapy cohort (Broad/Dana-Farber, Nat Genet 2018, N = 249) within 7 types of tumors as discovery stage, was used to explore the association of PAK family genes mutations with tumor mutation burden (TMB) and efficacy of immunotherapy. To further validate the predictive value of PAK family genes, we employed another ICI-treated cohort, MSKCC cohort (Samstein, Nat Genet 2019, n = 1661), as a validation cohort. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Results: In discovery cohort, compared to that in the PAK-Wt group, longer OS was observed in the PAK-Mut group (mOS: 31.3 vs 15.4 months, HR = 0.59, 95% CI: 0.36 to 0.96, P= 0.03). In addition, PAK-Mut group had higher TMB ( P< 0.001). Median TMB in PAK-Mut group and PAK-Wt group is 17.79 (IQR, 7.45-36.55) Mut/Mb and 5.47 (IQR, 2.46-9.09) Mut/Mb, separately. In validation cohort, PAK-Mut patients also achieved significant improved OS compared with PAK-Wt patients (mOS: 44.0 vs 17.0 months, HR = 0.51, 95% CI: 0.37 to 0.69, P< 0.001). Moreover, multivariable analysis of validation cohort demonstrated that PAK-Mut was associated with better OS (HR = 0.71; 95%CI, 0.52-0.98; P = 0.036), after adjusting for Age, Gender, Metastasis, Treatment, TMB, Cancer type. Compared with PAK-Wt group (median [IQR]: 5.90 [2.95-10.04]), PAK-Mut group (median [IQR]: 21.19 [11.81-43.29]) also had higher TMB ( P< 0.001). Conclusions: The results indicated that PAK family genes mutation was associated with a higher TMB both discovery and validation cohort. Analysis of discover and validation immunotherapy cohort data showed PAK family was associated with better OS. These findings indicate that these genes mutation may serve as a potential predictive biomarker for ICI in solid tumor patients.
WDR49 mutation as a novel predictive biomarker in patients with non–small cell lung cancer with immune checkpoint inhibitors.
Authors: Shi Zhihui , Liu Yaqin , Zhao Lele , Chen Lin , Yang Qidong , Xiao Mingzhe 
Published: June 2022

2615 Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value < 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation ( WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P < 0.001) and higher objective response rate (ORR) (76% vs 27%, P < 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P < 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p < 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.
PAPPA2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC and SKCM.
Authors: Dong Yiting , Wang Zhijie , Wang Jie , Duan Jianchun , Bai Hua , Zhao Lele , Chen Dong-sheng , Li Si , Yu Yangyang , Zhang Qin , Xiao Mingzhe , Qi Chuang 
Published: June 2022

2617 Background: Pappalysin 2 ( PAPPA2) mutation, most occurring in skin cutaneous melanoma (SKCM) and non-small cell lung cancer (NSCLC), is found to be related to anti-tumor immune response. However, the association between PAPPA2 and efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. Methods: Forty-one NSCLC patients receiving anti-PD-(L)1 (China cohort, n = 41) and seven public cohorts with whole-exome sequencing (WES) data were included to analyze the performance of PAPPA2 mutation as an indicator stratifying patients benefit from ICIs, consolidating a discovery set (n = 34) and two validation sets (NSCLC validation set, n = 172 ; SKCM validation set, n = 210). The mechanism was analyzed in the Cancer Genome Atlas (TCGA) database (n = 1467). Results: In the discovery set, patients with PAPPA2 mutation exhibited a significantly predominant PFS (HR, 0.11 [95% CI, 0.01-0.83]; P = 0.01), ORR (100.0% vs 21.4%; P < 0.001) and durable clinical benefit (DCB, 83.3% vs 32.1%; P = 0.012) compared to those with wide-type PAPPA2, consistent in NSCLC validation set (PFS, HR, 0.3 [95% CI: 0.16-0.56], P < 0.001; ORR, 70.8% vs. 20.9%, P < 0.001; DCB, 83.3% vs. 36.5%, P < 0.001) and SKCM validation set (OS, HR, 0.49 [95% CI: 0.31-0.78]; P = 0.002; ORR, 34.1% vs. 16.9%, P = 0.039; DCB, 50.0% vs. 30.7%; P = 0.036). Similar results were observed in multivariable models. In contrast, no association between PAPPA2 mutation and OS or PFS was observed in TCGA datasets, suggesting that PAPPA2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, we found that PAPPA2 mutation was significantly associated with higher activated CD4 memory T cells and lower Treg cells in tumor immune microenvironment, related with higher TMB ( P < 0.001) and neoantigen load ( P < 0.001). In addition, gene set enrichment analysis (GSEA) analysis revealed that PAPPA2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway. Conclusions: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies.
The expression of aryl hydrocarbon receptor predicts responses to anti-PD-1 antibodies in non-small cell lung cancer.
Authors: Han Si-Chong , Yang Yaning , Wang Gui-Zhen , Fang Wenfeng , Zhang Li , Wang Yan , Zhou Guang-Biao 
Published: June 2022

2628 Background: Blockade of programmed cell death receptor 1 (PD-1) by antibodies such as pembrolizumab has revolutionized treatment for patients with non-small cell lung cancer (NSCLC). However, a significant number of patients achieve only marginal benefit. The predictive abilities of the frequently used biomarkers, including programmed cell death 1 ligand (PD-L1) and tumor mutation burden (TMB), are yet limited, highlighting the urgent need for more reliable biomarkers. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that controls the transcription of its targets including PD-L1. Whether AhR could be used as a predictive biomarker for response to PD-1 blockade immunotherapy in NSCLC warrants further investigation. Methods: We collected formalin-fixed, paraffin-embedded (FFPE) slides from 104 NSCLC patients before PD-1 blockade immunotherapy treatment, who had sufficient follow-up data for progression-free survival (PFS), and detected the expression of nuclear localized AhR (AhRN) and membrane localized PD-L1 (PD-L1M) with multiplex immunohistochemistry (mIHC). H-score was applied to characterize the specific value with the following formula [1 × (% cells intensity =1) + 2 × (% cells intensity = 2) + 3 × (% cells intensity = 3)]. Survival curve for each group was estimated by the Kaplan–Meier method and log-rank test. The diagnostic performance was assessed with the area under the receiver operating characteristic (ROC) curve (AUC), which was calculated based on the Wilcoxon rank-sum test. All statistical tests were two-sided and P values less than 0.05 were considered statistically significant. Results: Both AhRN and PD-L1M could distinguish responders from non-responders, and patients with higher H-score had longer PFS than those with lower H score. The AUC of AhRN was 0.804 (95 % CI: 0.721-0.881), higher than that of PD-L1M (0.714; 95 % CI: 0.618-0.811) and AhRN+PD-L1M (0.743; 95 % CI: 0.649-0.837), indicating AhRN might show better predictive capacity to the efficacy of PD-1 blockade immunotherapy than PD-L1M. Besides, AhRN exhibited the most significant accuracy in prognosis prediction, since the hazard ratio (HR) of AhRN was 0.1529 (95 % CI: 0.07704-0.3033, P<0.0001), significantly higher than that of PD-L1M [HR:0.283 (95 % CI: 0.1525-0.525, P<0.0001)] and AhRN+PD-L1M [HR: 0.2456 (95 % CI: 0.1309-0.4607, P<0.0001)]. Yet, among the 54 smokers, AhRN+PD-L1M was the best classifier for the efficacy of immunotherapy, of which the AUC was 0.8937 (95 % CI: 0.816-0.971) and HR was infinitely approaching 0 ( P<0.0001). Conclusions: AhR might be a reliable predictive biomarker for PD-1 blockade immunotherapy in NSCLCs.
PD-L1 expression and microsatellite instability in tumors of unknown primary site.
Authors: Neif Joao , Lazarini Maria , Bonatelli Murilo , Berardinelli Gustavo Noriz , Preto Daniel D Almeida , Araujo Hadson Silva , da Silva Vinicius Duval , Pinheiro Celine Marques , Reis Rui Manuel , Carcano Flavio Mavignier 
Published: June 2022

2635 Background: Cancer of unknown primary site is a heterogeneous group of tumors for which the origin remains unknown, despite detailed investigation. Its clinical presentation occurs due to symptoms resulting from metastasis, which can be influenced not only by biological processes of the tumor, but also due to regulatory processes in the tumor microenvironment such as PD-L1. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status as well as co-occurrence with PD-L1 expression is poorly evaluated. The aim of this study was to evaluate the expression of PD-L1 and the status of MSI in tumors of unknown primary site and their possible associations with clinical-pathological characteristics and clinical outcomes in patients with this type of tumor. Methods: The PD-L1 expression was evaluated using the immunohistochemistry technique and measured by CPS and TPS scores. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Overall survival was analyzed using the Kaplan Meier method and comparisons of the curves using the log rank test. Results: Of the 121 conclusive cases for MSI status, only two cases (1,6%) were MSI-High. PD-L1 expression, assessed by both TPS and CPS, was positive in approximately 18% of 108 conclusive cases. PD-L1 expression is significantly less frequent in patients with a predominance of hepatic or bone metastasis and more frequent in patients with a predominance of nodal metastasis. The median overall survival was about 4 months, and the predominance of liver metastases was associated with a worse prognosis, while the use of chemotherapy and low ECOG-PS were associated with better survival. PD-L1 expression was associated with better overall survival. Conclusions: PD-L1 is expressed in a subset of patients with cancer of unknown primary site, while MSI is a rare event. It is necessary to better explore the microenvironment of this type of tumor as well as the role of immunotherapy to change such a dismal clinical outcome.
Phase Ia dose-escalation study of the anti-BTLA antibody icatolimab as a monotherapy in patients with advanced solid tumor.
Authors: Schilder Russell J. , Powderly John D. , Park Haeseong , Bilen Mehmet Asim , McKean Meredith , May Rena , Feng Hui , Yao Sheng , Keegan Patricia , Naing Aung 
Published: June 2022

2643 Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Icatolimab (TAB004 or JS004) is a humanized IgG4 monoclonal antibody (mAb) with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In preclinical studies, icatolimab monotherapy suppressed tumor growth in murine tumor models using human BTLA knock-in mice. In this first-in-human dose-escalation study, we report the preliminary safety and efficacy of icatolimab as a single agent in patients with advanced solid tumors. Methods: Eligible patients with advance solid tumors refractory to standard therapies were enrolled in this study. Icatolimab was administered at escalating doses of 0.3, 1, 3 and 10 mg/kg intravenously Q3W and followed by dose expansion in 3 and 10 mg/kg cohorts until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Results: A total of 25 patients with solid tumor were enrolled in the Part A of this phase I study (NCT04137900). The median age was 62 (range 32-85) years with 16 (64%) male patients. Patients were heavily pretreated with a median of 4 prior lines of therapy. Fifteen (60%) patients received and progressed upon prior anti-PD-1/L1 therapy. By the data cutoff date of December 31, 2021, the median follow-up was 32 weeks. No DLT was observed. 24 (96%) patients experienced treatment emergent adverse event (TEAEs), with 7 (28%) experienced grade 3 TEAEs. No grade 4 or 5 TEAE occurred. The incidence or severity of AE was not associated with the dose. The most common TEAEs were fatigue (32%), abdominal pain (20%), diarrhea (16%), arthralgia (16%), aspartate aminotransferase increased (16%), constipation (16%), and contusion (16%). One (4%) TEAE led to discontinuation of study drug. Four (16%) patients experienced immune related AE. Among 19 evaluable patients by the cutoff date, 1 confirmed PR (melanoma) and 6 SD were observed as assessed by the investigator per RECIST v1.1. The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. BTLA receptor was fully occupied in the 3 and 10 mg/kg cohorts. The mean elimination half-life of icatolimab was 7.5 to 19.2 days in four dose cohorts. Biomarker analysis indicated co-expression of HVEM and CD8 was associated with favorable response. Conclusions: Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Clinical trial information: NCT04137900.
Phase I study of the efficacy and safety of IBI319 in patients with advanced malignant tumors.
Authors: Wu Yi-Long , Zhou Jianfeng , Zhou Qing , Zhang Huilai , Ding Kefeng , Zhou Jianying , Wang Shuyan , Ji Wenting , Zhang Chengli , Wang Yanqi , Ni Ping 
Published: June 2022

2646 Background: IBI319 is a recombinant fully human anti-CD137/PD-1 bispecific antibody. In preclinical studies, IBI319 demonstrated a better anti-tumor efficacy and safety. Here we report the initial results from the first-in-human study of IBI319 in patients with advanced malignancies. Methods: Enrolled patients (pts), ECOG PS ≤ 1, had advanced solid tumors or hematological malignancies and failed standard treatment. This phase 1 monotherapy dose-escalation includes accelerated titration (0.03 and 0.1mg/kg) and conventional 3+3 dose escalation (0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg). IBI319 is administered intravenously every 14 days after dose-limiting toxicity (DLT) evaluation. Objectives include evaluation of safety, DLT, pharmacokinetic (PK) and antitumor activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. Results: At cutoff date of February 10, 2022, 21 pts were enrolled (median age 55 years; 81.0% male; 19.1% ECOG PS 1; 52.4% advanced solid tumors). The following dose levels have been evaluated; 0.03 mg; 0.1 mg; 0.3 mg; 1 mg; 3 mg and 6 mg. Dose escalation is ongoing. The maximum tolerated dose has not been reached. Treatment-emergent adverse events (TEAEs) was reported in 15 out of 21 (71.4%) pts, among which 1 pts had back pain and nausea of grade 3. The most common TEAEs ( > 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Eleven pts (52.4%) experienced treatment-related AEs; none were grade 3 or higher. The most common TRAEs ( > 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Importantly, no drug-related elevations in transaminases (ALT, AST) or bilirubin have been seen. No DLT was observed. PK analysis of IBI319 demonstrated consistent exposure with linear PK. For 14 evaluable pts, 1 classical Hodgkin lymphoma patient achieved PR as best response. Conclusions: IBI319 demonstrates good tolerability in patients with advanced solid tumors or hematological malignancies, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. Clinical trial information: NCT04708210.
Pan-cancer (ca) analysis of the safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) living with HIV (PLWH): Results from the international CATCH-IT consortium.
Authors: El Zarif Talal , Nassar Amin , Adib Elio , Huang Jiaming , McKay Rana R. , Dobbs Ryan , Dizman Nazli , Drolen Claire , Kozaily Elie , Saeed Anwaar , Nebhan Caroline , Lorentsen Michael , Baena Javier , Dalla Pria Alessia , Baden Lindsey , Ramaswami Ramya , Choueiri Toni K. , Lurain Kathryn Anne , Sonpavde Guru P. , Naqash Abdul Rafeh 
Published: June 2022

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct <200 cells/µL while 12/136 (9%) had VL ≥400 copies/mL. irAEs of any grade occurred in 43 (21%) pts and 13 (7%) were grade ≥3 while 19 (9%) required steroids. Pts with CD4 ct <200 cells/µL experienced fewer irAEs than pts with CD4 ct ≥200 cells/µL (2/36 vs 26/97; p<0.01). The incidence of any grade irAEs was similar between pts with CD4/CD8 ratio <0.4 vs ≥0.4 (8/54 vs 18/72; p=0.16) and between pts with HIV VL ≥400 vs <400 copies/mL (1/12 vs 28/124; p=0.46). Clinical outcomes are shown in the table below. Among 29 pts with met non-small cell lung ca (NSCLC) with available CD4 ct, the ORR of pts with CD4 ct <200 cells/µL was 13% (95% CI:0-53) vs 38% (95% CI:18-62) in pts with CD4 ct ≥ 200 cells/µL (1/8 vs 8/21; p=0.38). Conclusions: In the largest dataset to our knowledge, we demonstrate tolerability and activity of ICI among PLWH regardless of CD4 ct and HIV VL levels. CD4 ct <200 cells/µL may be associated with a lower incidence of irAEs. An analysis of a larger cohort is underway. [Table: see text]
Safety and efficacy of etigilimab in combination with nivolumab in select recurrent/advanced solid tumors.
Authors: McKean Meredith , Dumbrava Ecaterina Elena , Hamid Omid , Merriam Priscilla , Mettu Niharika B. , Call Justin A , Kapoun Ann M. , Lucas Jennifer , Seetharam Mahesh , Vaishampayan Ulka N. , Weroha Saravut John , Krishnan Suba , George Angela Joy 
Published: June 2022

2651 Background: Etigilimab (etig), a humanized IgG1 monoclonal antibody, blocks TIGIT interaction with PVR (poliovirus receptor) and inhibits downstream signalling with target cell killing. Etig +/- nivolumab (nivo) showed acceptable safety and preliminary activity in a FIH Phase 1a/b study in solid tumors. ACTIVATE, an open-label Phase 1b/2 basket study is evaluating further efficacy, safety, tolerability and PK/PD of etig+nivo. This is a preliminary efficacy and safety analysis from ACTIVATE. Methods: Subjects with advanced/metastatic solid tumors without curative/standard of care therapies are given IV etig+nivo Q2W until disease progression or intolerable toxicity. Six open cohorts are enrolling in parallel: endometrial cancer (post-front-line platinum), endometrial cancer (2-3 prior lines), PD-L1+ checkpoint-inhibitor-naïve (CPI-n) cervical cancer, rare cancers (germ cell tumor (GCT), sarcoma, uveal melanoma), ovarian cancer (post-front-line platinum) and TMB-h/MSS, (TMB >10mut/mb) tumors. Tumor assessments are done every 8 weeks following baseline scan. Primary endpoint is investigator-assessed ORR by RECIST 1.1. Secondary endpoints include duration of response and safety. Results: Of 27 efficacy-evaluable subjects enrolled in the 6 open cohorts with minimum 1 staging scan or radiological/clinical progression at data cut-off of 02/10/22, 12 had clinical benefit with 1 complete response (CR), 2 partial responses (PRs) and 9 stable diseases (SDs) and 15 had radiological/clinical progressive disease (PD), with an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Conclusions: Etig+nivo is safe and well tolerated with no new safety signals. Early efficacy was noted in cervical cancer (1CR, 1PR and 1SD) and uveal melanoma (3 SDs >20 weeks). Encouraging activity was also noted in ovarian cancer and post-CPI treated TMB-H/MSS NSCLC. These early data support continued evaluation of the combination of etig+nivo. Clinical activity was notable as below. Clinical trial information: NCT04761198. [Table: see text]