bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT099: First-in-human study of ALF501, polypeptide PSMA-targeted chimeric antigen receptor engineered natural killer cells) for castration-resistant prostate cancer
Authors: Shi Hui , Lin Yanan , Ran Jie , Jin Yan , Zhang Shengbang , Wang Qi , Zhang Huiyuan , Wu Lida , Gu Yuchun , Tan Shengjiang , Wang Yao 
Published: April 2023

Abstract
Abstract Background: The mortality of castration-resistant prostate cancer (CRPC) is high due to lack of an effective treatment. Chimeric antigen receptor (CAR) based therapy is a promising immunotherapeutic strategy. In preclinical models, we established ALF501, a novel CAR-NK cells with both a high affinity for PSMA and a clinically significant tumoricidal effect on CRPC. Here we report the results from the first-in-human case of ALF501 for CRPC.
Methods: In this study, ALF501was dosed intravenous for a total of three courses, with an interval of 3 months, each infusion of 5 × 108 cells, and 3 consecutive days of infusion as a course of treatment. Observation continued until progression or unacceptable toxicity for up to 1 years. Primary objectives were safety and tolerability; secondary objectives included preliminary antitumor activity.
Results: An 80-year-old man who underwent laparoscopic radical prostatectomy in February 2018 and developed a relapse in April 2021. Starting with July 16 2021, he received three courses of ALF501. No liver and kidney toxicity was observed, and the safety profile was good. Progression-free survival was 12months as of April 23, 2022, during which PSA decreased by 97.5% from baseline. Imaging follow-up showed that the tumor was stable, and chest CT showed that the original pleural effusion and pericardial effusion disappeared, and the high-density shadow previously considered osteogenic bone metastasis was reduced overall.
Conclusions: ALF501 is safe and feasible for the treatment of CRPC, and has preliminary anti-tumor efficacy. This is a case study, and it is necessary to expand the patient sample size in the future to confirm whether there is a difference in efficacy for different patients.
Citation Format: Hui Shi, Yanan Lin, Jie Ran, Yan Jin, Shengbang Zhang, Qi Wang, Huiyuan Zhang, Lida Wu, Yuchun Gu, Shengjiang Tan, Yao Wang. First-in-human study of ALF501, polypeptide PSMA-targeted chimeric antigen receptor engineered natural killer cells) for castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT099.
Abstract CT115: Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: A phase I clinical trial
Authors: Sersa Gregor , Cemazar Maja , Jamsek Crt , Strojan Primoz , Jesenko Tanja , Bosnjak Masa , Groselj Ales 
Published: April 2023

Abstract
Immunotherapies with monoclonal antibodies (checkpoint inhibitors) are currently being intensively researched and have led to excellent response in many cases in various tumors. Another potential approach to immunotherapy is the targeted intratumoral administration of interleukin 12 (IL -12), a cytokine with proven anti-tumor activity. Due to its immunomodulatory effect, it can be used as an immunostimulatory component for in situ vaccination of local ablative therapies. We have developed a phIL12 plasmid without antibiotic resistance markers using a transgene for the human IL -12 p70 protein. The plasmid can be introduced intratumorally by gene electrotransfer. In gene electrotransfer, electrical pulses are applied to the tumor to deliver the plasmid DNA into the cells. Based on nonclinical studies of safety, pharmacokinetics, pharmacodynamics, tolerability, and immunogenicity, a phase I clinical trial of phIL12 gene electrotransfer was conducted (ISRCTN15479959, ClinicalTrials NCT05077033). The primary objective of the study is to evaluate the safety and tolerability of phIL12 gene electrotransfer in the treatment of basal cell carcinoma in patients with operable tumors of the head and neck. The study, an exploratory, dose-escalating Phase I study, will enroll 9 patients in three dose-escalating cohorts. Treatment consists of plasmid injection followed by application of electrical pulses to the tumors. Patients are monitored for 30 days, with tumors removed if a complete response is not achieved. To date, two cohorts of patients have completed the study. No adverse effects or treatment-related toxicities have been observed, and treatment has been well tolerated by patients. The results of this study will provide the basis for the use of phIL12 gene electrotransfer as adjuvant therapy to local ablative therapies to enhance their local effect and elicit a systemic response.
Citation Format: Gregor Sersa, Maja Cemazar, Crt Jamsek, Primoz Strojan, Tanja Jesenko, Masa Bosnjak, Ales Groselj. Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region: A phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT115.
Abstract LB043: Pharmacological inhibition of ubiquitination sensitizes to DNA damaging agents by preventing homologous recombination repair
Authors: Awasthi Sharad , Yi S. Stephen , McGrail Daniel J. , Sahni Nidhi 
Published: April 2023

Abstract
Therapies inducing DNA damage have been the backbone of cancer treatment for decades, but they often cause significant adverse effects reducing quality of life. Recently, inhibition of poly-ADP-ribose polymerase (PARP) has been shown to target tumor cells with deficient DNA homologous recombination (HR) double-strand break repair by converting single-strand DNA breaks into toxic double-strand breaks that cannot be resolved. This approach has been advantageous as healthy cells with functional HR repair are less effective, resulting in a more tolerable treatment. However, most cancers will not respond to PARP inhibition. Here, using a genome-wide CRISPR knockout functional genomics screen we identified that depletion of ubiquitination enzymes induced sensitivity to PARP inhibition in HR proficient ovarian cancer cells, as well as KRAS-mutant colorectal cancer cells which are generally resistant to PARP and other DNA damaging agents. Validation studies across multiple cancer lineages using cell line and organoid models confirmed that either silencing or pharmacological inhibition of ubiquitin-activating enzyme E1 (UBA1), which is required for ubiquitination, sensitized to PARP inhibition and other DNA damaging therapies. In vivo testing of combination PARP and UBA1 inhibition was well tolerated, and significantly extended survival of patient-derived xenografts compared to either therapy alone. Mechanistically, we found that UBA1 inhibition not only blocked HR repair to sensitize to PARP inhibition, but it also induced global increases in PARylation, which was subsequently inhibited by PARP inhibition. Taken together, these results demonstrate that inhibition of UBA1 sensitizes to PARP via multiple pathways, and the combination is well tolerated making it an ideal strategy to expand the therapeutic benefit of PARP inhibition.
Citation Format: Sharad Awasthi, S. Stephen Yi, Daniel J. McGrail, Nidhi Sahni. Pharmacological inhibition of ubiquitination sensitizes to DNA damaging agents by preventing homologous recombination repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB043.
Abstract LB173: A bioinformatics approach to determine the potential benefit of blocking both Galectin-1 and Galectin-3 in cancer
Authors: Holyer Ian , Slack Rob 
Published: April 2023

Abstract
Galectins are a family of Beta-galactoside-binding lectins that control numerous cellular processes in health and disease, including fibrosis, carcinogenesis and tumour immune evasion. Evidence is starting to emerge that blockade of more than one galectin may provide additional benefit within the oncology arena due to the overlapping biological functions associated with these lectins. Due to the rich and robust external datasets associated with the two most previously studied galectins, we initially investigated the potential therapeutic benefit of a dual blockade approach of Galectin-1 (Gal-1) and Galectin-3 (Gal-3). A systematic assessment, consisting of three steps, was implemented to conclude the potential clinical effects of dual Gal-1 and Gal-3 inhibition and the specific cancers which may benefit the most from this approach. Step 1 consisted of pathway map reconstructions, depicting the role of Gal-1 and Gal-3 in tumor invasion, metastasis and angiogenesis, to confirm overlapping and independent cancer pathways associated with both galectins. These maps were constructed based on evidence from published literature and additional external databases. Step 2 aligned and ranked the associated expression of Gal-1 and Gal-3 at both the mRNA and protein level across different cancer types. This profiling included data from publicly available TCGA and CPTAC databases and additional external sources. Step 3 tested the highest ranked Gal-1 and Gal-3 mRNA and protein expressing cancers for association of survival by stratifying patients into four cohorts: Gal-1 low/Gal-3 low, Gal-1 high/Gal-3 low, Gal-1 low/Gal-3 high, Gal-1 high/Gal-3 high. Survival profiles quite clearly show that high expression of both galectins leads to poor survival in certain cancer types but not all. To summarize, using a bioinformatics approach, we have provided the initial evidence that Gal-1 and Gal-3 are highly expressed at both the gene and protein level in several cancers with their combined expression strongly correlating with poor survival rates. This data suggests, in certain cancer types, that targeting dual inhibition of Gal-1 and Gal-3 will have the potential to improve patient survival to a greater extent than a single Galectin blockade approach.
Citation Format: Ian Holyer, Rob Slack. A bioinformatics approach to determine the potential benefit of blocking both Galectin-1 and Galectin-3 in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB173.
Abstract LB292: GCC2 on small extracellular vesicles for the early diagnosis of lung adenocarcinoma: A multicenter trial
Authors: Choi Byeong Hyeon , An Hyonggin , Cho Sukki , Lee Sungsoo , Kim Hyeong Ryul , Cho Jong Ho , Shin Hyunku , Jeon Ok Hwa , Choi Yeonho , Kim Hyun Koo 
Published: April 2023

Abstract
Background: Early detection of lung cancer is extremely important for timely and effective therapeutic interventions to increase the survival rate of patients. Emerging evidence suggests that tumor-derived small extracellular vesicle (sEV) cargo may serve as cancer-specific biomarkers. We previously reported the identification of GRIP and coiled-coil domain-containing 2-enriched sEV (sEV-GCC2) as a promising biomarker for lung adenocarcinoma in a pilot study. In this multicenter study, we explored the diagnostic and therapeutic potential of sEV-GCC2 in early-stage lung adenocarcinoma.
Methods: A total of 470 blood plasma samples (150 healthy controls and 320 patients with lung adenocarcinoma) were retrospectively obtained from five institutions. sEVs were isolated by size exclusion chromatography and sEV-GCC2 was quantified by enzyme-linked immunosorbent assay. Effect of sEV-GCC2 on lung cancer cell proliferation was investigated in vitro and in vivo.
Results: sEV-GCC2 concentration was significantly higher in patients than that in controls with an area under the curve (AUC) of 0.856 (95% confidence interval [CI], 0.820-0.886). In patients at TisN0-T1miN0 stages vs controls, the AUC was 0.802 (95% CI, 0.734-0.859). The association between sEV-GCC2 and lung adenocarcinoma remained after adjustment for pathological TNM stage and tumor location in the left lower lobe. Immunohistochemical staining revealed that GCC2 expression was significantly higher in lung adenocarcinoma tissues than in the controls (p &lt; 0.001). Furthermore, sEV-GCC2 enhanced cancer cell proliferation and accelerated tumor growth and lymph node metastasis.
Conclusions: We identified sEV-GCC2 as a potential diagnostic marker for very early-stage lung cancer. sEV-GCC2 represents a promising therapeutic target for lung adenocarcinoma and may be quantified as key molecules in the progression of lung adenocarcinoma.
Citation Format: Byeong Hyeon Choi, Hyonggin An, Sukki Cho, Sungsoo Lee, Hyeong Ryul Kim, Jong Ho Cho, Hyunku Shin, Ok Hwa Jeon, Yeonho Choi, Hyun Koo Kim. GCC2 on small extracellular vesicles for the early diagnosis of lung adenocarcinoma: A multicenter trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB292.
Abstract LB333: Cytokine affinity tuning using the AlphaSeq platform to generate targeted immuno-oncology therapeutics
Authors: Swanson Ryan , Goodnight Davis , Adamo Jeff , Minch Kyle , Engelhart Emily , Lopez Randolph , Younger David 
Published: April 2023

Abstract
Here, we demonstrate a novel approach for generating affinity detuned cytokines that can be fused to antibodies for selective immune cell activation to improve anti-tumor responses and mitigate systemic toxicity. Although cytokine therapies have demonstrated curative effects in some cancer patients, clinical use remains limited with current toxicity profiles accompanying systemic administration. Next generation cytokine approaches include conditional signaling focused to sites of interest, including the tumor microenvironment or specific immune cell populations. In this presentation, we share a novel approach for generating detuned cytokine therapeutic candidates using the AlphaSeq platform, which involves the repurposing of yeast agglutination and mating to quantitatively measure protein-protein interactions at a library-on-library scale. We show, for the first time, how AlphaSeq can be used to measure interactions between cytokines and their receptors as well as generate engineered cytokines with a broad range of affinities. A saturated mutational library was created for a cytokine of interest and subsequently screened against a second library consisting of axis receptor chains, their species orthologs and off-target receptors. Cytokine variants with lower affinity than parental were recombinantly expressed as Fc fusion proteins to orthogonally measure affinity with biolayer interferometry and characterize potency with an in vitro human PBMC phosflow assay. Finally, detuned cytokine candidates were fused to antibodies recognizing surface antigens of interest to demonstrate cell population-specific signaling. Our results show the AlphaSeq platform can accurately quantitate thousands of cytokine variant affinities simultaneously against multiple relevant receptors which translates to signaling potency in primary human cells. When engineered as antibody fusion proteins, candidate immunocytokines are identified that only induce signaling in intended cell populations. AlphaSeq’s rapid, comprehensive affinity determination can be utilized to develop a portfolio of clinically relevant therapeutic immunocytokines.
Citation Format: Ryan Swanson, Davis Goodnight, Jeff Adamo, Kyle Minch, Emily Engelhart, Randolph Lopez, David Younger. Cytokine affinity tuning using the AlphaSeq platform to generate targeted immuno-oncology therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB333.
Abstract LB350: Novel mouse model to study HPV associated pathologies
Authors: Li Xue , Schrank Travis , Kothari Aditi , Rehmani Hina , Tasoulas Jason , Kim Sulgi , Yarbrough Wendell , Isaeva Natalia 
Published: April 2023

Abstract
Papillomaviruses are species specific, non-enveloped, double-stranded DNA viruses that have an ~8kb circular genome enclosed by a 55 nm icosahedral capsid. Human papillomaviruses (HPV) are associated with both benign and malignant epithelial lesions. High-risk HPV subtypes are the causative agents of cervical and the majority of oropharyngeal squamous cell carcinomas. Persistent HPV infection is required for HPV-associated tumorigenesis; however, cellular factors needed to support the viral persistence and HPV genes expression are not completely understood. Several transgenic mouse models, developed in last decades, helped tremendously to study HPV-induced carcinogenesis. However, the absence of HPV non-coding upstream regulatory region and late coding region, as well as targeted early genes expression driven by an artificial promoter - features that are shared by all existent HPV transgenic mice - limit our ability to investigate HPV-associated malignant transformation and the role of host factors in this process. Therefore, we generated HPV16 transgenic mouse by using CRISPR/Cas9-mediated genome editing to insert the full-length HPV16 genome into the Rosa26 locus. Two founder mice, with single HPV copy and with tandem HPV integration, were used to establish mouse colonies. Interestingly, regardless of HPV copy number, ~30% of the HPV knock-in mice exhibited early death during the first 2 weeks after birth, while survived pups were significantly smaller than the same age wild-type mice, and had severe hair loss. Intriguingly, the growth retardant and hair loss phenotype in the HPV16 knock-in mice disappeared in ~4 weeks, most likely indicating that viral genes compromise specific stages of mouse development. We evaluated the expression of HPV genes during development, in different mouse organs, and in established fibroblasts and epithelial cell cultures. Our newly developed HPV16 knock-in mouse model provides viral gene expression from natural viral promoters offering an essential basis to explore the role of cellular factors in HPV-driven pathologies.
Citation Format: Xue Li, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Sulgi Kim, Wendell Yarbrough, Natalia Isaeva. Novel mouse model to study HPV associated pathologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB350.
Microbiota Influences on Hematopoiesis and Blood Cancers: New Horizons?
Authors: Galloway-Peña Jessica R. , Jobin Christian 
Published: April 2023

Abstract

Hematopoiesis governs the generation of immune cells through the differentiation of hematopoietic stem cells (HSC) into various progenitor cells, a process controlled by intrinsic and extrinsic factors. Among extrinsic factors influencing hematopoiesis is the microbiota, or the collection of microorganisms present in various body sites. The microbiota has a profound impact on host homeostasis by virtue of its ability to release various molecules and structural components, which promote normal organ function. In this review, we will discuss the role of microbiota in influencing hematopoiesis and how disrupting the microbiota/host network could lead to hematologic malignancies, as well as highlight important knowledge gaps to move this field of research forward.

Significance:
Microbiota dysfunction is associated with many pathologic conditions, including hematologic malignancies. In this review, we discuss the role of microbiota in influencing hematopoiesis and how disrupting the microbiota/host network could lead to hematologic malignancies. Understanding how the microbiota influences hematologic malignancies could have an important therapeutic impact for patients.
Adipose Insulin Resistance Associates With Dyslipidemia Independent of Liver Resistance and Involves Early Hormone Signaling
Authors: Kerr Alastair G. , Andersson Daniel P. , Dahlman Ingrid , Rydén Mikael , Arner Peter 
Published: April 2023

Background:
Adipose tissue insulin resistance is linked to altered plasma levels of triglycerides and HDL (high-density lipoprotein)-cholesterol. However, its degree of independence from liver resistance and different metabolic traits (lipolysis, lipogenesis) effected is not clear and was presently investigated.

Methods:
In 3290 adult subjects, plasma levels of triglycerides and HDL-cholesterol were cross-sectionally measured and related to interindividual variations in measures of insulin resistance in the liver (homeostasis mode assessment of insulin resistance index) or adipose tissue (Adipo-IR index). In subgroups, insulin-induced antilipolysis and lipogenesis in isolated subcutaneous fat cells (n=578) were determined alongside global adipose tissue gene expression (n=132).

Results:

Using linear regression, homeostasis mode assessment of insulin resistance and Adipo-IR strongly correlated with the plasma lipids explaining 33% of the variations in triglycerides. Together with other variables (age, sex, body mass index, cardiometabolic disorders, nicotine use, ethnicity, and physical activity) in multiple regression, homeostasis mode assessment of insulin resistance, and Adipo-IR each remained an important regressor for triglycerides and HDL-cholesterol (
P
<0.0001). In fat cells, half-maximum effective concentration but not maximum effect of insulin on antilipolysis and lipogenesis contributed independently to variations in triglycerides and HDL-cholesterol (
P
=0.001 or lower). This was linked to expression of the insulin receptor, insulin receptor substrate-1, and AKT serine/threonine kinase 2 in adipose tissue.

Conclusions:
Markers of insulin resistance in the liver and adipose tissue each associate strongly, and independently of each other, to elevated triglycerides and decreased HDL levels. At the fat cell, early insulin receptor signaling and sensitivity, but not maximum insulin action contributes to the variations in circulating triglycerides and HDL-cholesterol.
Is Evidential Support the Same as Increase-in-Probability?
Authors: Tokhadze Tamaz 
Published: April 2023

Abstract
Evidential support is often equated with confirmation, where evidence supports hypothesis H if and only if it increases the probability of H. This article argues against this received view. As the author shows, support is a comparative notion in the sense that increase-in-probability is not. A piece of evidence can confirm H, but it can confirm alternatives to H to the same or greater degree; and in such cases, it is at best misleading to conclude that the evidence supports H. The author puts forward an alternative view that defines support in terms of measures of degree of confirmation. The proposed view is both sufficiently comparative and able to accommodate the increase-in-probability aspect of support. The author concludes that the proposed measure-theoretic approach to support provides a superior alternative to the standard confirmatory approach.