bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of synthetic lethality gene pairs in the DNA damage response pathway in response to immunotherapy in pan-cancer.
Authors: Huang Hongyan , Liu Miao , Zhang Ding 
Published: June 2023

2567 Background: The concept of synthetic lethality (SL) refers to the phenomenon where the simultaneous loss of function of two genes leads to cell death, while the loss of function of either gene alone has no effect. PARP inhibitors target poly ADP ribose polymerase (PARP) enzymes, which are involved in DNA repair, are the successful cases of utilizing synthetic lethality-based therapy to treat cancers with DNA damage response (DDR) deficiency. The prognosis for cancer patients already has a combination of synthetic lethal mutations especially in DDR pathway can vary and it is not yet fully understood how these mutations may impact the response to immunotherapy. Methods: SL gene combinations in the DDR pathway were screened out from SynLethDB database (http://histone.sce.ntu.edu.sg/SynLethDB/). The immunotherapy cohort (Samstein 2019, n=1661) and non-immunotherapy cohort (Zehir 2017, n=10336) with solid tumor were used to Kaplan-Meier analyze the correlation between SL gene combinations and prognosis. TMB scores were compared between DDR co-mutation group and non DDR co-mutation group. For investigating the associations between immune infiltrates and genetic features, TIMER 2.0 database ( http://timer.cistrome.org/ ) was conducted to estimation of immune infiltration levels on DDR mutation genes in pan-cancer. Results: 430 pairs of DDR mutation combinations were used to subgroup stratification, the DDR co-mutation group was associated with worse prognosis in non-immunotherapy cohort (HR=1.305, p<0.0001) but better in immunotherapy cohort (HR=0.741,p<0.0061). Interestingly, the TMB score in the DDR co-mutation group was significantly higher than non DDR co-mutation group (mean 50.03 vs 8.868, p<0.0001) in immunotherapy cohort. The high-frequency mutation combinations (>10%) were ATM-POLE(14.40%), ATM-ATR (13.60%), ATR-BRCA2 (13.60%), ATM-BRCA2 (12.00%) and BRCA2-RECQL4 (10.40%), respectively. Comparing common immune component with statistically significant under different DDR mutant genes, the ATM-POLE co-mutation tumor tended to have more CD4+ T cell infiltration while the ATM-ATR co-mutation tumor appeared to have more myeloid dendritic cell infiltration. Conclusions: The combinations of DDR SL mutation tumor might result to worse prognosis whereas these patients might benefit from immunotherapy. Our results will help to shed light on the complex interplay for the combinations of SL mutation in DDR pathway between cancer cells and the immune system and provide new insights into the development of effective cancer treatments.
SpliceIO: A robust platform for the discovery and validation of splicing-derived neoantigens.
Authors: Arun Gayatri , Anderson Kendall , Manzanares Miguel Angel , Gera Sakshi , Zumrut Hasan , Smith Shaleigh , Floyd Taylor , Shah Sanjana , Habib Nayab , Trahan Devon , Akerman Martin 
Published: June 2023

2581 Background: Splicing dysregulation is a major hallmark of cancer, affecting tumor progression, metastasis, and therapy resistance. Aberrant alternative splicing plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Such neoantigens cannot be discovered using conventional DNA-based tools; they require specialized software for alternative splicing analysis using RNA-seq data. Methods: Envisagenics has developed SpliceIO, a proprietary software platform for splicing-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins or presented to immune cells through the MHC complex. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as their protein localization, MHC binding affinity, epitope accessibility and cancer pathway relevance. Here, we summarize the discovery and validation of novel splicing-derived neoantigens identified using SpliceIO in acute myeloid leukemia and colorectal cancer. Results: We analyzed >10,000 RNA-seq samples from the four tumor types and controls derived from 32 normal tissues. To maximize the prevalence of neoantigen target candidates in patient subpopulations, RNA-seq samples were pre-stratified using SpliceSlice, a proprietary software for spliceosomal profiling. As a result, patients sharing common spliceosome alterations were grouped into 11 coherent subsets that are distinct from normal tissue. Using this approach, we have discovered several promising candidates that we prioritized for experimental validations. SpliceIO target candidates were validated experimentally in cancer cell lines and primary tumor tissues to confirm RNA expression, translation, and membrane localization. Additionally, we performed proteomics to evaluate the presence of neopeptides generated from the unique splicing events. Using this approach, we have discovered and validated several tumor specific splicing derived neoantigens that are also recurrent in >15 % of the population. Conclusions: Together, our results strongly support the role of aberrant splicing as a major source of tumor-specific neoantigens. Our combined computational and experimental approach promotes novel target discovery, enabling the development of novel immunotherapeutics for cancer treatment.
Clinical outcomes in phase 1 clinical trials (Ph1-CT) when treating patients (pts) with novel immunotherapy (IT) agents at early lines for advanced disease.
Authors: Soto Juan José , Llop-Serna Sandra , Stradella Agostina , Villanueva Rafael , Calvo Mariona , Jove Maria , Ruffinelli Jose Carlos , Cuadra Amor Carmen , Salazar Ramon , Gil Gil Miguel J. , Gil-Martin Marta , Oliva Marc , Martin Liberal Juan 
Published: June 2023

2586 Background: Cancer pts can be offered IT drugs within Ph1-CT before having exhausted standard of care (SoC) therapies. However, whether this strategy may improve pts’ outcomes remains unclear. We assess the benefits of receiving novel IT compounds within Ph1-CT at early lines for advanced disease. Methods: We retrospectively reviewed a correlative series of pts with advanced solid tumors treated with IT within Ph1-CT at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain, from January 2018 to July 2022. Primary aim was to assess clinical outcomes measured by median progression-free survival (mPFS) and median overall survival (mOS) according to number of prior lines (PL) for recurrent/metastatic disease, prior IT, availability of alternative SoC in our country, IT biomarker-selected population and grade 3-4 toxicity (G3-4 Tox) by multivariate analysis (MVA). Overall response rate (ORR) was evaluated by RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response + stable disease for ≥6 months (m). PFS/OS were calculated by Kaplan-Meier method. Log-rank test was used for comparisons. MVA was performed by Cox regression. Results: A total of 228 pts were assessed: IT monotherapy = 49 (21.5%), IT combinations = 179 (78.5%) (IT+IT = 111 [48.7%], IT+targeted therapy = 24 [10.5%], IT+others = 44 [19.3%]). Forty-nine (21.5%) pts were included according to IT biomarkers (PDL1, TIM3 expression, MSI-H, others). Median age was 62 y (24-83), 62.7% were men. All pts had ECOG ≤1. The 4 most frequent cancer types were HNSCC (19.7%), NSCLC (15.4%), glioblastoma (10.5%) and urothelial (10.1%). Number of PL: 0 = 33 (14.5%) pts, 1 = 92 (40.3%) pts, ≥2 = 103 (45.2%) pts. Sixty-three (27.6%) pts had received prior IT and 159 (69.7%) had alternative available SoC. Overall G3-4 Tox rate was 21.5% (20.6% in pts IT-treated). ORR and CBR were higher in pts IT-naïve than in pts IT-treated (21.2% vs 12.7% [p .18] and 35.7% vs 25.4% [p .26], respectively). With a median follow-up of 19m, overall mPFS and mOS were 3.5m (2.7-3.9) and 9.8m (8.5-11.5), respectively. In the MVA, lesser number of PL, SoC availability and biomarker selection positively impacted on mOS. After Ph1-CT treatment, 111 (48.7%) pts received further treatment: 19.3% within clinical trial, 29.4% with SoC. Conclusions: In our cohort of pts treated within IT Ph1-CT, those with less PL of treatment, with available alternative SoC and/or selected by biomarker achieved higher PFS and OS. These results suggest that treating pts with novel IT agents at early lines might positively impact on survival. [Table: see text]
Differences in real-world pembrolizumab dosing patterns (every 3 weeks versus every 6 weeks) across a large cancer center network.
Authors: Natesan Divya , Chablani Priyanka Vinod , Wang Hong , Jelinek Mark , Rosenzweig Margaret Q. , Wong Risa Liang 
Published: June 2023

2592 Background: Pembrolizumab (pembro) is an intravenous immune checkpoint inhibitor used for anti-cancer treatment, with equivalent monotherapy dosing options of 200 mg every 3 weeks (Q3W) or 400 mg every 6 weeks (Q6W). Pembro Q6W dosing was approved for use in April 2020 after the Q3W dose had already been established. As pembro dosing patterns in real-world practice are not well-described, we evaluated this in a large cancer center network consisting of a central site (CS) and 36 community network sites (NS). Methods: We retrospectively reviewed the charts of all patients who received pembro monotherapy for cancer treatment between 4/2020 – 4/2022 at UPMC Hillman Cancer Center sites across the state of Pennsylvania, as well as sites in New York and Ohio. We performed statistical comparisons using the Fisher’s exact test and Wilcoxon rank-sum test. Results: We identified 1,640 patients who received pembro monotherapy, including 377 patients at the CS and 1,263 patients in the NS, with characteristics displayed. Pembro Q6W dosing was significantly more common at the CS than in the NS (42% vs. 15%, p<0.0001). When analyzed by tumor type, pembro Q6W dosing was significantly more common at the CS than in the NS for head & neck (53% vs. 11%, p<0.0001), thoracic (49% vs. 15%, p<0.0001), skin (60% vs. 19%, p<0.0001), and genitourinary (30% vs. 16%, p=0.015) cancers, but not for other tumor types. Within the NS, 30% (11/36) of sites only utilized pembro Q3W dosing and never administered Q6W dosing to patients. Of note, some patients who received pembro Q6W dosing received pembro Q3W dosing initially, either as part of a pembro-containing multidrug regimen or as monotherapy. Excluding patients initially treated with a multidrug regimen to reduce confounding factors, we found that of the patients who received pembro Q6W dosing, 47% (65/137) at the CS and 28% (48/169) in the NS were initially treated with pembro Q3W monotherapy before transitioning to Q6W monotherapy (p=0.0008). Conclusions: In our large cancer center network, pembro Q6W dosing was significantly more common at the CS than in the NS. Switching from pembro Q3W to Q6W dosing was also significantly more common at the CS. Further work is needed to clarify the patient, provider, and institutional factors influencing differences in pembro dosing patterns in real-world practice, as well as the impact of dosing patterns on care delivery outcomes such as cost and accessibility. [Table: see text]
Phase II basket trial evaluating the efficacy of pembrolizumab (PE) combined with vorinostat (VO) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma (SCC).
Authors: Le Tourneau Christophe , Bigot Frédéric , Vansteene Damien , Kamal Maud , Ghiringhelli François , Mazzarella Luca , Borel Christian , Chaltiel Raphael , You Benoit , Gomez-Roca Carlos A. , Cousin Sophie , Coquan Elodie , Lambert Aurélien , Saada-Bouzid Esma , Durando Xavier , Legrand François , Lusque Amellie , Andre Fabrice , Filleron Thomas 
Published: June 2023

2597 Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. Patients and Methods: PEVOsq is an open-label, non-randomized, multi-center, basket phase II trial, evaluating the efficacy of pembrolizumab in combination with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of the cervix, head and neck, anus, vulva/vagina, penis, and lung. Patients had to be PD1/PD-L1 antagonist-naïve. There was no selection based on PD-L1 expression nor on HPV status, and no restriction in terms of prior lines of treatments. Pembrolizumab dose was 200 mg Q3W IV, and vorinostat 400 mg QD PO. Sample size was determined for each cohort using an A’Hern design. Primary endpoint was objective response rate (ORR) according to RECISTv1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Results: Among 112 included patients, 111 were evaluable for safety and 107 for efficacy. The lung cohort was closed prematurely because of lack of enrollment. Median age was 61 years old [range: 18-85] and the median number of prior lines of therapies was 1 [range: 0-4]. ORR, PFS, G3/4 treatment related adverse events (TRAE), and OS are reported. 28 patients (26%) had an objective response and median DOR was 9.7 months [95%CI: 3.1-15.2]. Results per PD-L1 status will be presented at the meeting. Pembrolizumab and vorinostat were stopped for toxicity in 9% and 39% of patients, respectively. 60% of patients had a dose-reduced of vorinostat for toxicity. Pembrolizumab safety was as expected. Main vorinostat toxicities included hematological toxicity, gastrointestinal disorders, and asthenia and creatinine increase. Conclusions: Pembrolizumab combined with vorinostat showed encouraging antitumor activity in squamous cell carcinoma with unselected PD1/PD-L1 status, especially in cervical and anal cancer, although vorinostat dose had to be reduced because of toxicity in a substantial proportion of patients. Clinical trial information: NCT04357873 . [Table: see text]
PD-1 inhibitors combined with radiotherapy and GM-CSF, sequentially followed by IL-2 (PRaG 2.0) regimen in advanced refractory solid tumors: A prospective, multicenter, single-arm clinical trial.
Authors: Xing Pengfei , Yang Jiabao , Xu Meiling , Wang Jian , Han Dali , Kong Yuehong , Zhang Junjun , Zhang Liyuan 
Published: June 2023

2603 Background: Low frequency of durable responses in patients treated with immune checkpoint inhibitors demands taking complementary strategies in order to boost immune responses against cancer. Our previous PRaG trial also demonstrated that PD-1 inhibitors in combination with radiotherapy and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with advanced refractory solid tumors (ChiCTR1900026175). In an effort to further enhance efficacy, we conducted the PRaG 2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG regimen by incorporating interleukin-2 (IL-2). Methods: The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The primary endpoint was Progression-Free Survival (PFS). Results: As of 31st October 2022, 51 patients were enrolled in the study, and 42 completed at least one tumor assessment. The median Progression-Free Survival (PFS) was 5.8 months, and the median overall survival (OS) was 13.5 months. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 61.9% according to RECIST version 1.1. Lower plasma levels of Interleukin (IL)-6 and IL-17 at baseline were found to be associated with improved PFS. Treatment-related adverse events (TRAE) experienced in 34 of 42 (78.6%) patients, with 4 patients (9.5%) experiencing Grade ≥ 3 TRAEs. TRAEs leading to discontinuation of all study treatments occurred in three patients (7.1%). Conclusions: The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with radiotherapy, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors, with an acceptable benefit/risk profile. Clinical trial information: NCT04892498 .
Durvalumab + tremelimumab in biologically selected advanced/metastatic solid tumors.
Authors: De La Fouchardiere Christelle , Gomez-Roca Carlos A. , De Montfort Aymeric , Italiano Antoine , Gilabert Marine , Tredan Olivier , Korakis Iphig nie , Ray-Coquard Isabelle Laure , Rochefort Pauline , Dufresne Armelle , Cousin Sophie , Le Tourneau Christophe , You Benoit , Bertucci Francois , Cassier Philippe Alexandre , Attignon Valéry , Mayet Romaine , Garin Gwenaelle , Pérol David , Blay Jean-Yves 
Published: June 2023

2604 Background: Tremelimumab (T) in combination with Durvalumab (D) is approved by the FDA for the treatment of unresectable hepatocellular carcinoma and metastatic non–small cell lung cancer. We prospectively examined its clinical activity in a cohort of biologically-selected advanced/metastatic solid tumors from the MOST Plus clinical trial (NCT NCT02029001). Methods: Adult patients (pts) previously treated by at least one prior line but immunotherapy-naive were eligible if their tumor harbored TMB-H (>10mut/Mb) and/or MSI/dMMR (by PCR and IHC tests), and/or PD1/PD-L1/CTLA4 amplification and/or POLD1 or POLE mutation. T was administered for up to 4 cycles (75mg, IV, Q4W) and D (1500mg, IV, Q4W) until disease progression, unacceptable toxicity or patient/investigator decision. Tumor response was assessed as per RECIST 1.1 and adverse events reported according to NCI-CTCAE v4.03. Results: 70 patients were enrolled (24 male, median age: 65 years [33-88], MSI n=56, TMB-H n=10, PDL1 and PDL2 ampl. n=1, POLE mut. n=1, MSH6 mut. n=1, MSH2 mut. n=1). The median number of prior lines of systemic therapy was 1 (range: 0-4). Main tumor types were colorectal (44%), endometrial (19%), and stomach (7%) carcinomas. As of October 2022, overall response (ORR) rate was 52.8% (21.4% CR, 31.4% PR). With a median follow-up of 37 months, median PFS and OS were 8.4 months [95% CI: 4.4- 22.1] and 37.2 months [95% CI: 10.4-NE], respectively. Median duration response of response was not reached. Overall, 24.3% of patients experienced at least one serious treatment-related (TR) adverse event. Two TR-deaths were reported (haemophagocytic lymphohistiocytosis and nephritis). ORR, median PFS and OS are reported. Conclusions: T+D is a highly efficient combination in biologically selected tumors leading to a high complete response rate. Enrolment is still ongoing, to further evaluate the utility of a maintenance treatment, i.e the optimal treatment duration. Clinical trial information: NCT02029001 . [Table: see text]
Prospective cardiovascular surveillance of immune checkpoint inhibitor-based combination therapy in patients with early-stage, triple-negative breast cancer.
Authors: Venkatesh Vishnu , Yen Christine , Zhang Ray , Rao Anjali , Chandra Alvin , Zaha Vlad , Vallabhaneni Srilakshmi , Zhang Kathleen W 
Published: June 2023

2607 Background: Both pembrolizumab and anthracyclines (AC) can cause adverse cardiovascular events; combination therapy is approved for high-risk, early-stage, triple-negative breast cancer (TNBC) and may further increase real-world cardiovascular risk. Cardiac surveillance with serial troponin measurements has been advocated in this population, though evidence supporting this approach is lacking. Methods: High-sensitivity troponin I (hs-TnI) was prospectively measured at baseline and with each treatment cycle in cancer patients receiving immune checkpoint inhibitors (ICI) at a single center as part of an institutional surveillance protocol for ICI-related adverse events from 2020-2022. Acute cardiac injury was defined as ≥1 abnormal hs-TnI value (>17ng/dL in women and >35ng/dL in men) with normal baseline hs-TnI, or at least 20% increase in hs-TnI from abnormal baseline. The incidence of acute cardiac injury and all-cause mortality were compared between patients receiving ICI in combination with AC versus ICI without AC. Results: Among 215 patients treated with ICI with baseline and ≥1 follow-up hs-TnI value, 28 patients (13%) received ICI with AC, all of whom were women with early-stage TNBC receiving pembrolizumab and AC-containing chemotherapy. 187 patients (87%) received ICI without AC for other oncological indications. Patients receiving ICI with AC were younger and more likely to be female than patients receiving ICI without AC (p<0.001) with lower rates of smoking, hypertension, and diabetes (p<0.04). Acute cardiac injury was observed in 33 patients, 21% of those receiving ICI with AC (N=6) and 14% of those receiving ICI without AC (N=27; p=0.34). Among these 33 patients, 2 patients were treated for ICI-associated myocarditis (1 receiving ICI with AC, 1 receiving ICI without AC); 67% of those receiving ICI with AC (N=4) were continued on ICI while only 30% of those receiving ICI without AC (N=8) were continued on ICI (p=0.16). The rate of all-cause mortality was significantly lower in patients receiving ICI with AC (0%) as compared to patients receiving ICI without AC (40%, p<0.001). Conclusions: Among women with early stage TNBC receiving pembrolizumab with AC, the rate of acute cardiac injury by surveillance troponin measurements was numerically but not statistically higher than for patients receiving ICI without AC for other oncological indications, though the rate of all-cause mortality was significantly lower. These findings suggest that surveillance troponin monitoring may have less clinical utility among women with early-stage TNBC receiving ICI-based combination therapy as compared to other patient populations receiving ICI. Further study is needed to understand the mechanistic and prognostic significance of acute cardiac injury in patients with TNBC receiving ICI-based combination chemotherapy.