bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliable determination of genetic ancestry from cancer-derived molecular data.
Authors: Belleau Pascal , Deschênes Astrid , Tuveson David A. , Krasnitz Alexander
Published: June 2022

e13588

Background: There is ample epidemiological evidence that, for multiple cancer types, incidence, stage at presentation and outcome correlate strongly with the patient’s race or ethnicity. Recent examination of cancer data repositories such as TCGA has revealed has revealed, for a number of cancers, ancestry dependence of somatic mutation spectrum and transcriptional phenotype. Further progress in genetic ancestry-oriented cancer research requires the ability to perform accurate and robust ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. Such inference is potentially challenging, given widespread somatic alterations in tumor genomes, observed in multiple types of cancer. Methods: In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we develop a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. We then infer the substitute individual’s ancestry, using well-established methods of population genetics and relying on the 1000 Genomes collection as a population reference data set. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference specifically for a given molecular profile, and separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. Results: We test our approach for three representative cancer types: pancreatic and ovarian cancers as representative of epithelial tumor types, and acute myeloid leukemia as an example of hematopoietic malignancy. We consider tumor-derived data acquired by the whole-exome sequencing, by exome sequencing restricted to a panel of cancer-associated genes, and by RNA sequencing. For all three cancer types, and across the three sequencing platforms, we demonstrate that global, continental-level ancestry of the patient can be inferred accurately and robustly. Specifically, we find the inferred ancestries to be in at least 97% agreement with the golden standard of the ancestry derived from the matching cancer-free genomes. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Conclusions: Our study demonstrates that vast amounts of existing cancer-derived molecular data are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients' self-identification by ancestry. Furthermore, the procedure we developed facilitates ancestry-oriented research using archived tumor tissue specimens, for which matching cancer-free specimens may not be available.
Characteristics and outcomes of COVID-19 in adult cancer patients: Tertiary cancer center experience.
Authors: Ababneh Hazim , Alqadi Fadwa , Ma'koseh Mohammad , Halahleh Khalid , Abo abed Layan , Akkawi Mohammad , Al-Rabi Kamal , Abdel-Razeq Hikmat
Published: June 2022

e13601

Background: The COVID-19 pandemic has led to deteriorated outcomes among immunocompromised patients, significantly impacting cancer patients. However, little is known about the impact of the COVID-19 pandemic on cancer patients in low and middle-income countries. Therefore, we sought to investigate the characteristics and clinical outcomes of cancer patients with COVID-19 treated at a single institution. Methods: A retrospective chart review was performed for cancer patients treated at King Hussein Cancer Center. Patients who were diagnosed with laboratory-confirmed SARS-CoV-2 infection by Real-time Polymerase chain reaction test between April 2020 and October 2020 were identified. Results: Overall, 327 COVID-19-infected cancer patients were included. At the time of COVID-19 diagnosis, the median age was 55 years (range, 18-87 years), 146 patients (45%) were males. The most common neoplasms were breast cancer (n = 90, 27.5%), gastrointestinal cancers (n = 60, 18.3%), and lymphoma (n = 36, 11%). The majority of patients had comorbidities (n = 200, 61%), of which hypertension and diabetes mellitus were the most common. Testing reason was presence of symptoms in 183 (56%) patients, previous exposure in 10 (3.1%), and before elective procedure in 142 (43.4%). 118 patients (56.5%) were hospitalized and 18 patients (5.5%) required admission to the intensive care unit (ICU). At the time of the last follow-up, 76% (n = 249) remained alive, and 24% (n = 78) died, among which death was considered to be COVID related in 41 (52.5% of deaths). Mortality was significantly increased in patients with comorbidities (29%, vs 15.7 %; p = 0.008), the use of cardiac medications (34.3% vs. 18.1%; p = 0.001), active cancer status vs. remission (28.2% vs 11.6% p = 0.002), receiving chemotherapy in the last four weeks (27.6% vs 16.4%, p = 0.028), and when testing reason was the presence of symptoms vs exposure and elective (37.7% vs. 10% and 7.7% p = < 0.001) respectively. Chemotherapy was delayed in 109 (33.4%) patients and permanently discontinued in 57 (17.5%) patients. Among patients required hospitalization and needed ICU admission, mortality rates were 55.1% and 88.9% respectively. Conclusions: COVID-19 infection is associated with significant mortality and negatively affects treatment plans in cancer patients. A follow-up study will be needed to evaluate the effect of vaccination on the outcomes.
Improving quality of life by promoting patient-provider communication and optimizing social support using a digital health platform.
Authors: Saria Marlon Garzo , Kesari Santosh
Published: June 2022

e13622

Background: The patient experience, including symptom burden, is often disease-specific and dependent on host factors, the environment, and the tumor itself. Patients with a previous diagnosis of breast cancer are often subjected to multiple and aggressive treatment modalities compounding the already existing symptom burden related to the disease. Digital health can potentially increase patient engagement, close communication gaps between patients and providers, improve providers’ ability to stratify patient populations and adapt services, enable patients and families to access convenient and cost-effective care, and improve decision-making by patients and providers. The primary purpose of this pilot study was to evaluate if the use of a digital health platform can improve quality of life in patients with breast cancer. Methods: Patients with diagnosis of breast cancer were enrolled in a nonblinded, randomized, controlled trial of a digital health platform in self-reporting and monitoring of cancer and cancer-treatment related symptoms compared with usual care. All participants were asked to register in an online mobile application called CancerLife. This novel cancer social network experience provides patients social support through their care journey while at the same time collects patient-reported outcomes displayed inside reports that they can share with their providers. CancerLife automatically randomized each participant and assigned them to the experimental or control arms. The control arm received usual care provided for in the clinics. This group did not have access to the social network, reports or any other intervention or digital tools associated with CancerLife. Participants were asked to self-report their quality of life using the European Quality of Life Survey (EQ-5) every three weeks. Participants in the treatment arm were asked use the CancerLife at least 1 times per week for up to 24 weeks. Participants were also asked to share their print-out report directly with their care team and were instructed to email the report to their care team via their patient portal. Welch’s Two Sample t-test was performed to measure any statistical difference in the mean scores within each group for each time period. Results: CancerLife users had significant improvements in their scores at 9, 12, and 18 weeks; the improvement at 15 weeks was not significant. By contrast, the control group did not have significant improvements in their scores in any of the time periods. Conclusions: Breast cancer patients who were users of CancerLife’s app have more improvement in their Quality-of-Life Scores than randomly assigned non-users. The improvements seen with the use of CancerLife center on two things: improving communication from patient to physician about symptoms and offering patients social support which creates emotional resiliency. Clinical trial information: NCT03094741.
Recurrent venous thromboembolism in cancer patients treated with direct oral anticoagulants.
Authors: Talbot Alice , Dean Andrew Peter , Brennan Ciara , Talbot Thomas , Angelov Sophia
Published: June 2022

e13648

Background: Malignancy associated thrombosis places a significant clinical and financial burden on all major oncology services worldwide. Cancer patients are at an increased risk of thrombosis and large studies have suggested a subsequent increased mortality. (1) Some studies have recorded higher risk associated with certain chemotherapy regimens such as platinum-based agents and gemcitabine. (2) Guidelines for anticoagulation often recommend low molecular weight heparin (LMWH) as first line for malignancy associated thrombosis. (3) In recent years ASCO guidelines have added DOACs as an option for VTE treatment. (4) We herein describe eight cases of recurrent venous thromboembolism despite direct oral anticoagulation. Methods: Data was gathered from electronic patient records for cancer patients attending a single centre in Western Australia between 2016 and 2021. Radiology and medication records were used to confirm VTE diagnoses and subsequent treatment. This data was recorded on an excel file and analysed accordingly. Results: We identified 8 patients with recurrent VTE on DOACs. Median age of patients was 61 years (range 50-72). The most common associated malignancy was pancreatic cancer (n = 3). Other associated cancer types were ovarian (n = 2), lung adenocarcinoma (n = 2) and colorectal cancer(n = 1). Most patients had metastatic disease at time of first VTE(n = 5). The most common site of thrombosis was in the upper limb with 3 cases of initial VTE and 4 cases of recurrent VTE. All of these occurred in patients with peripherally inserted central catheters. (PICC) One patient had a left central retinal vein thrombosis resulting in complete loss of vision in that eye. All but one patient had received either platinum based chemotherapy or gemcitabine. Median time to initial thrombotic event was 4 months from diagnosis. Median time to recurrent thrombotic event was 3.5 months. Rivaroxaban was the most common DOAC used with initial VTE (n = 5). All other patients received apixaban (n = 3). All patients were switched to either LMWH (n = 6) or unfractionated heparin (n = 2) following recurrent VTE. 75% of patients did not have further thrombosis after switch to heparin. One patient had chronic thrombosis on subsequent scans and another patient had recurrent pulmonary embolism despite unfractionated heparin and vena cava filter insertion. Conclusions: Venous thromboembolism is a common complication of malignancy with significant associated morbidity and mortality. A high index of suspicion is needed in patients with clinical signs of recurrent VTE while on a DOAC, especially for those with PICCs. While DOACs are common for patient preference, the differing rates of VTE recurrences should be further investigated and considered in oncology prescribing practice going forward.
Defining the optimal millimeter threshold for target lesion inclusion in the Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) based on outcome prediction.
Authors: Gidwani Mishka , Chang Ken , Patel Jay Biren , Kim Albert Eusik , Gerstner Elizabeth R. , Huang Raymond Yi-kun , Kalpathy-Cramer Jayashree
Published: June 2022

e14003

Background: The Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) is the standard for therapeutic response assessment in brain metastases (BM) patients. The criteria relies on a human reader to annotate target (≥10 mm) and non-target (<10mm) lesions of interest based on unidimensional measurement of lesion diameter on brain MRI. The change in the sum largest axial diameter of 5 target lesions (RANO-BM diameter) is then used to categorize intracranial response into 4 categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Methods: Automating the RANO-BM criteria (AUTO-RANO-BM) has enabled the rapid modulation of the threshold diameter required for inclusion of a brain metastasis as a target lesion. In this study, diameters below the RANO-BM 10mm recommendation were utilized when calculating the RANO-BM diameter. The ability of the RANO-BM diameter to predict overall survival for BM patients was then evaluated in a Cox Proportional Hazards model. In a cohort of 175 immunotherapy-treated BM patients, the optimal threshold for the RANO-BM diameter as measured by Concordance Index (C-Index) was 5mm, suggesting that the RANO-BM criteria should be amended.
Prevalence and survival of gastrointestinal malignancies with brain metastasis: Surveillance, Epidemiology, and End Results SEER database analysis 2010-2018.
Authors: Alkrekshi Akram , Elantably Dina , Hammad Faris , Al Armashi Abdul Rahman
Published: June 2022

e14004

Background: Gastrointestinal (GI) cancers are amongst the leading causes of cancer-related death worldwide. GI cancers with brain metastasis on presentation are rare; however, the oncologist will intermittently encounter such patients. Unfortunately, there is a paucity of data to inform the prevalence and prognosis of GI cancers with brain metastasis, especially in light of therapeutic developments in the past decade and whether that might have influenced the survival. In this study, we measured the prevalence of brain metastasis secondary to primary GI malignancies at the time of diagnosis, the observed median survival, and Kaplan-Meier 2-years overall survival. The aim is to highlight the burden and prognosis of this population. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) Program 18 registry (2010-2018) database. We identified the total number of patients and patients with brain metastasis at the time of diagnosis for the following gastrointestinal cancers: esophagus, stomach, pancreas, colon, rectum, liver, intrahepatic biliary duct, and gallbladder. We obtained the prevalence, the observed median survival, and the 2-years survival using the Kaplan-Meier method. Results: The total number of cases, prevalence, median survival, and 2-years overall survival are shown in the table. The prevalence of brain metastasis at diagnosis was highest for esophageal cancer at 1.41%, followed by stomach 0.52%, and gall bladder 0.37%. The lowest incidence was small intestinal cancers at 0.13%. The median survival was short, ranging between 2 to 4 months for all studied cancers except for the small intestine and rectum at about six months. Kaplan-Meier 2-years survival was highest for the small intestine at 17%, and the worst was gallbladder, where no one survived at the end of the 24 months. Conclusions: Brain metastasis at the time of diagnosis of GI cancer remains rare. However, its presence portends an abysmal prognosis of 2-4 months. This study helps to inform the practicing oncologist of the current prevalence and prognosis of GI malignancies with brain metastasis on presentation. In addition, these findings encourage prompt involvement of palliative care, setting realistic expectations, and discussing goals of care once such a grave diagnosis is made.[Table: see text]
Efficacy and safety study of fotemustine and bevacizumab in patients with recurrent glioblastoma.
Authors: Sánchez Escudero Laura , Amor Urbano María , Garcés María Yeray Rodríguez , Murillo Fátima Toscano
Published: June 2022

e14041

Background: Glioblastoma (GBM) is highly vascularized tumor with elevated expression of vascular endothelial growth factor (VEGF). Bevacizumab (Bz) is a humanized monoclonal antibody against VEGF, which alone or associated with chemotherapy has obtained optimal results. However, the most suitable combination with bevacizumab is yet unknown. The objective of our study is to evaluate the efficacy and safety of Bz and fotemustine (Ft) in patients (pts) with recurrent GBM of the Huelva area and to compare our results with those published in the phase II study of the Italian Association of Neuro-oncology (AINO). Methods: Observational and descriptive study of the combination of Ft-Bz in GBM at first relapse after standard radiotherapy and TMZ concomitant in the hospital area of Huelva during the years 2010-2021. We used the same therapeutic scheme of the phase II study of AINO and the IBM SPSS Statistics 22 program to analyze the variables. Results: 42 pts were treated, 16 women and 25 men. Median age 52 years. ECOG 0-1 in 85.4%. 65.9% and 92.7% received antiepileptics and corticosteroids, respectively. In 90.2%, methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was not evaluated. Previously, 56.1% of the pts underwent total/subtotal resection, 29.3% partial and 14.6% were not resected, followed by concomitant radiotherapy and temozolamide in 100% of cases. 35.7% relapsed in less than 3 months after adjuvant treatment. 61% presented unifocal relapse and 39% multifocal. 46.3% of the pts had stable disease, 24.4% partial response and 2.4% complete response. 22% presented grade 3-4 toxicity. The most frequent toxicities are listed in the table. The median progression-free survival (PFS) was 6 months (95% CI 4.18-7.82) and the median overall survival (OS) was 7 months (95% CI 4.22-9.77). Conclusions: The results obtained in our study were similar to those of other previously published studies of Bz in combination with Ft. Although PFS was slightly higher than the phase II study AINO, OS was lower, probably due to the inclusion of a high rate of rapid progressors pts. Treatment tolerance was similar to that in the phase II study AINO. An increase in hematologic adverse events stands out in our pts. Therefore, this scheme can be a valid alternative in the management of recurrent GBM.[Table: see text]
The use of a transient transfected expression system to deliver high quality bispecific T-cell engager drug product, NVG-111, to the clinic for a fraction of the cost and time associated with the development and use of a producer cell line.
Authors: O'Donovan Kieran , Bhatt Shivam , Baccaro Annalisa , Fernando Dinusha , Smith Angel , Gbajumo Ephraim , Bobrzynski Tomasz , McIntosh Jenny , Gore Jasmine , Nathwani Amit C. , Chester Kerry , Granger David
Published: June 2022

e14506

Background: Bispecific antibodies provide an opportunity to treat a diverse range of disorders because of their ability to simultaneously attenuate several different pathways precisely and effectively, thus overcoming many of the limitations of monoclonal antibodies. The adaptability of bispecifics has facilitated the generation of compelling preclinical data covering a range of malignant and non-malignant disorders. Proof-of-concept early phase clinical trials with bispecific antibodies, including bispecific T-cell engagers (TCE) have been hindered by manufacturing challenges, including a heavy burden in terms of time, quality and costs associated with generating a stable producer cell line. We took a more agile approach, using transient transfection to manufacture a ROR1×CD3 bispecific TCE drug product (DP [NVG-111]) for a first in human, Phase I/II clinical trial. Methods: A HEK293T cell line was expanded into 10-layer cell factories. The cells were transfected with a ROR1xCD3 scFv bispecific antibody (NVG-111) plasmid and incubated. Post incubation, the supernatant containing NVG-111 was clarified by filtration and subjected to solvent/detergent viral inactivation. This was followed by a concentration/buffer exchange step and subsequent DNA reduction using an endonuclease. NVG-111 was captured using a bind/elute Protein A column and the eluate polished on a multimodal anion exchange column in flow through mode to remove residual impurities. The eluate was formulated and concentrated to the target protein concentration, viral and sterile filtered and QC tested. The bulk drug substance was 0.2 µm filtered into Din 2R vials and the DP stored at ≤-65°C pending release. Results: The transient transfection approach resulted in the rapid tech transfer and GMP manufacture of clinical NVG-111 DP. Two batches of DP were manufactured producing 1,971 vials of NVG-111, sufficient to support the Phase I/II clinical trial in patients with advanced Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma (Clinical Trial.gov NCT04763083). Both batches met the approved specifications for identity, potency, purity/impurities, strength and safety. The exercise took less than 7 months from contract signature to DP in the freezer and cost ̃50% of the more traditional producer cell line approach. Conclusions: We established a novel GMP process in 7 months, using transient transfection to manufacture NVG-111 for Phase I/II trials. The process costed less than the more conventional manufacturing approach of using a producer cell line. The strategy offers a rapid, and very efficient way of reaching a first in human study without a trade-off between time, quality and cost.
Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: Evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications.
Authors: Akoulitchev Alexandre , Hunter Ewan , Santos Francisco C. , Dezfouli Mehrnoush , Koutsothanasi Christina , Salter Matthew , Powell Ryan , Dring Ann , Egan Benedict , Parnall Matthew , Thacker Morgan , Green Jayne , Ramadass Aroul , Ng Serene , Lim Chun Ren , Guiel Thomas , Heaton Robert , Levine Jedd
Published: June 2022

e14525

Background: Unprecedented advantages in cancer treatments with immune checkpoint inhibitors (ICI) remain limited to a subset of patients, with high demands for development of better biomarkers to access likely clinical response in advance of ICI therapeutic interventions. 3D genomics has emerged as a novel molecular biomarker modality with strong functional correlation to clinical outcomes (1). The last few years have seen rapid emergence of 3D genomics applications in clinical stratifications. They have demonstrated high sensitivity and specificity in patient stratifications, offered solutions in symptomatic and pre-symptomatic diagnosis, in prognosis, residual disease monitoring, and prediction of response to therapeutic interventions (2-8). EpiSwitch is a 3D genomic platform that has been reduced to practice for the discovery of 3D genomic blood-based biomarkers in a variety of immune-related and oncological diseases (7,8). Methods: A clinical blood assay based on 8 markers - Checkpoint Inhibitor Response Test (CiRT) - has been developed to predict response to PD-(L)1 immune checkpoint inhibition from over 30 million data points, with validations on several independent cancer patient cohorts. The predictive 8 biomarker set is based on an observational clinical trial and several retrospective cohorts, representing all together 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in over 15 diverse oncological indications, i.e. melanoma, lung, urethral, hepatocellular, bladder, prostate, head and neck, colon, breast, bone, brain, lymphoma, larynx. Results: CiRT has demonstrated high accuracy up to 85%, sensitivity of 93% and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach could be successfully utilized for development of a non-invasive predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients. CiRT can assist in treatment decisions, help improve patient selection for optimized treatment, utilize alternative effective treatments, minimize unnecessary toxicity, and efficiently manage the costs.
A novel virus-like drug conjugate (VDC) in combination with immune checkpoint inhibitors for the treatment of primary tumors and distant metastasis.
Authors: Huis in 't Veld Ruben Victor , Ma Sen , Kines Rhonda , Savinainen Anneli , Rich Cadmus Collins , Ossendorp Ferry , Jager Martine
Published: June 2022

e14544

Background: Although there has been great progress in the early diagnosis of choroidal melanoma, metastases remain the leading cause of cancer-related death. Therefore, improving the treatment efficacy against metastases is essential to enhance patient survival. A new targeted therapy, the virus-like drug conjugate (VDC) AU-011 (belzupacap sarotalocan), is currently in clinical development to treat early-stage choroidal melanoma with an intra-ocular administration followed by near-infrared (NIR) light activation using a photodynamic therapy (PDT) laser. Murine experiments have shown that AU-011 enhances immune checkpoint inhibition (ICI) and protects against tumor rechallenge. Methods: We investigated whether this combination therapy had an effect not only on primary tumors but also on distant, untreated tumors, as a model for treating metastatic cancer by abscopal immune effects and compared the efficacy of combining AU-011 with several ICI antibodies. Results: In vitro, AU-011 treatment induced a preferential cytotoxicity in cancer over antigen presenting cells, confirming the tumor-targeting of AU-011. AU-011 treatment induced immunogenic cell death in several murine cancer cell lines through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells. Furthermore, AU-011 in combination with ICI antibodies demonstrated greater efficacy than AU-011 alone, or ICI antibodies alone against established MC38 tumors in mice, resulting in complete tumor response in all treated animals for specific combinations. Finally, AU-011 and anti-PD-L1/ anti-LAG-3 antibody treatment was an optimal combination in an abscopal model of metastatic disease, inducing complete cures in approximately 75 % of animals. Conclusions: Based on our observations, we conclude that AU-011 treatment combined with immune checkpoint inhibition is effective against both primary tumors and distant metastases, and identify anti-PD-L1/ anti-LAG-3 as the most potent combination with AU-011. These data may support an investigation of AU-011 in this combination in future clinical trials.[Table: see text]
The Hu2G10 mAb targets the cleaved-activated form of Trop-2 and exploits vulnerability of multiple human cancers.
Authors: Alberti Saverio , Trerotola Marco , Guerra Emanuela
Published: June 2022

e14548

Background: FDA granted accelerated approval to the anti-Trop-2 sacituzumab govitecan-hziy (TRODELVY) antibody-drug conjugate (ADC), for patients with metastatic triple-negative breast cancer. Skin rash and mucosal inflammation were, though, dose-limiting toxicities of other high-effectiveness anti-Trop-2 antibodies, and impeded their development. These adverse events appeared as on-target/off-cancer effects, related to the expression of Trop-2 by normal tissues. Trop-2 is a transmembrane glycoprotein (E. Guerra et al., The Trop-2 signalling network in cancer growth. Oncogene 32, 1594-1600 (2013)), that is cleaved and activated by ADAM10 to induce cancer growth and metastatic diffusion (M. Trerotola et al., Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis. Neoplasia 23, 415-428 (2021); E. Guerra et al., Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer. Neoplasia 23, 898-911 (2021)). This cleavage causes a spatial rearrangement of the extracellular portion of Trop-2 and exposes hidden, activation-specific epitopes. We succeeded in generating monoclonal antibodies (mAbs) capable of recognizing these cancer-exposed sites. Methods: Most Trop-2-targeted approaches are based on anti-Trop-2 mAbs that recognize a single immunodominant epitope. Such mAbs have limited therapeutic index. We removed the immunodominant epitope by deletion mutagenesis, and optimized breadth of immune response, by immunizing mice with recombinant proteins with diverse end-glycosylation patterns. Screening for cancer-specific mAbs was performed on mutagenized Trop-2, by cell-based ELISA assays, bio-layer interferometry, flow cytometry and fluorescence microscopy. Results: mAbs were obtained that efficiently bound Trop-2 expressing cancer cells and were able to inhibit cell growth in vitro. We humanized the 2G10 mAb into the Hu2G10 IgG1, with an affinity for recombinant, cancer-specific, cleaved Trop-2 that is several orders of magnitude higher than existing competitor mAbs. In vivo the naked Hu2G10 antibody was effective at inhibiting the growth of breast, colon, ovary and prostate cancers. In the ADC setting Hu2G10 drove high anticancer specificity and effectiveness. Conclusions: Hu2G10 shows unprecedented specificity and efficacy, for best-in-class anti-Trop-2 anticancer therapy.
Irradiation combined with PD-1 inhibitor aggravates immune-related pneumonitis of the non-irradiated lung in a preclinical model.
Authors: Zhu Xiaoxia , Qiao Simiao , Liao Xuejiao
Published: June 2022

e14569

Background: The combination of radiation with PD-1 inhibitors for lung cancer is a trend. However, the combination is limited by immune-related adverse effects, particularly checkpoint inhibitor pneumonitis (CIP). The incidence and the mechanism of CIP of the non-irradiated lung caused by radiation plus PD-1 inhibitors remain unknown. This study was designed to evaluate the incidence of CIP and lung tissue morphology in the preclinical model induced by radiation combined with a PD-1 inhibitor (αPD-1). Methods: Fifty-four C57BL/6 mice were divided randomly into the normal group, the irradiation combined with the αPD-1 group (RT + αPD-1 group), and the single irradiation group (RT group). Mice in the RT + αPD-1 group were treated with right lung irradiation (8 Gy once) on day1 and anti-mouse PD-1 monoclonal antibody three times a week. Mice in the RT group received right lung irradiation alone. The mice were euthanized on day10, day15, and day20 after the end RT. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining. Lung fibrosis was evaluated by Masson staining and analysis of hydroxyproline. Results: Histopathological examination revealed that the inflammation in the irradiated lung is more severe than the unirradiated site. With the extension of time, the lung inflammation of mice in the RT group and RT + αPD-1 group was significantly aggravated, and the whole lung fibrosis appeared on day20. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions, and hydroxyproline contents in lung tissues were all significantly higher in mice administered αPD-1 plus irradiation than in the other groups. In particular, the inflammation is significantly worse in the unirradiated site of the mice administered PD-1 inhibitor plus irradiation than in the RT group on day15 and day20. Conclusions: Radiotherapy combined with PD-1 inhibitors could aggravate CIP on both sides. Further studies on the mechanism are under investigation. Our findings highlight the potential risk of CIP in non-irradiated lung in patients treated with radiotherapy and PD-1 inhibitors. Research Sponsor: This work was supported by the National Natural Science Foundation of China [No. 81972853, No. 81572279] and Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2019ZD009).
NPAP1 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Yang Nuo , Huang Liwen , Liu Jun , Guo Jianji , Zhao Lele , Chai Huizi , Xiao Mingzhe , Qi Chuang
Published: June 2022

e14574

Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Nuclear pore associated protein 1 ( NPAP1) encodes an protein is associated with the nuclear pore complex and has been previously reported as a potential prognostic biomarker for laryngeal, colorectal and lung cancers. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between NPAP1 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between NPAP1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with NPAP1 mutation were significantly associated with better PFS (HR = 0.37; 95% CI, 0.19-0.71; P = 0.002), objective response rate (ORR, 54.2% vs 28.4%; P = 0.048) and durable clinical benefit (DCB, 75.0% vs 42.6%; P= 0.003) after ICIs therapy, compared with those with wide-type NPAP1. NPAP1 mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between NPAP1 mutation and PFS remained significant (HR = 0.46; 95% CI, 0.23-0.92; P = 0.028). In contrast, no association between NPAP1 mutation and OS (LUAD: P = 0.24 ; LUSC: P = 0.94) or PFS (LUAD: P = 0.3; LUSC: P = 0.72) was observed in TCGA datasets, suggesting that NPAP1 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, NPAP1 mutation was significantly associated with higher activated memory CD4+ T cell and CD8+ T cell. Moreover, NPAP1 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that NPAP1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of NPAP1 in immunotherapy is needed to be further studied.
Rechallenge with immune checkpoint inhibitors beyond severe toxicities, an utopia?
Authors: Medina Rodriguez Laura , Jimenez-Rodriguez Begona , Llácer Casilda , Trigo Perez Jose Manuel Manuel
Published: June 2022

e14601

Background: Immunotherapy (IO) has substantially improved clinical outcomes in different types of tumours. Its use has been associated with so-called immune-related adverse effects (IrAEs), some of them, potentially severe and/or fatal. Current guidelines recommend discontinuation of IO in severe IrAEs (grades 3/4). Therefore, there is very limited evidence about the safety of “rechallenge” or re-treatment with IO in patients who have experienced severe toxicities. The objective of this study is to describe the toxicities experienced by patients treated with IOs in our unit and identify the recurrence rate of these rEAIs in those patients in whom immunotherapy is re-administered. Methods: We carried out a retrospective analysis of patients treated with IO from January 2015 to April 2021. As inclusion criteria, we selected the condition that the patients have had at least one tumour reevaluation after the IO was started. We have collected clinical and epidemiological variables, efficacy (mesured by RECIST 1.1 and iRECIST criteria) and, as well as recorded toxicity data (mesured by CTCAE V4.3). Results: 220 patients have received some IO drug between the indicated periods. The characteristics of the patients are shown in the attached table. 66% of patients treated with IO have received anti-PD-1/PD-L1 therapy as monotherapy. 60% (134/220) of patients experienced at least 1 IrAE. Of the IrAEs, only 20% were grade 3/4. Only 34 (25%) of the 134 patients who experienced any toxicity required IO stop. Of these 34, only 17 patients achieved retreatment with IO after resolution of initial toxicity. In 14 of the 17 patients who underwent rechallenge, IO was permanently discontinued due to recurrence of the same IrAEs. The IrAE that recurs most frequently after rechallenge was colitis (35% of cases), followed by nephritis (28%). 41% of the patients who experienced toxicity had an objective response to their disease, compared to only 9% in those who did not present any IrAE, which was statistically significant (p<0.05%). Conclusions: In our serie, rechallange with IO after toxicity was associated with the appearance of the same IrAE, which is consistent with what has been published in other series. We are doing further analyses in order to explore IO toxicity deeply, increasing the number of patients which have received immune checkpoint inhibitors.[Table: see text]
Validation of a clinically relevant humanized mouse model for the safety assessment of 4-1BB agonists utomilumab and urelumab.
Authors: Keck James G. , He Wenqian , Buetow Bernard S. , Vitsky Allison , Liu Maggie , Yang Jiwon , Yang Guoxiang , Cai Danying , Jessen Bart
Published: June 2022

e14602

Background: Immunotherapy is proven to be powerful and effective in treating cancer. One of the strategies for the therapy is to boost a patient’s immune system by stimulating tumor necrosis factor receptors via the activation of 4-1BB (CD137) costimulatory molecule. Urelumab was the first 4-1BB agonist investigated in clinical trials and showed clinical promise but doses were limited by severe liver toxicity. Preclinical assessment of toxicity failed to predict the clinical safety outcome. Methods: To address the critical needs of in vivo evaluation of toxicity in a preclinical setting, we have developed an animal model using PBMC humanized mice to assess the safety of immunotherapy. In this model, agents targeting human immune system including monoclonal and bispecific antibodies can induce an acute response of cytokine release within hours of treatment and with some therapies a systemic response can manifest in tissue damage and lethality of mice days later. Results: The potential clinical relevance of the PBMC humanized mouse model was demonstrated using 4-1BB agonists urelumab and utomilumab. The antibody-treated PBMC humanized mice were evaluated daily for clinical score and assessed for clinical chemistry and liver histopathology at study terminus. Animals dosed with urelumab at 10 mg/kg exhibited body weight loss and underwent early euthanasia, while animals dosed with utomilumab survived to scheduled euthanasia with minimum body weight loss. Urelumab showed marked liver toxicity relative to utomilumab and controls with more necrosis in the tissue and higher mean ALT, AST and GLDH activities, and the tolerability of urelumab was increased by lowering the dose to 1 mg/kg. The differences captured by the humanized mouse model presented a safety profile similar to the findings about urelumab and utomilumab from the clinical trials. Utomilumab was well tolerated at the dose that caused severe toxicity for urelumab in patients, and the toxicity of urelumab could be reduced by lowering the dose. Conclusions: Our data suggest that the PBMC humanized mouse model could identify human 4-1BB agonists that caused potentially severe liver toxicity. Preclinical safety assessment using humanized mouse models as used for these studies could be an important step in the course of the development of novel immunotherapy for the safety of patients as well as mitigating drug development cost.
Justifying integration of liquid biopsy into routine molecular diagnostics to complement tissue genomic profiling: Experience at Fox Chase Cancer Center.
Authors: Baldwin Don A , Gigli Cheyenne , Su Yanrong , Fernandez Sandra Viviana
Published: June 2022

e15029

Background: Plasma-based liquid biopsy has rapidly evolved from a novel research tool toward translation into clinical use for many diseases including cancer. While there are still some gaps regarding standardization and clinical utility, as tissue next-gen sequencing had previously faced and overcome, there is a growing body of evidence supporting integration of liquid biopsy into standard of care as a diagnostic tool for precision oncology. Selected from a larger cohort, several cases are presented here illustrating the use of the PGDx elio plasma resolve assay to profile circulating tumor DNA (ctDNA) from patients whose tumor and matched normal DNA had also been characterized by a next-generation sequencing panel. Methods: The PGDx elio plasma resolve assay and bioinformatics detects single and multi-nucleotide variants in 33 genes, select amplifications and translocations, as well as microsatellite instability by sequencing on the Illumina NextSeq 500/550 platform. DNA from matched tumor and normal FFPE samples were assessed using the 275 gene Molecular Diagnostics Laboratory’s Comprehensive Cancer Panel (CCP), also on the NextSeq platform. Selected cases represent the range of diagnostic utility that might be expected from ctDNA. Results: Across all cases, there were varying levels of concordance between tissue and plasma as well as novel variants in the plasma that were not present in the tissue DNA demonstrating the benefit of incorporating ctDNA profiling to capture critical genomic information. In one rectal adenocarcinoma case, DNA variants from the primary tumor were detected in ctDNA eight months later during evaluation of a recurrent tumor, suggesting that plasma profiling might have provided early biomarker detection of recurrence. An aggressive and recurrent melanoma, however, showed no concordance between ctDNA and tumor DNA variants, indicating that some tumors may not shed sufficient DNA into the bloodstream to make ctDNA clinically relevant. Another case of melanoma had concordant detection of the driver BRAF V600E mutation in tumor and ctDNA, but ctDNA also contained a pathogenic ATM truncation not observed in the tumor sample. Current clinical trials are investigating the combination of PARP- and ATR-inhibiting drugs, which causes excessive DNA damage and cell death in the context of ATM-deficient cancers. Conclusions: These cases show that combined tissue and ctDNA profiling at the time of initial diagnosis can reveal tumor heterogeneity or distinct metastases not observed in a selected tissue sample, and that profiling during and after therapy may provide early detection of recurrence, appearance of resistance mutations, or monitoring of measurable residual disease.
Pan-Cancer analysis of the mutation frequency of genes in TGF-beta pathway.
Authors: Fu Qiang , Su Junyan
Published: June 2022

e15113

Background: The TGF-β signaling pathway governs key cellular processes under physiologic conditions and deregulates in cancer, including a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early-stage tumors to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. However, the genomics profiles of TGF-β signaling pathway genes are unclear. In this study, we evaluated the genomic features in Chinese pan-cancer patients and investigated the mutation frequency of genes in the TGF-β pathway. Methods: A total of 5420 patients consisting of 22 cancer types were enrolled in this study. Utilizing target next-generation sequencing (NGS) platform, genomic profiling of 599 cancer-related genes, including genes of TGF-β pathway (SMAD2/3/4, PDGFRB, CDH1, MDM2, CDKN1A, and CDKN2B), was performed on tumor tissue or blood samples. Results: We observed 25.57% (1386/5420) of cases harbored at least one alteration in the TGF-β pathway genes. The mutation frequency ranges 9.09% to 39.77% among the 22 cancer types, including 39.77% (247/621) in gastric cancer, 39.31 (320/814) in bowel cancer, 36.84% (7/19) in endometrial cancer, 11.11% (8/72) in esophageal cancer, 10.46% (7/67) in kidney cancer, and 9.09% (2/22) in the gastrointestinal stromal tumor, respectively. The mutation of tumor-promoting effects genes SMAD2/3/4, PDGFRB, CDH1and MDM2 in the TGF-β pathway were found in all cancer types and mainly occurred in CNS tumor, gastrointestinal stromal tumor, pancreatic cancer, sarcoma, gastric cancer, and bowel cancer. The tumor-suppressing effective genes CDKN1A and CDKN2B primarily mutated in melanoma, endometrial cancer, and kidney cancer. Approximately 21.77% of patients had CNV in the TGF-β pathway of all tumor types. The most frequently mutated TGF-β genes were MDM2 and CDKN2B, mainly altered in sarcoma, melanoma, and CNS Tumor. Conclusions: We found a unique genomic feature of the TGF-β pathway of Chinese pan-cancer patients. Targeting mutant of TGF-β pathway genes remains a potentially effective treatment in the future.
Comprehensive analysis of FGFR mutations in Chinese cancer patients.
Authors: Yu Tao , Fu Zhichao
Published: June 2022

e15117

Background: Fibroblast growth factor receptors (FGFRs) are highly conserved transmembrane tyrosine kinase receptors (RTKS) that regulating several cellular processes such as proliferation, differentiation, migration and survival. In recent years, some studies have documented that signaling through FGFRs impact progression of cancer and the survival of patients with cancer. As a potential therapeutic target, exploring the mutation frequency of FGFRs in more different cancers are necessary. Here we performed a comprehensive analysis of the frequency and types of FGFRs mutations in Chinese cancer patients and provided reference for targeted therapy development. Methods: From January 2020 to December 2021, a total of 4,102 patients with nine common cancers were included in the study. The next-generation sequencing was utilized for detecting genetic mutations. Results: A total 328 patients (7.9%) with FGFR mutation were identified. The FGFR 3 was the most frequently gene in our cohort. Among all the cancer patients, the highest frequency of FGFR mutations was observed in bladder cancer (32.5%) and the percentages in FGFR1, FGFR2 and, FGFR3 were 2.7%, 1.35%, and 6.76% respectively. Furthermore, the proportion of FGFR mutation in lung carcinoma, cholangiocarcinoma, colorectal carcinoma, melanoma, breast carcinoma and ovarian carcinoma was 8.64%, 11.58%, 13%, 16.7%, 9.62% and 10.81% respectively. Additionally, FGFR mutation have been detected in other tumor types, including renal cell carcinoma (5.63%), prostate cancer (5.45%), and gastric carcinoma (13.72%). Conclusions: The present study provided the comprehensive FGFR mutation data of Chinese cancer patients. A high frequency mutation in FGFR have been found in Chinese patients with different cancers, which mean that patients with multiple cancer types might benefit from development of efficient EGFR inhibitors.