bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 588: Regional administration of IL-12 endowed CAR T cells effectively targets systemic disease
Authors: Lee Hee Jun , Priceman Saul 
Published: June 2022

Abstract
While chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical efficacy for hematological malignancies, efficacy remains limited for solid tumors due in large part to the immunosuppressive tumor microenvironment. Tumor-associated glycoprotein 72 (TAG72) is an aberrantly glycosylated protein overexpressed on ovarian cancer and is an exciting target for CAR T cell immunotherapy. Our lab previously developed a second-generation TAG72 CAR T cell product and showed its potency against TAG72-expressing ovarian tumor cells both in vitro and in preclinical mouse models. We report here further modification of our TAG72 CAR T cells, with incorporation of interleukin-12 (IL-12) and interleukin-15 (IL-15), and evaluate the therapeutic benefits in peritoneal ovarian tumor models.
In this preclinical study, we build upon our earlier work with in vitro and in vivo evaluation of 9 different second-generation TAG72 CAR constructs varying in single-chain variable fragment, extracellular spacer, transmembrane, and intracellular co-stimulatory domains. We then engineer CAR T cells with two types of cytokines - IL-12 and IL-15 - and put these engineered cells against challenging in vivo tumor models.
Through in vitro and in vivo studies, we identified the most optimal construct with which we aim to evaluate in a phase 1 clinical trial targeting TAG72-positive ovarian cancer in early 2022. Despite thorough optimizations to the CAR backbone, CAR T cells can be additionally engineered for improved anti-tumor response. Therefore, we further engineered CAR T cells with IL-12 or IL-15 production that greatly improved the effectiveness of TAG72-CAR T cells in difficult-to-treat in vivo tumor models. We observed that modification of CAR T cells with IL-15 displayed toxicity when regionally delivered in vivo, yet introduction of IL-12 not only demonstrated safe and superior therapeutic responses, but also allowed the regional administration of CAR T cells to address systemic disease. We are now expanding these findings by evaluating these therapies using syngeneic immunocompetent mouse tumor models.
The tumor microenvironment (TME) harbors various factors that thwart the killing of tumor cells by CAR T cells. Thus, CAR T cells will likely require further engineering to overcome this barrier. We show that amplifying cytokine pathways is one way to overcome the TME and improve the efficacy of CAR T cell therapy for solid tumors.
Citation Format: Hee Jun Lee, Saul Priceman. Regional administration of IL-12 endowed CAR T cells effectively targets systemic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 588.
Abstract 5919: Regulation of SLPI secretion by NFX1-123 and HPV 16 E6 in cervical cancer
Authors: Chintala Sreenivasulu , Quist Kevin , Katzenellenbogen Rachel 
Published: June 2022

Abstract
Background: Secretory Leukocyte Peptidase Inhibitor (SLPI) functions in cancer progression, cellular invasion, metastasis, immune evasion, and chemoresistance. Our previous studies showed increased SLPI with overexpressed NFX1-123 and co-expressed high-risk (HR) human papillomavirus type 16 E6 oncogene (16E6) in primary keratinocytes (HFKs) as well as high SPLI levels in cervical cancers. The HR viral oncogenes E6 and E7 partner with host cell proteins to regulate cell cycle regulation and immortalization pathways. Understanding the mechanisms of SLPI upregulation in HPV-associated cancers is critical to validating SLPI as a non-invasive biomarker as well as to test its utility in future cancer treatments. This study was designed to quantify intracellular and secreted SLPI protein in cervical cancer and to determine the roles NFX1-123 and 16E6 have on SLPI expression and secretion.
Methods: Using HPV- and HPV+ cervical cancer cell lines and HFKs transduced with overexpressed NFX1-123 and 16E6, or vector controls, we measured intracellular and secreted SLPI by Western blot and ELISA, respectively. In HPV+ cervical cancer cell lines, NFX1-123 was knocked down or out by shRNA or CRISPR-Cas9, respectively, and 16E6 and 16E7 were knocked down by siRNA. In those cells, intracellular and secreted SLPI was quantified and the relative role of NFX1-123, 16E6, and 16E7 were studied. Selected classical and non-classical secretory pathways markers were also measured to assess their effects on SLPI secretion. Finally, SLPI’s concentration was measured by ELISA in cervical cancer patient sera and compared to healthy controls.
Results: Our results showed increased intracellular as well as secreted SLPI in HFKs with overexpressed NFX1-123 and 16E6. Similarly, we found increased SLPI secretion in HPV+ cervical cancer cell lines (SiHa, Caski and HeLa) when compared to HPV- C33A cells. A reduction in NFX1-123 and 16E6 led to decreased SLPI secretion, pointing to a regulation of SLPI by NFX1-123 and 16E6 on SLPI secretion. Analysis of classical and non-classical secretory pathway markers suggested that NFX1-123 regulated non-classical pathways, which may drive greater secretion of SLPI in HPV+ cervical cancers. Higher SLPI protein amounts were found cervical cancer patient sera when compared to healthy controls.
Conclusions: Our results suggest a functional role for NFX1-123 and 16E6 in SLPI secretion in cervical cancer and that SLPI may be a potential biomarker in cervical cancer.
Citation Format: Sreenivasulu Chintala, Kevin Quist, Rachel Katzenellenbogen. Regulation of SLPI secretion by NFX1-123 and HPV 16 E6 in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5919.
Abstract 5925: Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis
Authors: Toshikuni Nobuyuki , Tsuchishima Mutsumi , Tsutsumi Mikihiro , George Joseph 
Published: June 2022

Abstract
Background: The newly developed albumin-bilirubin (ALBI) score has been proved to be a simple and useful marker for predicting prognosis in patients with hepatocellular carcinoma (HCC). However, evidence is scarce regarding the use of ALBI score to predict occurrence of HCC in patients with chronic liver disease. In the current study, we examined the usefulness of ALBI score to predict occurrence of HCC in patients with liver cirrhosis.
Methods: In this retrospective study, we included only cirrhotic patients without previous history of HCC. A total of 68 cirrhotic patients (median age, 68 years old; 36 males and 32 females; 42 compensated and 26 decompensated cirrhosis) were included. Using a Cox proportional hazard model, we identified the risk factors for HCC occurrence and mortality. The potential factors were age, gender, causes of cirrhosis (hepatitis virus infection vs others), platelet count, serum alpha-fetoprotein (AFP) level, serum endocan level, ALBI score, and successful treatment for cirrhosis (yes vs no).
Results: The leading cause of cirrhosis was hepatitis virus infection (9 HBV- and 20 HCV-infected patients), followed by alcohol-related liver disease (23 patients), nonalcoholic steatohepatitis (5 patients), and other causes (2 patients). The median follow-up period was 10 years. During the study period, 16 patients had HCC and 22 patients died (12 liver failure, 3 HCC, 2 variceal rupture, 2 bacterial infection, and 3 other causes). Cumulative survival rates were 92%, 72%, and 59%, at 5, 10, and 15 years, respectively. Regarding risk factors for HCC occurrence, univariate analysis identified a low platelet count and an increased ALBI score as significant factors. However, on multivariate analysis, an increased ALBI score was the only significant factor [hazard ratio, 7.49 (1.65−34.04); p = 0.009]. Regarding risk factors for mortality, univariate analysis identified older age as the only significant factor; male gender and hepatitis virus infection tended to be significant. However, on multivariate analysis, older age, male gender, and hepatitis virus infection were significant factors.
Conclusion: The results indicate that an increased ALBI score is a useful factor to predict occurrence of HCC in patients with liver cirrhosis.
Citation Format: Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi, Joseph George. Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5925.
Abstract 594: FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients
Authors: Bennion Kelsey B. , Tariq Marvi , Baecher Kirsten M. , Paulos Chrystal M. , Kudchadkar Ragini , Lowe Michael C. , Ford Mandy L. 
Published: June 2022

Abstract
In this study, we show that FcγRIIB on the surface of CD8+ T cells reduces responsiveness to αPD-1 antibody in melanoma patients, and we suggest therapeutic strategies to improve CD8+ T cell response to PD-1 blockade. Immune checkpoint blockade (ICB) such as PD-1 blockade has drastically improved melanoma patient survival, but not all patients respond to ICB. Elevated expression of inhibitory molecules on CD8+ T cells dampens the antitumor T cell response and limits patient response to ICB. We recently showed that the inhibitory receptor FcγRIIB is expressed on effector-like memory CD8+ T cells and functions in a cell-intrinsic manner to temper activated CD8+ T cells in vivo. We found that FcγRIIB+ CD8+ T cells were more proliferative and secreted more pro-inflammatory cytokines than their FcγRIIB- counterparts. FcγRIIB+ CD8+ T cells also expressed elevated levels of exhaustion/activation markers (PD-1, CTLA-4, etc.). As these markers are also the targets of immune checkpoint blockade, we investigated the response of these cells to checkpoint therapy. Interestingly, FcγRIIB+ cells exhibited significantly reduced proliferation to αPD-1 and αCTLA-4 in vitro compared to FcγRIIB- cells (p&lt;0.05). In stage-IV melanoma patients, we observed a decrease in FcγRIIB+ CD8+ T cells (p&lt;0.05) following administration of nivolumab (αPD-1), a finding replicated in mouse models in vivo. Because ICB utilizes IgG antibody, a canonical ligand for FcγRs, we hypothesized that ICB antibodies could bind FcγRIIB on CD8+ T cells and elicit counterproductive negative signaling. In a B16-melanoma mouse model, genetic deletion of FcγRIIB on CD8+ T cells increased CD8+ T-cell infiltration and IFNγ production at the tumor in αPD-1 treated mice (p&lt;0.05). Further, blocking inhibitory signaling through FcγRIIB in αPD-1-treated animals increased the number of Ki67+, TNF+, and IFNγ+ CD8+ T cells at the tumor and delayed tumor growth compared to αPD-1 treatment alone (p&lt;0.05). Thus, we show that FcγRIIB is a novel inhibitory molecule on CD8+ T cells that limits T-cell responsiveness to αPD-1 immunotherapy and that T cell-expressed FcγRIIB should be a consideration in the development of therapeutic antibodies. We also demonstrate the efficacy of blocking FcγRIIB to enhance the CD8+ T-cell response to αPD-1 in mice, illuminating a potential new therapeutic target to improve melanoma patient response to ICB.
Citation Format: Kelsey B. Bennion, Marvi Tariq, Kirsten M. Baecher, Chrystal M. Paulos, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford. FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 594.
Abstract 5948: Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells
Authors: Ogden Julia , Dive Caroline , Garcia Carlos Lopez 
Published: June 2022

Abstract
Background: Lung squamous cell carcinoma (LUSC) arises from the accumulation of genetic driver alterations in bronchial basal cells. LUSC genomes lack obvious actionable mutations and present with a high degree of inter-tumor heterogeneity. Tractable, patient relevant models are needed to study LUSC pathogenesis and investigate the role of recurrent genomic alterations in driving cancer progression. Therefore, we are developing a tractable human model of LUSC progression to increase our understanding of this disease.
Methods: To investigate the contribution and co-operation of frequently mutated genes (TP53 and CDKN2A) and commonly deregulated pathways (SOX2/P63, PI3K/AKT and KEAP1/NRF2 pathways) in driving LUSC progression, we genetically engineered primary human bronchial basal cells. This culminated in eight basal cell mutants harboring ubiquitous LOF alterations in TP53 and CDKN2A combined with additional pathway alterations. To assess the function of the genetic alterations in LUSC progression, we investigated proliferation using cell cycle analysis and colony forming assays. Air-liquid interface organotypic cultures were used to model histological changes in the bronchial epithelium driven by different combinations of mutations. The resultant cultures were analyzed for changes in histology indicative of LUSC progression using immunostaining to evaluate changes to epithelial cell proliferation, and expression of LUSC biomarkers.
Results: Increases in proliferation were driven by inactivation of TP53, CDKN2A and PTEN, whereas SOX2 overexpression inhibited mutant basal cell proliferation. LUSC alterations also drove striking phenotypic changes in 3D organotypic cultures of the bronchial epithelium. All mutant cultures displayed thickening of the bronchial epithelium and significantly increased cellularity (p&lt;0.001), indicating hyper-proliferation. SOX2 overexpression inhibited mucociliary differentiation and drove the appearance of a disordered epithelium with clear cellular and nuclear pleomorphism, indicative of high-grade premalignant lesions.
Conclusions: We developed a basal cell model of recurrent LUSC genetic alterations. This approach is unique due to [1] the use of primary human cells and [2] the representation of interpatient heterogeneity and developmental stages by introducing different combinations of pathway alterations. Early results indicate that basal cells carrying cumulative alterations display increasingly complex phenotypes with features of low and high-grade premalignant lesions. Further work is required to assess the tumorigenicity of mutant cells.
Citation Format: Julia Ogden, Caroline Dive, Carlos Lopez Garcia. Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5948.
Abstract 5950: A novel biguanide as a potential head and neck cancer therapeutic in Fanconi anemia
Authors: Archibald Hunter , Wuertz Beverly , Ondrey Frank 
Published: June 2022

Abstract
Introduction: Fanconi Anemia (FA) patients develop head and neck squamous cell carcinoma (HNSCC) at significantly elevated rates and conventional adjunctive chemotherapy and radiation are exquisitely toxic to these patients. We endeavor to find a safer chemotherapeutic agent for treatment of head and neck cancer in this population. Currently, agents such as metformin are in FA clinical trials for marrow failure and are also high interest agents in head and neck cancer chemoprevention. HNSCC in FA is a disease model that has applications to typical head and neck cancer, as its mutational defects are felt to be similar.
Methods: We completed cell proliferation assays on FA-derived HNSCC cell lines MOP FA-1 and VU-1131. MTT, Cell Titer Glo, trypan blue, and clonogenic assays were completed on each cell line to evaluate the effect of N1-hexyl-N5-benzyl-biguanide (HBB) in comparison with standard cisplatin chemotherapy. We also compared the caspase activity in an effort to evaluate a putative mechanism of HBB cellular inhibition.
Results: HBB showed a statistically significant dose-dependent inhibition of cellular proliferation. In MTT assays, 5 uM HBB showed 28-46% inhibition at 72 hours and 10uM HBB showed 77-82% inhibition at 72 hours. There was an additive inhibition of cellular proliferation when HBB was combined with low-dose cisplatin.
Conclusion: HBB is a novel biguanide that inhibited cellular proliferation in two FA HNSCC cell lines and chemosensitized to low-dose cisplatin. This may be an alternative adjunct treatment agent, or may be chemosensitizing for low-dose cytotoxic agents such as platinum-based chemotherapeutics in this unique population.
Citation Format: Hunter Archibald, Beverly Wuertz, Frank Ondrey. A novel biguanide as a potential head and neck cancer therapeutic in Fanconi anemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5950.
Abstract 5968: Ethnodyne Visio™ affects EGFR signaling in breast cancer
Authors: Samant Rishab Rajeev , Samant Rajeev 
Published: June 2022

Abstract
Breast Cancer (BC), the most common form of female cancer, is one of the most extensively studied diseases. Metastasis is the process by which a cancer cell travels to another part of the body and starts to multiply. This detrimental occurrence is one of the primary forms of disease relapse in cancer patients and accounts for an estimated 90 percent of cancer deaths. Ethnodyne Visio™ is a new drug for Age-Related Macular Degeneration (AMD), the primary cause for blindness in people 65 and older. It is a mixture of phytochemicals Withaferin A, Gallic Acid, and Bacopaside I. However, the exact mechanism of action of Ethnodyne Visio™ is not known. Macular Degeneration occurs in two primary forms: wet and dry. Wet Macular Degeneration shows surprising similarities with metastatic Breast Cancer in terms of their progression and causation. As both diseases evolve, the retina (in the case of Wet AMD) and the tumor (in the case of BC) secrete Vascular Endothelial Growth Factor (VEGF) to encourage vascular development. In Wet AMD, this new and unregulated vascular growth, or angiogenesis, causes “leaky” blood vessels that allow fluid to enter the retina, ultimately causing blindness. In BC, this blood vessel growth provides a means for the tumor to obtain nutrients as well as disseminate metastatic cells. We determined if there exists any easily accessible nutraceuticals possessing effective antiangiogenic properties. We used CAMs (chick chorioallantoic membrane), grown ex-ovo, to study angiogenesis. We found that Ashwagandha (Withaferin A) blocked angiogenesis of CAMs by 67%. Taking clues from these observations, we wanted to determine possible molecular signaling mechanisms triggered by Ethnodyne Visio™ that may counter progression of BC. We hypothesized that Ethnodyne Visio™ may have anti-angiogenic properties. Using multiple online gene association platforms, we compiled a list of transcriptomic changes caused by Withaferin A, Gallic Acid, and Bacopaside I on breast tumor cells. A g:Profiler analysis of the combined transcriptomic changes revealed Epidermal Growth Factor Receptor (EGFR) signaling as a downstream target of the components of Ethnodyne Visio™. Our analysis reveals that Ethnodyne Visio™ potentially regulates VEGF signaling through the EGFR pathway.
Citation Format: Rishab Rajeev Samant, Rajeev Samant. Ethnodyne Visio™ affects EGFR signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5968.
Abstract 5971: DEPDC1B promotes melanoma angiogenesis and metastasis through sequestration of ubiquitin ligase CDC16 to stabilize secreted SCUBE3
Authors: Hu Feng , Fong Ki On , Cheung May P.L , Liu Jessica A.J , Liang Rui , Li Tsz Wai , Sharma Rakesh , Ip Philip P.C , Yang Xintao , Cheung Martin 
Published: June 2022

Abstract
The ability of melanoma to acquire metastasis through the induction of angiogenesis is one of the major causes of skin cancer death. Here, we find that high transcript levels of DEPDC1B in cutaneous melanomas are significantly associated with a poor prognosis. Tissue microarray analysis indicates DEPDC1B expression is positively correlated with SOX10 in the different stages of melanoma. Consistently, DEPDC1B is both required and sufficient for melanoma growth, metastasis, angiogenesis, and functions as a direct downstream target of SOX10 to partly mediate its oncogenic activity. In contrast to other tumor types, the DEPDC1B-mediated enhancement of melanoma metastatic potential is not dependent on the activities of RHO GTPase signaling and canonical Wnt signaling, but is acquired through secretion of SCUBE3, which is crucial for promoting angiogenesis in vitro and in vivo. Mechanistically, DEPDC1B regulates SCUBE3 protein stability through the competitive association with ubiquitin ligase CDC16 to prevent SCUBE3 from undergoing degradation via the ubiquitin-proteasome pathway. Importantly, expression of SOX10, DEPDC1B, and SCUBE3 are positively correlated with microvessel density in the advanced stage of melanomas. In conclusion, we reveal a SOX10-DEPDC1B-SCUBE3 regulatory axis promotes melanoma angiogenesis and metastasis, which suggests targeting secreted SCUBE3 can be a therapeutic strategy against metastatic melanoma.
Citation Format: Feng Hu, Ki On Fong, May P.L Cheung, Jessica A.J Liu, Rui Liang, Tsz Wai Li, Rakesh Sharma, Philip P.C Ip, Xintao Yang, Martin Cheung. DEPDC1B promotes melanoma angiogenesis and metastasis through sequestration of ubiquitin ligase CDC16 to stabilize secreted SCUBE3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5971.