Articles de revues : « PSCA »

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Sun, Shi-Qi, Xiang-Tao Liu, Hui-Chen Guo, Shuang-Hui Yin, You-Jun Shang, Xia Feng, Zai-Xin Liu et Qing-Ge Xie. « Protective immune responses in guinea pigs and swine induced by a suicidal DNA vaccine of the capsid gene of swine vesicular disease virus ». Journal of General Virology 88, n^o 3 (1 mars 2007) : 842–48. http://dx.doi.org/10.1099/vir.0.82504-0.

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A suicidal DNA vaccine based on a Semliki Forest virus (SFV) replicon was evaluated for the development of a vaccine against swine vesicular disease virus (SVDV). The 1BCD gene of SVDV was cloned and inserted into pSCA1, an SFV DNA-based replicon vector. The resultant plasmid, pSCA/1BCD, was transfected into BHK-21 cells and the antigenicity of the expressed protein was confirmed using an indirect immunofluorescence assay. Immunogenicity was studied in guinea pigs and swine. Animals were injected intramuscularly three times with pSCA/1BCD at regular intervals. Anti-SVDV antibodies were detected by ELISA, the lymphocyte proliferation response was tested by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide method and neutralizing antibodies were measured by microneutralization tests. The data showed that SVDV-specific antibodies, neutralizing antibodies and lymphocyte proliferation were induced in both guinea pigs and swine. Furthermore, after three successive vaccinations with pSCA/1BCD, half of the pigs were protected against challenge with SVDV. These results should encourage further work towards the development of a DNA vaccine against SVDV.

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Arndt, Claudia, Ralf Bergmann, Franziska Striese, Keresztély Merkel, Domokos Máthé, Liliana R. Loureiro, Nicola Mitwasi et al. « Development and Functional Characterization of a Versatile Radio-/Immunotheranostic Tool for Prostate Cancer Management ». Cancers 14, n^o 8 (14 avril 2022) : 1996. http://dx.doi.org/10.3390/cancers14081996.

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Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with 64Cu2+, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with 225Ac3+ and applied for targeted alpha therapy. A single injection of the 225Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy.

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Zou, Qiong, Leping Yang, Zhulin Yang, Jiangsheng Huang et Xi Fu. « PSCA and Oct-4 Expression in the Benign and Malignant Lesions of Gallbladder : Implication for Carcinogenesis, Progression, and Prognosis of Gallbladder Adenocarcinoma ». BioMed Research International 2013 (2013) : 1–9. http://dx.doi.org/10.1155/2013/648420.

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PSCA and Oct-4 have been thought as markers of cancer stem cells. Although overexpression of PSCA and Oct-4 in cancer has been reported, little is known about the clinical and pathological significance with PSCA and Oct-4 expression in gallbladder adenocarcinoma. In this study, overexpression of PSCA and Oct-4 was detected in gallbladder adenocarcinoma (54.6% and 55.6%). Less expression of PSCA and Oct-4 was detected in the pericancerous tissues (19.6% and 21.7%), gallbladder polyps (13.3% and 13.3%), and gallbladder epithelium with chronic cholecystitis (14.3% and 14.3%). The overexpression of PSCA and Oct-4 was significantly associated with differentiation, tumor mass, lymph node metastasis, invasion of gallbladder adenocarcinoma, and decreased overall survival. Our study suggested that overexpression of PSCA and Oct-4 might be closely related to the carcinogenesis, progression, metastasis, or invasive potential and prognosis of gallbladder carcinoma.

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Xiang, Qian, Zhiguo Zhu, Lianmin Luo, Jiamin Wang, Yangzhou Liu, Yihan Deng, Mingda Zhou et Zhigang Zhao. « The Correlation between PSCA Expression and Neuroendocrine Differentiation in Prostate Cancer ». BioMed Research International 2020 (24 septembre 2020) : 1–9. http://dx.doi.org/10.1155/2020/5395312.

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The prostate stem cell antigen (PSCA), as a predominantly prostate-specific marker, is overexpressed in most prostate cancer specimens, is positively correlated with prostate cancer androgen independence, and has the potential to be treated with castration-resistant prostate cancer (CRPC) as a gene therapy target. Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients’ age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

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Garcia-Gonzalez, Ulises, Daniel D. Cavalcanti, Abhishek Agrawal, Robert F. Spetzler et Mark C. Preul. « Anatomical Study on the “Perforator-free Zone” : Reconsidering the Proximal Superior Cerebellar Artery and Basilar Artery Perforators ». Neurosurgery 70, n^o 3 (6 septembre 2011) : 764–73. http://dx.doi.org/10.1227/neu.0b013e3182351f8e.

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Abstract Background: The proximal superior cerebellar artery (pSCA) is often considered a perforator-free area. Precise anatomical knowledge of this region clarifies the pathophysiology underlying posterior fossa ischemic syndromes and helps avoid treatment-related complications. Objective: To anatomically evaluate perforating branches arising from the pSCA and the upper basilar artery (BA). Methods: Forty-four SCAs from 20 cadaveric heads were examined to determine patterns of the pSCA; its morphometry for medial and lateral branches; and frequency, number, diameter, distribution, and vascular territory of perforators arising from the pSCA and rostral BA. Results: SCA arose as a single trunk in 36 sides (90%): mean diameter at origin was 1.38 mm; mean length was 14.± 6 7.9 mm. Ninety-nine pSCA perforator branches were present in 82% of specimens (mean, 2.3 ± 1.6; range, 0-7 perforators/side). Of these, 59% were direct, belonging to the interpeduncular group in 85% of cases; 28% were short circumflex, belonging to lateral and medial pontine group; and 13% were long circumflex, reaching the medullary perforation zone (basal cerebellar group). Median distance to the first perforator was 2.0 mm (range, 0.1–15 mm). There were 132 perforator branches in the last centimeter of the BA. Conclusion: The pSCA should not be regarded as a perforator-free area. Although the pSCA territories likely overlap with the posterior cerebral artery, BA, and anterior inferior cerebellar artery, the pSCA segment cannot be surgically manipulated with impunity.

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Isomoto, Hajime, Takuki Sakaguchi, Tatsuo Inamine, Shintaro Takeshita, Daisuke Fukuda, Ken Ohnita, Tsutomu Kanda et al. « SNP rs2920280 in PSCA Is Associated with Susceptibility to Gastric Mucosal Atrophy and Is a Promising Biomarker in Japanese Individuals with Helicobacter pylori Infection ». Diagnostics 12, n^o 8 (16 août 2022) : 1988. http://dx.doi.org/10.3390/diagnostics12081988.

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Helicobacter pylori infection results in gastric cancer (GC) with gastric mucosal atrophy (GMA). Some single-nucleotide polymorphisms (SNPs) in the prostate stem cell antigen gene (PSCA) are associated with GC and duodenal ulcers. However, the relationship of other identified SNPs in PSCA with these diseases remains unclear. Herein, the association between PSCA SNPs and GMA among 195 Japanese individuals with H. pylori infection was evaluated. The definition of GMA or non-GMA was based on serum pepsinogen levels or endoscopic findings. Five tag PSCA SNPs were analyzed using PCR high-resolution melting curve analysis with nonlabelled probes. The frequencies of alleles and the genotypes of each tag SNP were compared between the GMA and non-GMA groups. Subsequently, a genetic test was performed using associated SNPs as biomarkers to detect patients developing GMA. Two tag PSCA SNPs (rs2920280 and rs2294008) were related to GMA susceptibility. Individuals with the rs2920280 G/G genotype or the rs2294008 T/T genotype in PSCA had 3.5- and 2.1-fold susceptibility to GMA, respectively. In conclusion, SNP rs2920280 is a possible biomarker for detecting individuals developing GMA. PSCA polymorphisms may be useful biomarkers for predicting GMA linked to GC risk and a screening endoscopy strategy to detect GC related to early stage H. pylori associated GMA.

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Kim, Sung Han, Weon Seo Park, Sang Jin Lee, Moon Kyung Choi, Seung Min Yeon, Jeong Nam Joo, Ara Ko et al. « The Quantified Level of Circulating Prostate Stem Cell Antigen mRNA relative to GAPDH Level Is a Clinically Significant Indictor for Predicting Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy ». BioMed Research International 2015 (2015) : 1–7. http://dx.doi.org/10.1155/2015/292454.

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The study quantified the relative absolute PSCA level in relation to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) level in the peripheral blood of 478 hormone-naive prostate cancer (PC) patients who underwent radical prostatectomy from 2005 to 2012 and evaluated its prognostic significance as a risk factor for predicting biochemical recurrence (BCR), compared to known parameters. Nested real-time polymerase chain reaction (RT-PCR) and gel electrophoresis detected PSCA levels and measured the PSCA/GAPDH ratio. Clinicopathological data from the institutional database were examined to determine the adequate cut-off level to predict postoperative BCR. A total of 110 patients had a positive PSCA result (23.0%) via RT-PCR (mean blood ratio 1.1 ± 0.4). The BCR was significantly higher in the PSCA-positive detection group (p=0.009). A multivariate model was created to show that a PSCA/GAPDH ratio between 1.0 and 1.5 (HR 12.722), clinical T2c stage (HR 0.104), preoperative PSA (HR 1.225), extraprostatic capsule extension (HR 0.006), lymph node dissection (HR 16.437), and positive resection margin (HR 27.453) were significant predictive factors for BCR (p<0.05). The study showed successful quantification of PSCA with its significance for BCR-related risk factor; however, further studies are needed to confirm its clinical predictive value.

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Nejatollahi, Foroogh, Soghra Abdi et Mahdi Asgharpour. « Antiproliferative and Apoptotic Effects of a Specific Antiprostate Stem Cell Single Chain Antibody on Human Prostate Cancer Cells ». Journal of Oncology 2013 (2013) : 1–8. http://dx.doi.org/10.1155/2013/839831.

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Prostate stem cell antigen (PSCA) is a highly glycosylated cell surface protein which is overexpressed in several malignancies including prostate, pancreas, and urinary bladder cancers. Tumor suppression has been reported by anti-PSCA antibody. Small and high affinity single chain antibodies (scFv) have been introduced as effective agents for cancer immunotargeting approaches. In the present study, we used a phage antibody display library of scFv and selected two antibodies against two immunodominant epitopes of PSCA by panning process. The reactivity of the scFvs for the corresponding epitopes was determined by phage ELISA. The binding specificity of antibodies to PSCA-expressing prostate cancer cell line, DU-145, was analyzed by flow cytometry. The antiproliferative and apoptotic induction effects were evaluated by MTT and Annexin-V assays, respectively. Results represented functional scFv C5-II which could bind specifically to DU-145 cells and significantly inhibited the proliferation of these cells (61%) with no effect on PSCA-negative cells. The antibody also induced apoptosis in the PSCA expressing cells. The percentage of the apoptotic cells after 24 hrs of exposure to 500 scFv/cell was 33.80%. These results demonstrate that the functional anti-PSCA scFv C5-II has the potential to be considered as a new agent for targeted therapy of prostate cancer.

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Hodges, Ron. « How might harmonization influence the future prevalence of public sector creative accounting ? » Tékhne 16, n^o 1 (17 novembre 2018) : 3–14. http://dx.doi.org/10.2478/tekhne-2019-0001.

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Abstract This paper considers the significance of future harmonization on public sector creative forms of accounting (PSCA) in the context of both national accounting and government financial reporting. The analysis is carried out through a review of studies provided in the academic and official literatures. Examples are provided of PSCA in a ‘broad’ context of any manipulation of financial information and in a ‘focused’ context, referring to the reporting of deficit / surplus and associated levels of debt. The analysis is related to the influence of harmonization using the classification of information-manipulating behaviour drawn from Birnberg, Turopolec, and Young (1983). There is potential for accounting harmonization to improve the analysability of data to restrict PSCA. However, although many techniques of PSCA have been identified, the drivers and controllers of PSCA remain unclear. Accounting researchers should use their specialist understanding to draw out the differences between apparently consistent frameworks of accounting and to understand the policy effects and social implications of harmonization and related creative forms of accounting. There are relatively few studies of PSCA. This paper represents the first study that seeks to relate PSCA to the increasing tendency towards harmonisation of accounting in the public sector context. An agenda is included to guide researchers towards issues that are worthy of further consideration in this important area of study.

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Plé, Sophie, Viviana Job, Andréa Dessen et Ina Attree. « Cochaperone Interactions in Export of the Type III Needle Component PscF of Pseudomonas aeruginosa ». Journal of Bacteriology 192, n^o 14 (21 mai 2010) : 3801–8. http://dx.doi.org/10.1128/jb.00117-10.

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ABSTRACT Type III secretion (T3S) systems allow the export and translocation of bacterial effectors into the host cell cytoplasm. Secretion is accomplished by an 80-nm-long needle-like structure composed, in Pseudomonas aeruginosa, of the polymerized form of a 7-kDa protein, PscF. Two proteins, PscG and PscE, stabilize PscF within the bacterial cell before its export and polymerization. In this work we screened the 1,320-Å2 interface between the two chaperones, PscE and PscG, by site-directed mutagenesis and determined hot spot regions that are important for T3S function in vivo and complex formation in vitro. Three amino acids in PscE and five amino acids in PscG, found to be relevant for complex formation, map to the central part of the interacting surface. Stability assays on selected mutants performed both in vitro on purified PscE-PscG complexes and in vivo on P. aeruginosa revealed that PscE is a cochaperone that is essential for the stability of the main chaperone, PscG. Notably, when overexpressed from a bicistronic construct, PscG and PscF compensate for the absence of PscE in cytotoxic P. aeruginosa. These results show that all of the information needed for needle protein stabilization and folding, its presentation to the T3 secreton, and its export is present within the sequence of the PscG chaperone.

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Bouslah, Naima, Nabila Haddadine, Farouk Amrani et Rabah Hammachin. « Comparison of specific interactions in P4VP/PSCA and PS4VP/PSCA blends and complexes ». Journal of Applied Polymer Science 108, n^o 5 (2008) : 3256–61. http://dx.doi.org/10.1002/app.28018.

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Ramello, M. Cecilia, Emiliano Roselli et Daniel Abate-Daga. « The length of the intracellular domain conditions the antitumor efficacy of CAR-T cells ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 170.20. http://dx.doi.org/10.4049/jimmunol.204.supp.170.20.

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Abstract Among the variables affecting CAR-T cell function, evidence shows that CAR architecture is a common factor influencing clinical outcomes. Previously, we demonstrated that a 2nd generation (gen.) CAR targeting the prostate stem cell antigen (PSCA) was more efficient than a 3rd gen. counterpart, in a preclinical model of pancreatic adenocarcinoma. This superior anti-tumor capacity was associated with greater tonic signaling. To further characterize this phenomenon, we compared the antitumor activity and phenotype of two 2nd gen. CAR-T cells (CAR-Ts) that differed in the length of the intracellular domain (ICD) by only 24 amino acids: PSCA-8t28Z vs. PSCA-8t(+24)28Z. Upon adoptive transfer into tumor-bearing mice, PSCA-8t28Z CAR-Ts displayed significantly greater antitumor efficacy. This was not due to differences in CAR surface expression, or in trafficking or persistence of T cells, since CAR-T numbers in spleen and tumor were comparable among groups. However, it was associated with significantly higher phosphorylation of CD3ζ in PSCA-8t28Z CAR-Ts in spleen, suggesting spontaneous CAR-signaling activity. Unsupervised analysis revealed that proliferation was similar between CAR-T and GFP T cells in spleen. In contrast, tumor-infiltrating (TI) PSCA-8t28Z CAR-Ts exhibited a cluster of Ki-67hi cells that was absent in the other groups. Moreover, TI PSCA-8t28Z CAR-Ts showed the highest expression of inhibitory receptors, suggesting antigen-induced CAR signaling within the tumor. Together, our results show that shorter ICDs are associated with higher tonic signaling and higher T cell activation after antigen recognition. These data highlights the importance of CAR-ICD length for optimal CAR-T function in solid tumors.

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Dorff, Tanya B., Suzette Blanchard, Patti Carruth, Jamie Wagner, Peter Kuhn, Ammar Chaudhry, Lauren Adkins et al. « A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 38, n^o 6_suppl (20 février 2020) : TPS250. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.tps250.

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TPS250 Background: Although treatment options have improved, mCRPC remains highly lethal. Immunotherapy holds potential for durable remissions but not yet in mCRPC. CAR-T cell therapy has yielded cure for patients with refractory hematologic malignancies, and shows promise in solid tumors. Identifying and targeting the optimal antigen will be key to successful translation in solid tumors. Prostate stem cell antigen (PSCA) is highly expressed on prostate cancer cells, especially metastatic foci, and has limited expression on normal tissues. City of Hope has developed a second-generation PSCA CAR-T cell therapy containing an intracellular 4-1BB co-stimulatory domain (PSCA-BBζ) for first-in-human testing in men with mCRPC refractory to standard therapy (NCT03873805). Methods: The toxicity equivalence range (TEQR) design of Blanchard and Longmate will be used to evaluate select doses of PSCA-BBζ cells and determine the maximum tolerated dose (MTD). Doses include Cohort 1 = 100 million (M) CAR-T x 1 alone; Cohort 1b = 100M CAR-T x1 after lymphodepletion; Cohort 2 = 300M after lymphodepletion; Cohort 3 = 600M after lymphodepletion. 12 subjects will be accrued at the MTD. Eligibility: mCRPC treated with either abiraterone, enzalutamide or both; prior chemotherapy and/or radium223 allowed but not mandated. Tumor tissue, primary or metastatic, must stain positive for PSCA by IHC (Abcam 15168) and biopsy is repeated 28 days post infusion. Endpoints: Primary: all toxicities and dose-limiting toxicities defined as grade 3+ toxicity with attribution of possibly related or above, except CRS grade 3 resolved to < grade 2 within 72 hours or grade 3 encephalopathy resolved to baseline within 28 days. Secondary: persistence/expansion of CAR-T, response (soft tissue by RECIST, bone by PCWG3 criteria). Correlative studies include blood (immunophenotyping, cytokines, circulating tumor cell enumeration and PSCA expression), MRI (enhancement/diffusion changes in target lesions) and metastatic core biopsies (PSCA expression and local immune phenotype changes). Progress: 4 subjects have successfully manufactured PSCA-BBζ T cells; 1 completed treatment. Clinical trial information: NCT03873805.

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Quinaud, Manuelle, Jacqueline Chabert, Eric Faudry, Emmanuelle Neumann, David Lemaire, Alexandrine Pastor, Sylvie Elsen, Andréa Dessen et Ina Attree. « The PscE-PscF-PscG Complex Controls Type III Secretion Needle Biogenesis in Pseudomonas aeruginosa ». Journal of Biological Chemistry 280, n^o 43 (22 août 2005) : 36293–300. http://dx.doi.org/10.1074/jbc.m508089200.

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Type III secretion (T3S) systems play key roles in pathogenicity of many Gram-negative bacteria and are employed to inject toxins directly into the cytoplasm of target cells. They are composed of over 20 different proteins that associate into a basal structure that traverses both inner and outer bacterial membranes and a hollow, needle-like structure through which toxins travel. The PscF protein is the main component of the Pseudomonas aeruginosa T3S needle. Here we demonstrate that PscF, when purified on its own, is able to form needle-like fibers of 8 nm in width and >1 μm in length. In addition, we demonstrate for the first time that the T3S needle subunit requires two cytoplasmic partners, PscE and PscG, in P. aeruginosa, which trap PscF in a ternary, 1:1:1 complex, thus blocking it in a monomeric state. Knock-out mutants deficient in PscE and PscG are non-cytotoxic, lack PscF, and are unable to export PscF encoded extrachromosomally. Temperature-scanning circular dichroism measurements show that the PscE-PscF-PscG complex is thermally stable and displays a cooperative unfolding/refolding pattern. Thus, PscE and PscG prevent PscF from polymerizing prematurely in the P. aeruginosa cytoplasm and keep it in a secretion prone conformation, strategies which may be shared by other pathogens that employ the T3S system for infection.

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Jakobovits, Aya, Kendall Morrison, Xiao-Chi Jia, Hui Shao, Zili An, Arthur B. Raitano, Karen Morrison, Steven B. Kanner et Jean M. Gudas. « AGS-PSCA : A FULLY HUMAN ANTIBODY TO PSCA FOR THE TREATMENT OF PANCREATIC CANCER ». Pancreas 31, n^o 4 (novembre 2005) : 448. http://dx.doi.org/10.1097/01.mpa.0000193690.98329.92.

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Cheng, Fan, Weimin Yu, Xiaobin Zhang et Yuan Ruan. « Quantum-dot-based technology for sensitive and stable detection of prostate stem cell antigen expression in human transitional cell carcinoma ». International Journal of Biological Markers 24, n^o 4 (octobre 2009) : 271–76. http://dx.doi.org/10.1177/172460080902400409.

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Quantum dots (QDs) as a biological labeling material for medical applications need to be evaluated for the sensitivity and stability of their fluorescence. Comparison of QD-based immunolabeling and commonly used immunohistochemical staining in detecting the expression of prostate stem cell antigen (PSCA) in bladder tumor tissues revealed that the two methods had similar sensitivity in the differential display of PSCA expression correlated with tumor stage and grade (κ=0.92, p<0.001). In addition, the intensity of QD fluorescence remained stable for at least 10 days after conjugation to the PSCA protein and nearly 96% of the positive expression in samples lasted for one month.

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Jugel, Willi, Stefanie Tietze, Jennifer Daeg, Dietmar Appelhans, Felix Broghammer, Achim Aigner, Michael Karimov, Gabriele Schackert et Achim Temme. « Targeted Transposition of Minicircle DNA Using Single-Chain Antibody Conjugated Cyclodextrin-Modified Poly (Propylene Imine) Nanocarriers ». Cancers 14, n^o 8 (11 avril 2022) : 1925. http://dx.doi.org/10.3390/cancers14081925.

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Among non-viral vectors, cationic polymers, such as poly(propylene imine) (PPI), play a prominent role in nucleic acid delivery. However, limitations of polycationic polymer-based DNA delivery systems are (i) insufficient target specificity, (ii) unsatisfactory transgene expression, and (iii) undesired transfer of therapeutic DNA into non-target cells. We developed single-chain antibody fragment (scFv)-directed hybrid polyplexes for targeted gene therapy of prostate stem cell antigen (PSCA)-positive tumors. Besides mono-biotinylated PSCA-specific single-chain antibodies (scFv(AM1-P-BAP)) conjugated to neutravidin, the hybrid polyplexes comprise β-cyclodextrin-modified PPI as well as biotin/maltose-modified PPI as carriers for minicircle DNAs encoding for Sleeping Beauty transposase and a transposon encoding the gene of interest. The PSCA-specific hybrid polyplexes efficiently delivered a GFP gene in PSCA-positive tumor cells, whereas control hybrid polyplexes showed low gene transfer efficiency. In an experimental gene therapy approach, targeted transposition of a codon-optimized p53 into p53-deficient HCT116p53−/−/PSCA cells demonstrated decreased clonogenic survival when compared to mock controls. Noteworthily, p53 transposition in PTEN-deficient H4PSCA glioma cells caused nearly complete loss of clonogenic survival. These results demonstrate the feasibility of combining tumor-targeting hybrid polyplexes and Sleeping Beauty gene transposition, which, due to the modular design, can be extended to other target genes and tumor entities.

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Slawin, Kevin Mark, Aruna Mahendravada, Nicholas Shinners, Peter Chang, An Lu, Jeannette Crisostomo, Eva Morschl et al. « Inducible MyD88/CD40 to allow rimiducid-dependent activation for control of proliferation and survival of chimeric antigen receptor (CAR) T cells targeting prostate stem cell antigen (PSCA). » Journal of Clinical Oncology 34, n^o 2_suppl (10 janvier 2016) : 206. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.206.

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206 Background: PSCA is a cell surface antigen that is overexpressed in a majority of metastatic prostate, transitional cell and pancreatic carcinomas. We describe a novel T cell costimulation switch, inducible MyD88/CD40 (iMC), activated by a small molecule, rimiducid, to enhance survival, proliferation and anti-tumor activity of CAR-T cells targeting PSCA. Methods: T cells were transduced with a retrovirus encoding tandem rimiducid-binding domains,cloned in-frame with MyD88 and CD40 signaling elements and first generation CARs (CAR.ζ) targeting PSCA (SFG-iMC-2A-PSCA.ζ). iMC activation was assessed with and without rimiducid treatment of T cells. Coactivation via iMC and CAR was tested in coculture assays with or without rimiducid using various PSCA+tumor cells, e.g. Capan-1 and HPAC pancreatic adenocarcinoma. Efficacy of iMC-modified CAR-T cells in vivo was assessed using an NSG mouse tumor model. Results: T cells transduced with iMC-PSCA.ζ produced cytokines (e.g., IFN-γ and IL-6) in response to rimiducid; however, IL-2 was only produced when both iMC and CAR were activated simultaneously by rimiducid and tumor antigen. Treatment of NSG mice bearing large (> 200 mm3) HPAC tumors with a single i.v. dose of 1x107 iMC-PSCA.ζ cells resulted in complete tumor elimination in 10/10 mice including both rimiducid-treated and untreated animals, compared to mice receiving non-transduced T cells (p = 0.0003). Weekly rimiducid administration dramatically increased CAR-T cell numbers, resulting in a 23-fold expansion of iMC-PSCA.ζ-modified T cells in the spleen compared to mice not receiving rimiducid four weeks after infusion (p = 0.02). In a dose-titration study, rimiducid administration was required for tumor control, and led to 565- and 948-fold T cell expansion at the tumor site, respectively, when lower numbers (1.25x106 or 6.25x105, respectively) of iMC-PSCA.ζ-modified T cells were given. Conclusions: GoCAR-T cells targeting PSCA, which contain an inducible MyD88/CD40 activation switch, may be an effective adoptive cell therapy for patients with pancreatic, prostate, bladder, and other cancers that overexpress PSCA.

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Smith, C., P. Lochhead, U. Basavaraju, G. Hold, N. Fyfe, G. Murray et E. El-Omar. « PWE-075 Lack of association between the PSCA rs2294008 polymorphism, or PSCA expression, and colorectal neoplasia ». Gut 61, Suppl 2 (28 mai 2012) : A327.3—A328. http://dx.doi.org/10.1136/gutjnl-2012-302514d.75.

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Jugel, Willi, Achim Aigner, Susanne Michen, Alexander Hagstotz, Alexander Ewe, Dietmar Appelhans, Gabriele Schackert, Achim Temme et Stefanie Tietze. « Targeted RNAi of BIRC5/Survivin Using Antibody-Conjugated Poly(Propylene Imine)-Based Polyplexes Inhibits Growth of PSCA-Positive Tumors ». Pharmaceutics 13, n^o 5 (8 mai 2021) : 676. http://dx.doi.org/10.3390/pharmaceutics13050676.

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Delivery of siRNAs for the treatment of tumors critically depends on the development of efficient nucleic acid carrier systems. The complexation of dendritic polymers (dendrimers) results in nanoparticles, called dendriplexes, that protect siRNA from degradation and mediate non-specific cellular uptake of siRNA. However, large siRNA doses are required for in vivo use due to accumulation of the nanoparticles in sinks such as the lung, liver, and spleen. This suggests the exploration of targeted nanoparticles for enhancing tumor cell specificity and achieving higher siRNA levels in tumors. In this work, we report on the targeted delivery of a therapeutic siRNA specific for BIRC5/Survivin in vitro and in vivo to tumor cells expressing the surface marker prostate stem cell antigen (PSCA). For this, polyplexes consisting of single-chain antibody fragments specific for PSCA conjugated to siRNA/maltose-modified poly(propylene imine) dendriplexes were used. These polyplexes were endocytosed by PSCA-positive 293TPSCA/ffLuc and PC3PSCA cells and caused knockdown of reporter gene firefly luciferase and Survivin expression, respectively. In a therapeutic study in PC3PSCA xenograft-bearing mice, significant anti-tumor effects were observed upon systemic administration of the targeted polyplexes. This indicates superior anti-tumor efficacy when employing targeted delivery of Survivin-specific siRNA, based on the additive effects of siRNA-mediated Survivin knockdown in combination with scFv-mediated PSCA inhibition.

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Karan, Dev, Seema Dubey et Brantley Thrasher. « Dual antigen target based immunotherapy for prostate cancer eliminates the growth of established tumors in mice (155.3) ». Journal of Immunology 186, n^o 1_Supplement (1 avril 2011) : 155.3. http://dx.doi.org/10.4049/jimmunol.186.supp.155.3.

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Abstract Generation of antigen-specific CD8 T cells is considered optimal for an effective immunotherapy against cancer. Knowing that heterogeneity of prostate cancer limits the therapeutic benefit, we developed a recombinant adenovirus type 5 (rAd5) co-expressing a fusion of PSA (prostate-specific antigen) and PSCA (prostate stem cell antigen) genes. The selection of these genes is based on their restricted distribution within the prostate and their association with the development and progression of prostate cancer. Immunization of mice with rAd5 vector co-expressing PSA and PSCA antigens (Ad5-PSPA) simultaneously induces the expansion of anti-PSA, and anti-PSCA T cells as measured by intracellular cytokine staining for IFN-y. To analyze the impact on therapeutic efficacy of Ad5-PSPA vaccine against the tumor cells co-expressing cognate antigens (RM11-PSA/PSCA cells), injection of mice with Ad5-PSPA vaccine inhibited the growth of established tumors. Initially, the mice developed slow growing tumors and eventually upto 80% of the mice remain tumor free following immunization with Ad5-PSPA vaccine. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and their additive anti-tumor effect has the ability to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials.

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Jain, Anjali, Amanda Lam, Igor Vivanco, Michael F. Carey et Robert E. Reiter. « Identification of an Androgen-Dependent Enhancer within the Prostate Stem Cell Antigen Gene ». Molecular Endocrinology 16, n^o 10 (1 octobre 2002) : 2323–37. http://dx.doi.org/10.1210/me.2002-0004.

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Abstract Prostate stem cell antigen (PSCA) is emerging as an important diagnostic marker and therapeutic target in prostate cancer. Previous studies indicated that PSCA was directly regulated by androgens, but the mechanism has not been elucidated. Here we describe the identification of a compact cell-specific and androgen-responsive enhancer between 2.7 and 3 kb upstream of the transcription start site. The enhancer functions autonomously when positioned immediately adjacent to a minimal promoter. Deoxyribonuclease I footprinting analysis with recombinant androgen receptor (AR) reveals that the enhancer contains two AR binding sites at one end. Mutational analysis of the AR binding sites revealed the importance of the higher affinity one. The dissociation constant of the high affinity binding site (androgen response element I) was determined to be approximately 87 nm. The remainder of the enhancer contains elements that function synergistically with the AR. We discuss the structural organization of the PSCA enhancer and compare it with that found in other AR-regulated genes.

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Diaz, Jose Antonio, Patrick A. Lester, Jeffrey C. Kurz, Shirley K. Wrobleski, Angela E. Hawley, Robert E. Sigler, Thomas W. Wakefield, Robert G. Schaub et Daniel Myers. « Evaluation of a Novel Anti-P-Selectin Aptamer ARC5690 On Venous Inflammation Following Acute Venous Thrombosis. » Blood 114, n^o 22 (20 novembre 2009) : 3599. http://dx.doi.org/10.1182/blood.v114.22.3599.3599.

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Abstract Abstract 3599 Poster Board III-536 Introduction P-selectin is a pro-inflammatory molecule that increases neutrophil recruitment to the vein wall at the site of thrombosis. Aptamers are short single-stranded oligonucleotides with the ability to bind small molecules and diverse proteins such as P-selectin. P-selectin could be targeted by a specific inhibitor or novel aptamer to limit inflammation following deep vein thrombosis (DVT). In this study, the effect of a novel anti-P-selectin aptamer on reducing DVT associated inflammation was evaluated. Methods Male C57BL/6J mice (20-25g) were placed into groups: anti-P-selectin aptamer ARC5690 (APSA, 2mg/kg, 5mg/kg, and 10mg/kg intraperitoneal [IP]), anti-P-selectin control aptamer “scrambled sequence” (PSCA 1mg/kg and 10 mg/kg IP), anti-P-selectin antibody (APSB 0.2mg/kg IP), ligation only (LO), or true control (TC). Inferior vena cava (IVC) ligation, below the renal vein, was performed on all groups except TC. Groups PSCA and APSA received daily injections starting two days pre-IVC ligation and continued up to 3 days post-IVC ligation. Groups TC and LO did not receive test compounds. At 3 days post-IVC ligation, mice were euthanized. The IVC was harvested and weighed or submitted for vein wall morphometric inflammatory cell histological analysis. Blood was collected via cardiac puncture for plasma soluble P-selectin (sP-sel) protein analysis. Data was analyzed using a student t-test and Kruskal-Wallace test with a Dunn's multiple comparison test. Results The total leukocyte counts in APSA groups 5 mg/kg and 10 mg/kg were significantly reduced compared to the PSCA groups and APSA group 2 mg/kg (p<0.05). The inflammatory cell count in APSA groups 5mg/kg and 10mg/kg confirmed this same trend for neutrophils, monocytes, lymphocytes versus the PSCA and APSA 2 mg/kg groups. Increased neutrophil counts were observed in the PSCA group compared to the TC group Figure 1). The thrombus weight (TW) was significantly decreased in the APSA 5mg/kg group compared to the LO group and the PSCA 1mg/kg group (p<0.05). The TW in the APSB group was significantly decreased compared to the LO group, the PSCA group (1mg/kg and 10mg/kg). There was a positive correlation between TW and sP-sel (Spearman correlation r=0.55). Conclusions ARC5690 showed a significant anti-inflammatory effect at the 5 mg/kg and 10 mg/kg doses. A reduction in TW was observed using an anti P-selectin aptamer with a positive correlation between TW and sP-sel levels, providing evidence that sP-sel could be a clinical biomarker of venous thrombosis. The reduction of venous inflammation by p-selectin blockade could have benefit in reducing the sequelae of DVT including venous fibrosis. Disclosures: Kurz: Archemix: Research Funding. Schaub:Archemix: Research Funding.

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Hadji, Noureddine. « More Accurate Formulas for Determination of Absolute Atom Concentration Using Electron Energy-Loss Spectroscopy ». Microscopy and Microanalysis 22, n^o 6 (8 novembre 2016) : 1381–88. http://dx.doi.org/10.1017/s1431927616011776.

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AbstractWhen the value of the dispersion coefficient is “greatly different from 0.5,” as is the case for “free-electron” materials such as sodium (Na), the approximate expression for the volume plasmon critical wave vector (PCV) used by Hadji stops being valid and a different, more precise, expression must be used. Here a more accurate PCV formula is used to get a more accurate expression for plasmon scattering cross-section per atom (PSCA) species. This PSCA is then employed to calculate some physical quantities for several “free-electron” materials and together with the techniques from the quoted paper to determine values for physical quantities from amorphous silicon (a-Si) experimental data. The program source used to obtain these values is supplied. Any valid formula for the PSCA species is, in fact, relevant for use together with the two quoted techniques. The PCV and the dispersion coefficient have upper limits. Negative dispersion coefficient values are allowed. A PCV-related dimensionless universal function that can represent all ideal “free-electron” materials is given. “Not greatly different from 0.5” is mathematically expressed.

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Grant, Anthony M., et Margie Hartley. « Exploring the impact of participation in a Leader as Coach programme using the Personal Case Study Approach ». Coaching Psychologist 10, n^o 2 (décembre 2014) : 51–58. http://dx.doi.org/10.53841/bpstcp.2014.10.2.51.

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Effective coaching skills are an essential part of contemporary leadership. All too frequently organisations invest significant resources into ‘Leader as Coach’ development programmes only to find that, despite initial enthusiasm, coaching skills are not applied back in the workplace. To facilitate such transfer of training we utilised and evaluated a new approach to evaluating and embedding coaching skills, the Personal Case Study Approach (PSCA), and we used this in a large-scale ‘Leader as Coach’ programme for the Commonwealth Bank of Australia (CBA). This paper presents the theoretical rationale underpinning the PSCA, its practical application and data related to its use in a two-day ‘Leader as Coach’ coaching programme. The data indicates that the coaching programme was effective at enhancing quality of leadership and coaching skills as well as increasing participants’ ability to recognise when to coach and when to delegate. The programme also increased workplace engagement. The PSCA, when used in a ‘Leader as Coach’ programme, appears to be an effective way of enhancing and fostering transfer of training.

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Shaw, Joanne, Brandon Ballard, Xiaohui Yi, Aditya Malankar, Matthew R. Collinson-Pautz, Carlos Roberto Becerra, Joseph Paul Woodard et Aaron E. Foster. « Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors. » Journal of Clinical Oncology 38, n^o 4_suppl (1 février 2020) : 734. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.734.

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734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.

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Priceman, Saul J., et Stephen J. Forman. « YIA19-005 : Immunotherapy for Prostate Cancer Combining CAR-Engineered T Cells with Targeted Immune Checkpoint Inhibition ». Journal of the National Comprehensive Cancer Network 17, n^o 3.5 (8 mars 2019) : YIA19–005. http://dx.doi.org/10.6004/jnccn.2018.7213.

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Repairing defects in antitumor immunity has been a longstanding challenge in prostate cancer, and in recent years cellular immunotherapy has emerged as a promising approach for controlling advanced disease. To date, therapies including tumor vaccine and adoptive T-cell immunotherapy have made remarkable headway in solid cancers. Several validated prostate-specific tumor antigens are available as targets for T-cell therapy, including prostate stem cell antigen (PSCA), which is overexpressed in metastatic disease. We are in late-stage preclinical development of PSCA-specific chimeric antigen receptor (CAR)-engineered T cells with plans to initiate a clinical trial early 2019 for the treatment of metastatic castration-resistant prostate cancer. Immune checkpoint pathways, including the programmed cell death protein-1 (PD-1) and the cytotoxic T lymphocyte-associated protein-4 (CTLA4), have emerged as critical drivers of immunosuppression in solid cancers, by limiting both adaptive antitumor immunity as well as adoptive T-cell therapies. Unfortunately in prostate cancer, checkpoint inhibition has led to underwhelming responses, likely due to the low mutational load and immunologically “cold” tumor microenvironment. We hypothesize that antitumor activity of PSCA-CAR T cells will elicit checkpoint pathways that dampen antitumor immune responses and reduce overall clinical outcomes. Herein, we utilize an shRNA approach to knockdown checkpoint receptors as a rational combinatorial strategy that targets checkpoint pathways to improve overall therapy with PSCA-CAR T cells for metastatic prostate cancer. We have successfully developed a multiple shRNA knockdown approach to simultaneously disrupt 3 pathways that may hamper CAR T-cell activity in the tumor. These CAR T cells with shRNA knockdown of checkpoint receptors will be directly compared with checkpoint pathway inhibitor antibody therapies in xenograft models of prostate cancer, with the hope that next generation CARs will resist this break on the immune system in solid tumors.

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Kaskel, Anna K., Robert Zeiser, Rosa Jochim, Wolfgang Schultze-Seemann, Cornelius Waller et Hendrik Veelken. « Vaccination of Advanced Prostate Cancer Patients with PSCA and PSA Peptide-Loaded Dendritic Cells Induces Cellular Immune Responses That Correlate with Superior Overall Survival. » Blood 106, n^o 11 (16 novembre 2005) : 2394. http://dx.doi.org/10.1182/blood.v106.11.2394.2394.

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Abstract Prostate stem cell antigen (PSCA) and prostate-specific antigen (PSA) are overexpressed in most prostate cancers. PSCA- and PSA-derived, HLA-A2 binding peptides are specific targets for T cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety, and induction of antigen-specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone- and chemotherapy-refractory prostate cancer. Patients received four vaccinations with median of 2.7x10e7 peptide-loaded mature DC s.c. in biweekly intervals. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease (SD) after four vaccinations. One patient had a complete disappearance of lymphadenopathy by ultrasound despite rising PSA. Regarding PSA kinetics, in one patient, the log PSA slope became negative after treatment, and three patients had significant decreases in the log PSA slopes. However, duration of response was short, with a median time to progression of 65 days (12–223). Four patients with SD and one progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH-positivity was associated with significantly superior survival (22 vs. 8 months, p=0.003). HLA tetramer analysis detected high frequencies of peptide-specific T cells after two vaccinations in one patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Taken together, vaccination with PSA/PSCA peptide-loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients which were associated with superior outcome. The retardation of PSA kinetics upon vaccination suggest a causal influence of the treatment on the natural course of the disease. Testing of DC-based vaccination is warranted for patients at earlier stages of prostate cancer.

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Hishida, Asahi, Tomotaka Ugai, Ryosuke Fujii, Masahiro Nakatochi, Michael C. Wu, Hidemi Ito, Isao Oze et al. « GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy ». Carcinogenesis 40, n^o 5 (8 février 2019) : 661–68. http://dx.doi.org/10.1093/carcin/bgz016.

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Abstract Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10−7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10−8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10−27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

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Tanikawa, Chizu, Keitaro Matsuo, Michiaki Kubo, Atsushi Takahashi, Hidemi Ito, Hideo Tanaka, Yasushi Yatabe et al. « Impact of PSCA Variation on Gastric Ulcer Susceptibility ». PLoS ONE 8, n^o 5 (21 mai 2013) : e63698. http://dx.doi.org/10.1371/journal.pone.0063698.

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Joosten, M. « Leukemic predisposition of pSca-1/Cb2 transgenic mice ». Experimental Hematology 30, n^o 2 (février 2002) : 142–49. http://dx.doi.org/10.1016/s0301-472x(01)00779-2.

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Geng, Peiliang, Jianjun Li, Ning Wang, Juanjuan Ou, Ganfeng Xie, Chen Liu, Xiaoxin Zhao, Lisha Xiang, Yunmei Liao et Houjie Liang. « PSCA rs2294008 Polymorphism with Increased Risk of Cancer ». PLOS ONE 10, n^o 8 (26 août 2015) : e0136269. http://dx.doi.org/10.1371/journal.pone.0136269.

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Descamps, Géraldine, Ruddy Wattiez et Sven Saussez. « Proteomic Study of HPV-Positive Head and Neck Cancers : Preliminary Results ». BioMed Research International 2014 (2014) : 1–16. http://dx.doi.org/10.1155/2014/430906.

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Human papillomavirus (HPV) was recently recognized as a new risk factor for head and neck squamous cell carcinoma. For oropharyngeal cancers, an HPV+ status is associated with better prognosis in a subgroup of nonsmokers and nondrinkers. However, HPV infection is also involved in the biology of head and neck carcinoma (HNC) in patients with a history of tobacco use and/or alcohol consumption. Thus, the involvement of HPV infection in HN carcinogenesis remains unclear, and further studies are needed to identify and analyze HPV-specific pathways that are involved in this process. Using a quantitative proteomics-based approach, we compared the protein expression profiles of two HPV+ HNC cell lines and one HPV− HNC cell line. We identified 155 proteins that are differentially expressed (P<0.01) in these three lines. Among the identified proteins, prostate stem cell antigen (PSCA) was upregulated and eukaryotic elongation factor 1 alpha (EEF1α) was downregulated in the HPV+ cell lines. Immunofluorescence and western blotting analyses confirmed these results. Moreover, PSCA and EEF1αwere differentially expressed in two clinical series of 50 HPV+ and 50 HPV− oral cavity carcinomas. Thus, our study reveals for the first time that PSCA and EEF1αare associated with the HPV-status, suggesting that these proteins could be involved in HPV-associated carcinogenesis.

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Yamaguchi, Yukiko, Jackson Gibson, Kevin Ou et Saul Priceman. « 224 M2 macrophage-mediated immune suppression of chimeric antigen receptor T cells via PD-L1 signaling in prostate cancer ». Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembre 2021) : A238. http://dx.doi.org/10.1136/jitc-2021-sitc2021.224.

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BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and anti-tumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant macrophages, and infiltration of M2 macrophages correlates with metastasis and poor prognosis.MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, prostate stem cell antigen (PSCA)-directed CAR T cells, and polarized macrophages. To investigate the TME in vivo, we took advantage of ”humanized” MISTRG mice, which are immunocompromised mice with knocked-in human genes that support human hematopoiesis and efficient tumor-infiltration of myeloid cell populations. Humanized MISTRG mice were intratibially engrafted with LAPC9 tumor cells to model bone metastatic disease.ResultsWe observed significant hampering of PSCA-CAR T cell activity in vitro with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of PD-L1 in both tumor cells and macrophages. We also observed PD-L1 expression in tumor-associated macrophages infiltrating tumors following PSCA-CAR T cell therapy in the humanized mice. Anti-PD-L1 monoclonal antibodies in combination with CAR-T cell therapy altered phenotype and survival of M2 macrophages, resulting in improved anti-tumor activity of PSCA-CAR T cells in the presence of M2 macrophages.ConclusionsRecently, immune checkpoint (IC) blockade (ICB) has been utilized in combination with chimeric antigen receptor (CAR) T cell therapy, with the notion that induction of immune responses with CAR T cells may instigate checkpoint pathways in immunologically cold tumors that would otherwise not respond to ICB. This study gives insights to a mechanism by which CAR T cells and ICB work in synergy to modulate immune landscape of immunologically cold tumors, and our ongoing studies will continue to elucidate the TME-mediated immunosuppression of CAR T cell therapy.

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Liu, Wen-Kang, Xiang-Yang Jiang et Zhen-Xi Zhang. « Expression of PSCA, PIWIL1, and TBX2 in Endometrial Adenocarcinoma ». Onkologie 33, n^o 5 (2010) : 241–45. http://dx.doi.org/10.1159/000305098.

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Becerra, Carlos Roberto, Pamela Hoof, Andrew Scott Paulson, Gulam Abbas Manji, Olivia Gardner, Aditya Malankar, Joanne Shaw et al. « Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors : Preliminary results from a dose escalation. » Journal of Clinical Oncology 37, n^o 4_suppl (1 février 2019) : 283. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.283.

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283 Background: PSCA, a cell surface protein, is upregulated in many solid tumors and correlates with disease stage. BPX601 is an autologous, T-cell product engineered to contain a PSCA-CD3ζ CAR plus the small molecule rimiducid (Rim)-inducible MyD88/CD40 costimulatory domain. BPX601 is optimized for antigen-directed and independent T cell activation, proliferation and persistence, potentially enhancing efficacy in solid tumors versus traditional CARs. This first-in-human study assesses the safety, biological and clinical activity of BPX601 plus Rim in select PSCA-positive cancers. Methods: NCT02744287 is a two-part, open-label trial. Part 1 is an ongoing 3+3 cell dose escalation to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single Rim dose (0.4 mg/kg; Day 7). Eligibility criteria include previously treated metastatic pancreatic cancer (mPDAC) with measurable disease & positive PSCA expression. Results: Patients received only cyclophosphamide (CTX) for lymphodepletion (LD) within three days before BPX601 infusion. Nine adults have been treated across three cell dose levels (cells/kg): 1.25x106 (cells only), 1.25x106+Rim, 2.5x106+Rim. All had mPDAC with ≥ two prior therapies. Common AEs were fatigue and nausea. No DLTs, related SAEs, neurotoxicity or CRS events were reported. Rapid cell engraftment by Day 4 was observed in all patients. No evidence of LD with CTX was seen. Of six patients that received Rim: two had cell expansion 10- to 20-fold within seven days; two had cell persistence > three weeks; all had elevated serum cytokines (IP-10, TNFα) correlated with cell expansion. Best response after ≥ one scan was 4 SD ≥ eight weeks with two minor responses (not confirmed; one patient had matched CA19-9 decrease) and 2 PD. Disease control without new therapy was 16 and > 11 weeks (ongoing) in one and two patients, respectively. Conclusions: BPX601 with single-dose Rim was well-tolerated and resulted in enhanced T cell expansion and prolonged persistence in some patients despite lack of LD. Evidence of clinical benefit in this heavily pretreated mPDAC population was seen. Part 2 is planned to open soon and will include CTX/fludarabine LD to maximize engraftment as well as gastric and prostate cancers. Clinical trial information: NCT02744287.

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Ma, Hong, Shuguang Huang, Carlos Becerra et Annemarie Moseley. « mRNA expression of PSCA and ERBB2 in pancreatic ductal adenocarcinoma. » Journal of Clinical Oncology 34, n^o 15_suppl (20 mai 2016) : e15709-e15709. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.e15709.

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Dorff, Tanya B., Suzette Blanchard, Hripsime Martirosyan, Lauren Adkins, Gaurav Dhapola, Aidan Moriarty, Jamie R. Wagner et al. « Phase 1 study of PSCA-targeted chimeric antigen receptor (CAR) T cell therapy for metastatic castration-resistant prostate cancer (mCRPC). » Journal of Clinical Oncology 40, n^o 6_suppl (20 février 2022) : 91. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.091.

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91 Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We undertook a phase 1, first-in-human study of a PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. The trial followed the Target equivalence range design with an equivalence range of.20-.35 and too toxic level of 0.51 following participants in cohorts of 3. The plan was to begin at a dose of 100 million (M) without lymphodepletion (LD) chemotherapy consisting of fludarabine and cyclophosphamide, then add LD to 100M prior to dose escalation to maximum 600M. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on prior chemotherapy or other treatments. Primary objective is to define the dose limiting toxicity (DLT) and recommended phase 2 dose as well as to describe preliminary bioactivity and efficacy. Correlative studies include MRI for target bone lesion response, CAR T cell persistence, circulating tumor cells, and serum cytokines. Results: 12 pts have been treated to date, median age 68 (42-72). Three pts were treated at the 100M dose with no DLTs. In the 100M plus LD dose level there 2 pts experienced DLT of grade 3 cystitis non-infective and fatigue. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3 and intensify monitoring with early intervention for cystitis. No DLT occurred in 3 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), DLTs and best response by RECIST are presented by dose level in the table. PSA declines (one >90%) were seen as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Correlative studies indicated bioactivity of PSCA-CAR T cells. Conclusions: PSCA-CAR T cell therapy is feasible in pts with mCRPC with DLT of cystitis, and shows preliminary anti-tumor effect at a dose of 100M plus LD. Dose escalation to 300M may proceed. Clinical trial information: NCT03873805. [Table: see text]

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Jakobovits, A., J. M. Gudas, X. Jia, K. Morrison, Z. An, H. Shao, A. B. Raitano, K. J. Morrison, P. Challita et S. B. Kanner. « Therapeutic potential of AGS-PSCA : A fully human monoclonal antibody to prostate stem cell antigen (PSCA) for the treatment of prostate and pancreatic cancers ». Journal of Clinical Oncology 23, n^o 16_suppl (juin 2005) : 4722. http://dx.doi.org/10.1200/jco.2005.23.16_suppl.4722.

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Liu, Haiyan, Jianhui Shi, Vasuki Anandan, Hanlin L. Wang, David Diehl, Joseph Blansfield, Glenn Gerhard et Fan Lin. « Reevaluation and Identification of the Best Immunohistochemical Panel (pVHL, Maspin, S100P, IMP-3) for Ductal Adenocarcinoma of the Pancreas ». Archives of Pathology & ; Laboratory Medicine 136, n^o 6 (1 juin 2012) : 601–9. http://dx.doi.org/10.5858/arpa.2011-0326-oa.

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Context.—Differentiation of ductal adenocarcinoma of the pancreas from nonneoplastic pancreatic tissues can be challenging, especially in small biopsy and fine-needle aspiration specimens. Objective.—To investigate the utility of 26 immunohistochemical markers (CAM 5.2, CK [cytokeratin] 7, CK20, CK17, CK19, MUC1, MUC2, MUC4, MUC5AC, MUC6, p53, DPC4/SMAD4, CDX2, pVHL [von Hippel-Lindau tumor suppressor gene protein], S100P, IMP-3 [insulin-like growth factor 2 messenger RNA binding protein 3], maspin, mesothelin, claudin 4, claudin 18, annexin A8, fascin, PSCA [prostate stem cell antigen], MOC31, CEA [carcinoembryonic antigen], and CA19-9 [cancer antigen 19-9]) in the diagnosis of ductal adenocarcinoma of the pancreas. Design.—Immunohistochemical staining for these markers was performed in 60 cases of pancreatic ductal adenocarcinoma on routine and tissue microarray sections. In addition, immunohistochemical staining for maspin, S100P, IMP-3, and pVHL was performed on cell blocks from 67 pancreatic fine-needle aspiration cases, including 44 cases of pancreatic ductal adenocarcinoma. Results.—The results demonstrated that (1) more than 90% of cases of ductal adenocarcinoma were positive for maspin, S100P, and IMP-3; (2) nearly all adenocarcinoma cases were negative for pVHL, whereas nonneoplastic ducts and acini were positive for pVHL in all cases; (3) normal/reactive pancreatic ducts were frequently positive for CK7, CK19, MUC1, MUC6, CA19-9, MOC31, PSCA, mesothelin, annexin A8, claudin 4, and claudin 18; (4) normal pancreatic ducts were usually negative for IMP-3, maspin, S100P, CK17, MUC2, MUC4, and MUC5AC; (5) 60% of adenocarcinomas were negative for DPC4/SMAD4; and (6) strong background staining was frequently seen with fascin, PSCA, and annexin A8. Conclusions.—pVHL, maspin, S100P, and IMP-3 constitute the best diagnostic panel of immunomarkers for confirming the diagnosis of pancreatic ductal adenocarcinoma in both surgical and fine-needle aspiration specimens.

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Becerra, Carlos Roberto, Gulam Abbas Manji, Dae Won Kim, Olivia Gardner, Aditya Malankar, Joanne Shaw, Devin Blass, Xiaohui Yi, Aaron E. Foster et Paul Woodard. « Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors : Preliminary results with cyclophosphamide (Cy) ± fludarabine (Flu) lymphodepletion (LD). » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 2536. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2536.

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2536 Background: Cell-surface protein PSCA is upregulated in many solid tumors and correlates with disease stage. BPX-601, an autologous T-cell product expressing a PSCA-CD3ζ CAR and a rimiducid (Rim)-inducible MyD88/CD40 co-activation switch to augment T-cell proliferation and persistence, is designed to have enhanced efficacy in solid tumors vs traditional CARs. This ongoing first-in-human study assesses safety, biologic, and clinical activity of BPX-601+Rim in PSCA+ cancers. Updated results, including those from patients (pts) who underwent LD with Flu/Cy, are presented. Methods: BP-012 is a 2-part, open-label trial. Part 1 is a 3+3 dose escalation of BPX-601 (1.25–5.0x106 cells/kg; Day [D] 0) given prior to a single, fixed Rim dose (0.4 mg/kg; D7) in pts with previously treated PSCA+ metastatic pancreatic, gastric, or prostate cancers with measurable disease. Results: As of Jan-22-2019, 15 pts have received BPX-601±Rim. Two pts at the highest cell dose received Flu/Cy for LD on D−5 to D−3 before BPX-601; LD after Flu/Cy was 96.6% and 84.3%. Thirteen pts received Cy alone on D−3; in these pts, LD ranged from 0–68.6%. Rapid cell expansion by D4 was observed in all pts with peak vector copy number 8.3-fold higher with Flu/Cy (n = 2) vs Cy LD (n = 13). Serum IP-10, IL-6 and TNFα increased > 2-fold from baseline in ≥1 pt in all Rim cohorts, with 3- to 20-fold Rim-dependent cell expansion in 6 pts. No CRS or DLTs were reported. After Rim, one Flu/Cy pt experienced a serious Grade 2 AE (encephalopathy) related to BPX-601+Rim that resolved with IV steroids; despite time-matched nonserious Grade 1 pyrexia, the pt had no other CRS symptoms. After BPX-601+Rim and ≥1 scan, best responses were 8 SD and 3 PD (1 non-evaluable). With a median follow-up of 9.8 wks, time to next treatment (tx) after BPX-601 ranged from 2.7–22.1 wks (n = 8) and ongoing tx-free intervals range from 9.1–30.1 wks (n = 4). Conclusions: BPX-601+Rim was well-tolerated with manageable safety and early evidence of enhanced CAR T-cell expansion and prolonged persistence after Flu/Cy vs Cy. Additional pts will undergo Flu/Cy LD prior to BPX-601 with single- and repeat-dose Rim. Clinical trial information: NCT02744287.

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Maalla, Allam, Qiwei Jia, Donghua Zheng et Lizhu Ye. « Research on Double-Circuit Direct Current Control System Based on PSCA ». IOP Conference Series : Earth and Environmental Science 687, n^o 1 (1 mars 2021) : 012066. http://dx.doi.org/10.1088/1755-1315/687/1/012066.

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Qiu, Li-Xin, Lei Cheng, Jing He, Zhi-Rui Zhou, Meng-Yun Wang, Fei Zhou, Wei-Jian Guo et al. « PSCA polymorphisms and gastric cancer susceptibility in an eastern Chinese population ». Oncotarget 7, n^o 8 (2 février 2016) : 9420–28. http://dx.doi.org/10.18632/oncotarget.7137.

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Watabe, T., M. Lin, H. Ide, A. A. Donjacour, G. R. Cunha, O. N. Witte et R. E. Reiter. « Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter ». Proceedings of the National Academy of Sciences 99, n^o 1 (18 décembre 2001) : 401–6. http://dx.doi.org/10.1073/pnas.012574899.

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Bajgain, Pradip, Roopa Mucharla, Usanarat Anurathapan, Natalia Lapteva, Ann M. Leen, Helen E. Heslop, Cliona M. Rooney et Juan F. Vera. « Optimizing the Manufacture of CAR-T Cells for Clinical Applications ». Blood 120, n^o 21 (16 novembre 2012) : 348. http://dx.doi.org/10.1182/blood.v120.21.348.348.

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Abstract Abstract 348 Chimeric antigen receptors (CARs) are artificial molecules that can be used to redirect T cell immune response against antigens expressed on the surface of tumor cells. Recent encouraging clinical data from our group and others has shown that T cells engineered with these molecules can effectively traffic to distant tumor sites, penetrate even bulky disease, and eradicate disseminated tumors. Although promising, most current protocols expand engineered T cells non-specifically using IL2 and OKT3, which often results in a decrease in the frequency of transgenic populations over time. Additionally, cell expansion using conventional cultureware is complicated and labor intensive, which limits the broader application of this therapy. With the purpose of optimizing and streamlining CAR-T cell manufacture, we assessed whether cell expansion could be improved by: (i) supplementing non-specific stimuli (IL2) with an artificial antigen presenting cell (a-APC) engineered to express cognate antigen and co-stimulatory molecules, and (ii) efficiently and rapidly expanding cells in a simple and scalable gas permeable culture device (G-Rex), developed by Wilson Wolf Manufacturing for expanding suspension cells. As a proof of principle, we sought to expand T cells engineered with a CAR targeting the prostate cancer antigen, PSCA. We first generated an antigen-expressing a-APC cell line by modifying K562 cells, which already expressed a range of co-stimulatory molecules including CD80, CD86, and 41BBL, with a retroviral vector encoding the PSCA antigen. After the co-culture of CAR-PSCA T cells with the irradiated a-APC, we found that a-APCs co-expressing PSCA antigen, CD80, and 41BBL were the most effective in inducing T cell expansion, with a 1.9 fold increase in total cell numbers when compared with CAR T cells expanded in the presence of IL2 alone. We also saw an increase in the frequency of transgenic CAR-modified T cells in cultures expanded in the presence of a-APCs co-expressing PSCA antigen, CD80, and 41BBL, which increased from 36.5% CAR-modified cells to 88.1% after 10 days of culture. In contrast, the percentage of transgenic T cells was sustained when culture in the presence of IL2 (36.5% on day 0 and 37.2% on day 10). Thus, culture of CAR-T cells with antigen-expressing a-APCs not only improves total cell output, but also enriches for transgene-expressing. Next, to assess whether we could scale up cell production for clinical application we transferred the engineered a-APCs and CAR-PSCA modified T cells (at a 2:1 ratio) into a static GMP-compliant G-Rex with a surface area of 100cm2. In these G-Rex devices, O2 and CO2 are exchanged across a silicone membrane at the base, which allows for the addition of an increased depth of medium above the cells, providing more nutrients while the waste products are diluted. These culture conditions have been shown to increase cell output when compared with conventional commercial products such as bags, flasks, and 24-well tissue culture plates, without increasing the number of cell doublings. From an initial seeding density of 25E+06 CAR-modified T cells (0.25E+06 cells per cm2), we obtained a total of 2200–2500E+06 cells (22-25E+06 T cells per cm2) within 10 days of culture. Thus, without any intervention we obtained a 93 fold increase in cell numbers using only 1 liter of T cell culture media. As expected, the co-culture of antigen-expressing a-APCs with CAR-T cells also resulted in an enrichment of transgenic T cells (from 33.2% to 81.7% after 10 days of culture). Thus, we achieved a 2.4±1.2 fold increase in the frequency of transgenic T cells. Taken together the total T cell fold expansion (93) and the enrichment for the transgene (2.4±1.2), we calculate a 223.5±111.6 fold expansion of CAR T cells with 10 days of culture. Importantly we demonstrated the robustness of this manufacture process by successfully extending this approach to other CAR T cell products. Disclosures: Vera: Wilson Wolf Manufacturing: Consultancy.

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Usui, Yoshiaki, Keitaro Matsuo, Isao Oze, Tomotaka Ugai, Yuriko Koyanagi, Yoshinobu Maeda, Hidemi Ito et al. « Impact of PSCA Polymorphisms on the Risk of Duodenal Ulcer ». Journal of Epidemiology 31, n^o 1 (5 janvier 2021) : 12–20. http://dx.doi.org/10.2188/jea.je20190184.

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Wang, S., J. Tang, M. Wang, L. Yuan et Z. Zhang. « Genetic variation in PSCA and bladder cancer susceptibility in a Chinese population ». Carcinogenesis 31, n^o 4 (18 janvier 2010) : 621–24. http://dx.doi.org/10.1093/carcin/bgp323.

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Zhang, Xiaopeng, Changming Yu, Jian Zhao, Ling Fu, Shaoqiong Yi, Shuling Liu, Ting Yu et Wei Chen. « Vaccination with a DNA vaccine based on human PSCA and HSP70 adjuvant enhances the antigen-specific CD8+ T-cell response and inhibits the PSCA+ tumors growth in mice ». Journal of Gene Medicine 9, n^o 8 (2007) : 715–26. http://dx.doi.org/10.1002/jgm.1067.

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Iwasaki, Risa L., Koji Ishiya, Hideaki Kanzawa-Kiriyama, Yosuke Kawai, Jun Gojobori et Yoko Satta. « Evolutionary History of the Risk of SNPs for Diffuse-Type Gastric Cancer in the Japanese Population ». Genes 11, n^o 7 (10 juillet 2020) : 775. http://dx.doi.org/10.3390/genes11070775.

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A genome wide association study reported that the T allele of rs2294008 in a cancer-related gene, PSCA, is a risk allele for diffuse-type gastric cancer. This allele has the highest frequency (0.63) in Japanese in Tokyo (JPT) among 26 populations in the 1000 Genomes Project database. FST ≈ 0.26 at this single nucleotide polymorphism is one of the highest between JPT and the genetically close Han Chinese in Beijing (CHB). To understand the evolutionary history of the alleles in PSCA, we addressed: (i) whether the C non-risk allele at rs2294008 is under positive selection, and (ii) why the mainland Japanese population has a higher T allele frequency than other populations. We found that haplotypes harboring the C allele are composed of two subhaplotypes. We detected that positive selection on both subhaplotypes has occurred in the East Asian lineage. However, the selection on one of the subhaplotypes in JPT seems to have been relaxed or ceased after divergence from the continental population; this may have caused the elevation of T allele frequency. Based on simulations under the dual structure model (a specific demography for the Japanese) and phylogenetic analysis with ancient DNA, the T allele at rs2294008 might have had high frequency in the Jomon people (one of the ancestral populations of the modern Japanese); this may explain the high T allele frequency in the extant Japanese.

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Xu, Li-pu, Hai-bo Qiu, Shu-qiang Yuan, Yong-ming Chen, Zhi-wei Zhou et Ying-bo Chen. « Downregulation of PSCA promotes gastric cancer proliferation and is related to poor prognosis ». Journal of Cancer 11, n^o 9 (2020) : 2708–15. http://dx.doi.org/10.7150/jca.33575.

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