34 results on '"Levy-Barda A"'
Search Results
2. Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy
- Author
-
Jair Bar, Raya Leibowitz, Niels Reinmuth, Astrid Ammendola, Eyal Jacob, Mor Moskovitz, Adva Levy-Barda, Michal Lotem, Rivka Katsenelson, Abed Agbarya, Mahmoud Abu-Amna, Maya Gottfried, Tatiana Harkovsky, Ido Wolf, Ella Tepper, Gil Loewenthal, Ben Yellin, Yehuda Brody, Nili Dahan, Maya Yanko, Coren Lahav, Michal Harel, Shani Raveh Shoval, Yehonatan Elon, Itamar Sela, Adam P. Dicker, and Yuval Shaked
- Subjects
PD-1 ,PD-L1 ,NSCLC ,proteomics ,biological process ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionImmune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.MethodsPre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes.ResultsThe levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage.ConclusionsOur study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.
- Published
- 2024
- Full Text
- View/download PDF
3. Is serum‐derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study
- Author
-
Orit Uziel, Andrew A. Kanner, Einat Beery, Sapir Lev, Meir Lahav, Suzana Horn‐Fichman, Sagi Har Nof, Yuseph Laviv, S. Yust‐Katz, Alexandra Amiel, Ramez Abu Shkara, Mustafa Siddeeq, Adva Levy‐Barda, Pia Raanani, Yaron Sela, Zvi Cohen, and Tali Siegal
- Subjects
atypical meningioma ,exosomes ,glioblastoma ,liquid biopsy ,meningioma ,telomerase ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e‐hTERT‐trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. Methods Exosomes were isolated from the pre‐operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e‐hTERT‐trans were measured in 81 healthy controls, 117 meningiomas, 17 low‐grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e‐hTERT‐trans. Results The upper normal limit of controls e‐hTERT‐trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17 ± 11.7) versus with recurrence (3.59 ± 4.42; p = 0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. Conclusions We demonstrated for the first time that the expression of e‐hTERT‐trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.
- Published
- 2024
- Full Text
- View/download PDF
4. 1229 Pre-treatment plasma proteomics-based predictive biomarkers for immune related adverse events in non-small cell lung cancer
- Author
-
Jarushka Naidoo, Igor Puzanov, Jair Bar, Niels Reinmuth, Alona Zer, Michal Harel, Adam Dicker, Michal Lotem, Anirban Chatterjee, Mahmoud Abu-Amna, Mor Moskovitz, Adam Hassani, Itamar Sela, Yehonatan Elon, Iris Kamer, Adva Levy-Barda, Abed Agbarya, Ina Koch, David Farrugia, Gillian Price, Tatiana Harkovsky, Rivka Katzenelson, Ben Yelin, and Raya Leibowitz
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
5. Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity
- Author
-
Modi Safra, Zvi Tamari, Pazit Polak, Shachaf Shiber, Moshe Matan, Hani Karameh, Yigal Helviz, Adva Levy-Barda, Vered Yahalom, Avi Peretz, Eli Ben-Chetrit, Baruch Brenner, Tamir Tuller, Meital Gal-Tanamy, and Gur Yaari
- Subjects
machine learning ,BCR ,AIRR-seq ,COVID-19 ,somatic hypermutation ,B cell ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionThe success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance.MethodsWe report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls.ResultsIn contrast to previous studies, our approach successfully stratifies non-infected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients.DiscussionThese features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges.
- Published
- 2023
- Full Text
- View/download PDF
6. Detection of gene mutations and gene–gene fusions in circulating cell‐free DNA of glioblastoma patients: an avenue for clinically relevant diagnostic analysis
- Author
-
Vikrant Palande, Tali Siegal, Rajesh Detroja, Alessandro Gorohovski, Rainer Glass, Charlotte Flueh, Andrew A. Kanner, Yoseph Laviv, Sagi Har‐Nof, Adva Levy‐Barda, Marcela Viviana Karpuj, Marina Kurtz, Shira Perez, Dorith Raviv Shay, and Milana Frenkel‐Morgenstern
- Subjects
circulating cell‐free DNA ,druggable ,gene mutation ,gene‐gene fusion ,glioblastoma ,liquid biopsy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell‐free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole‐genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene–gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL−1), as compared to healthy controls (1.4 ± 0.4 ng·mL−1) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene–gene fusion database, ChiTaRS 5.0, we identified gene–gene fusions in cfDNA and tumour DNA, such as KDR–PDGFRA and NCDN–PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR–ABL1 (in 8% of patients), COL1A1–PDGFB (8%), NIN–PDGFRB (8%), and FGFR1–BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L–ROS1 and GOPC–ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene–gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real‐time information on the evolving molecular landscape of the tumour.
- Published
- 2022
- Full Text
- View/download PDF
7. Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis
- Author
-
Sarit Cohen-Kedar, Efrat Shaham Barda, Keren Masha Rabinowitz, Danielle Keizer, Hanan Abu-Taha, Shoshana Schwartz, Kawsar Kaboub, Liran Baram, Eran Sadot, Ian White, Nir Wasserberg, Meirav Wolff-Bar, Adva Levy-Barda, and Iris Dotan
- Subjects
Candida albicans ,intestinal epithelial cells ,LC3-associated phagocytosis ,organoids ,dectin-1 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundIntestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3-associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles via LAP.MethodsColonic (n=18) and ileal (n=4) organoids from individuals undergoing bowel resection were grown as monolayers. Fluorescent-dye conjugated zymosan (β-glucan particle), heat-killed- and UV inactivated C. albicans were applied to differentiated organoids and to human IEC lines. Confocal microscopy was used for live imaging and immuno-fluorescence. Quantification of phagocytosis was carried out with a fluorescence plate-reader.Resultszymosan and C. albicans particles were phagocytosed by monolayers of human colonic and ileal organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases.ConclusionsOur results show that human IECs sense luminal fungal particles and internalize them via LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi.
- Published
- 2023
- Full Text
- View/download PDF
8. Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα
- Author
-
Edelman-Klapper, Hadar, Zittan, Eran, Bar-Gil Shitrit, Ariella, Rabinowitz, Keren Masha, Goren, Idan, Avni-Biron, Irit, Ollech, Jacob E., Lichtenstein, Lev, Banai-Eran, Hagar, Yanai, Henit, Snir, Yifat, Pauker, Maor H., Friedenberg, Adi, Levy-Barda, Adva, Segal, Arie, Broitman, Yelena, Maoz, Eran, Ovadia, Baruch, Golan, Maya Aharoni, Shachar, Eyal, Ben-Horin, Shomron, Perets, Tsachi-Tsadok, Ben Zvi, Haim, Eliakim, Rami, Barkan, Revital, Goren, Sophy, Navon, Michal, Krugliak, Noy, Werbner, Michal, Alter, Joel, Dessau, Moshe, Gal-Tanamy, Meital, Freund, Natalia T., Cohen, Dani, and Dotan, Iris
- Published
- 2022
- Full Text
- View/download PDF
9. Serologic Response and Safety after a Third Dose of the COVID-19 BNT162b2 Vaccine in Patients with Inflammatory Bowel Diseases
- Author
-
Hadar Edelman-Klapper, Keren Masha Rabinowitz, Eran Zittan, Ariella Bar-Gil Shitrit, Idan Goren, Irit Avni-Biron, Jacob E. Ollech, Lev Lichtenstein, Hagar Banai-Eran, Henit Yanai, Yifat Snir, Maor H. Pauker, Adi Friedenberg, Adva Levy-Barda, Yelena Broitman, Haim Ben Zvi, Tsachi-Tsadok Perets, Rami Eliakim, Revital Barkan, Sophy Goren, Dani Cohen, and Iris Dotan
- Subjects
COVID-19 ,anti-TNFα ,inflammatory bowel diseases ,BNT162b2 vaccine ,Medicine - Abstract
Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population.
- Published
- 2023
- Full Text
- View/download PDF
10. Three-month follow-up of durability of response to the third dose of the SARS-CoV-2 BNT162b2 vaccine in adults aged 60 years and older: a prospective cohort study
- Author
-
Noa Eliakim-Raz, Haim Ben-Zvi, Erez Bar-Haim, Salomon M Stemmer, Amos Stemmer, Yaara Leibovici-Weisman, Asaf Ness, Muhammad Awwad, Nassem Ghantous, Noam Erez, Avital Bareket-Samish, Adva Levy-Barda, and Neta Moskovits
- Subjects
Medicine - Abstract
Objective To evaluate the durability of response 3 months after the third BNT162b2 vaccine in adults aged 60 years and older.Design Prospective cohort study.Setting Single tertiary centre.Participants Healthcare workers/family members aged ≥60 years old who received the third BNT162b2 dose.Interventions Blood samples were drawn immediately before (T0), 10–19 days (T1) and 74–103 days (T2) after the third dose.Primary and secondary outcome measures Anti-spike IgG titres were determined using a commercial assay and seropositivity was defined as ≥50 arbitrary units (AU)/mL. Neutralising antibody titres were determined at T2. Adverse events, COVID-19 infections and Clinical Frailty Scale (CFS) levels were documented.Results The analysis included 97 participants (median age, 70 years (IQR, 66–74), 58% CFS level 2). IgG titres, which increased significantly from T0 to T1 (median, 440 AU/mL (IQR, 294–923) and median, 25 429 AU/mL (IQR, 14 203–36 114), respectively; p
- Published
- 2022
- Full Text
- View/download PDF
11. Blood-Derived Exosomal hTERT mRNA in Patients with Lung Cancer: Characterization and Correlation with Response to Therapy
- Author
-
Ofer Rotem, Alona Zer, Lilach Yosef, Einat Beery, Hadar Goldvaser, Anna Gutkin, Ron Levin, Elizabeth Dudnik, Tamar Berger, Meora Feinmesser, Adva Levy-Barda, Meir Lahav, Pia Raanani, and Orit Uziel
- Subjects
small-cell lung carcinoma (SCLC) ,non-small-cell lung carcinoma (NSCLC) ,hTERT ,exosomes ,Biology (General) ,QH301-705.5 - Abstract
Background: Telomerase (human telomerase reverse transcriptase (hTERT) is considered a hallmark of cancer, being active in cancer cells but repressed in human somatic cells. As such, it has the potential to serve as a valid cancer biomarker. Exosomal hTERT mRNA can be detected in the serum of patients with solid malignancies but not in healthy individuals. We sought to evaluate the feasibility of measuring serum exosomal hTERT transcripts levels in patients with lung cancer. Methods: A prospective analysis of exosomal hTERT mRNA levels was determined in serum-derived exosomes from 76 patients with stage III–IV lung cancer (11 SCLC and 65 NSCLC). An hTERT level above RQ = 1.2 was considered “detectable” according to a previous receiver operating characteristic curve (ROC) curve. Sequential measurements were obtained in 33 patients. Demographic and clinical data were collected retrospectively from patients’ charts. Data on response to systemic therapy (chemotherapy, immunotherapy, and tyrosine kinase inhibitors) were collected by the treating physicians. Results: hTERT was detected in 53% (40/76) of patients with lung cancer (89% of SCLC and 46% of NSLCC). The mean hTERT levels were 3.7 in all 76 patients, 5.87 in SCLC patients, and 3.62 in NSCLC patients. In total, 25 of 43 patients with sequential measurements had detectable levels of hTERT. The sequential exosomal hTERT mRNA levels reflected the clinical course in 23 of them. Decreases in hTERT levels were detected in 17 and 5 patients with partial and complete response, respectively. Eleven patients with a progressive disease had an increase in the level of exosomal hTERT, and seven with stable disease presented increases in its exosomal levels. Another patient who progressed on the first line of treatment and had a partial response to the second line of treatment exhibited an increase in exosomal hTERT mRNA levels during the progression and a decrease during the response. Conclusions: Exosomal hTERT mRNA levels are elevated in over half of patients with lung cancer. The potential association between hTERT levels and response to therapy suggests its utility as a promising cancer biomarker for response to therapy. This issue should be further explored in future studies.
- Published
- 2023
- Full Text
- View/download PDF
12. Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases
- Author
-
Keren Masha Rabinowitz, Michal Navon, Hadar Edelman-Klapper, Eran Zittan, Ariella Bar-Gil Shitrit, Idan Goren, Irit Avni-Biron, Jacob E. Ollech, Lev Lichtenstein, Hagar Banai-Eran, Henit Yanai, Yifat Snir, Maor H. Pauker, Adi Friedenberg, Adva Levy-Barda, Arie Segal, Yelena Broitman, Eran Maoz, Baruch Ovadia, Maya Aharoni Golan, Eyal Shachar, Shomron Ben-Horin, Nitsan Maharshak, Michal Mor, Haim Ben Zvi, Rami Eliakim, Revital Barkan, Tali Sharar-Fischler, Sophy Goren, Noy Krugliak, Edward Pichinuk, Michael Mor, Michal Werbner, Joel Alter, Hanan Abu-Taha, Kawsar Kaboub, Moshe Dessau, Meital Gal-Tanamy, Dani Cohen, Natalia T. Freund, Iris Dotan, and on behalf of the Responses to COVID-19 Vaccine Israeli IBD Group
- Subjects
COVID-19 ,vaccine ,mRNA-BNT162b2 ,anti-SARS-CoV-2 antibodies ,serologic response longevity ,circulating B cells ,Medicine - Abstract
Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.
- Published
- 2022
- Full Text
- View/download PDF
13. Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy.
- Author
-
Bar, Jair, Leibowitz, Raya, Reinmuth, Niels, Ammendola, Astrid, Jacob, Eyal, Moskovitz, Mor, Levy-Barda, Adva, Lotem, Michal, Katsenelson, Rivka, Agbarya, Abed, Abu-Amna, Mahmoud, Gottfried, Maya, Harkovsky, Tatiana, Wolf, Ido, Tepper, Ella, Loewenthal, Gil, Yellin, Ben, Brody, Yehuda, Dahan, Nili, and Yanko, Maya
- Subjects
NON-small-cell lung carcinoma ,PROTEOMICS ,BLOOD proteins ,CANCER patients ,IMMUNE checkpoint inhibitors ,IPILIMUMAB ,ACTIVATED protein C resistance - Abstract
Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
14. Is serum-derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study.
- Author
-
Uziel, Orit, Kanner, Andrew A., Beery, Einat, Lev, Sapir, Lahav, Meir, Horn-Fichman, Suzana, Nof, Sagi Har, Laviv, Yuseph, Yust-Katz, S., Amiel, Alexandra, Shkara, Ramez Abu, Siddeeq, Mustafa, Levy-Barda, Adva, Raanani, Pia, Sela, Yaron, Cohen, Zvi, and Siegal, Tali
- Subjects
TELOMERASE reverse transcriptase ,EXOSOMES ,DISEASE relapse ,GLIOBLASTOMA multiforme ,GLIOMAS ,BRAIN tumors - Abstract
Background: In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e-hTERT-trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. Methods: Exosomes were isolated from the pre-operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e-hTERT-trans were measured in 81 healthy controls, 117 meningiomas, 17 low-grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e-hTERT-trans. Results: The upper normal limit of controls e-hTERT-trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17±11.7) versus with recurrence (3.59±4.42; p=0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. Conclusions: We demonstrated for the first time that the expression of ehTERT-trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
15. Serologic Response and Safety after a Third Dose of the COVID-19 BNT162b2 Vaccine in Patients with Inflammatory Bowel Diseases.
- Author
-
Edelman-Klapper, Hadar, Rabinowitz, Keren Masha, Zittan, Eran, Shitrit, Ariella Bar-Gil, Goren, Idan, Avni-Biron, Irit, Ollech, Jacob E., Lichtenstein, Lev, Banai-Eran, Hagar, Yanai, Henit, Snir, Yifat, Pauker, Maor H., Friedenberg, Adi, Levy-Barda, Adva, Broitman, Yelena, Ben Zvi, Haim, Perets, Tsachi-Tsadok, Eliakim, Rami, Barkan, Revital, and Goren, Sophy
- Subjects
INFLAMMATORY bowel diseases ,COVID-19 vaccines ,COVID-19 - Abstract
Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
16. Blood-Derived Exosomal hTERT mRNA in Patients with Lung Cancer: Characterization and Correlation with Response to Therapy.
- Author
-
Rotem, Ofer, Zer, Alona, Yosef, Lilach, Beery, Einat, Goldvaser, Hadar, Gutkin, Anna, Levin, Ron, Dudnik, Elizabeth, Berger, Tamar, Feinmesser, Meora, Levy-Barda, Adva, Lahav, Meir, Raanani, Pia, and Uziel, Orit
- Subjects
CANCER patients ,LUNG cancer ,EXOSOMES ,TELOMERASE reverse transcriptase ,RECEIVER operating characteristic curves - Abstract
Background: Telomerase (human telomerase reverse transcriptase (hTERT) is considered a hallmark of cancer, being active in cancer cells but repressed in human somatic cells. As such, it has the potential to serve as a valid cancer biomarker. Exosomal hTERT mRNA can be detected in the serum of patients with solid malignancies but not in healthy individuals. We sought to evaluate the feasibility of measuring serum exosomal hTERT transcripts levels in patients with lung cancer. Methods: A prospective analysis of exosomal hTERT mRNA levels was determined in serum-derived exosomes from 76 patients with stage III–IV lung cancer (11 SCLC and 65 NSCLC). An hTERT level above RQ = 1.2 was considered "detectable" according to a previous receiver operating characteristic curve (ROC) curve. Sequential measurements were obtained in 33 patients. Demographic and clinical data were collected retrospectively from patients' charts. Data on response to systemic therapy (chemotherapy, immunotherapy, and tyrosine kinase inhibitors) were collected by the treating physicians. Results: hTERT was detected in 53% (40/76) of patients with lung cancer (89% of SCLC and 46% of NSLCC). The mean hTERT levels were 3.7 in all 76 patients, 5.87 in SCLC patients, and 3.62 in NSCLC patients. In total, 25 of 43 patients with sequential measurements had detectable levels of hTERT. The sequential exosomal hTERT mRNA levels reflected the clinical course in 23 of them. Decreases in hTERT levels were detected in 17 and 5 patients with partial and complete response, respectively. Eleven patients with a progressive disease had an increase in the level of exosomal hTERT, and seven with stable disease presented increases in its exosomal levels. Another patient who progressed on the first line of treatment and had a partial response to the second line of treatment exhibited an increase in exosomal hTERT mRNA levels during the progression and a decrease during the response. Conclusions: Exosomal hTERT mRNA levels are elevated in over half of patients with lung cancer. The potential association between hTERT levels and response to therapy suggests its utility as a promising cancer biomarker for response to therapy. This issue should be further explored in future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
17. Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity.
- Author
-
Safra, Modi, Tamari, Zvi, Polak, Pazit, Shiber, Shachaf, Matan, Moshe, Karameh, Hani, Helviz, Yigal, Levy-Barda, Adva, Yahalom, Vered, Peretz, Avi, Ben-Chetrit, Eli, Brenner, Baruch, Tuller, Tamir, Gal-Tanamy, Meital, and Yaari, Gur
- Subjects
COVID-19 ,B cell receptors ,ANTIGEN receptors ,SARS-CoV-2 ,HUMAN body - Abstract
Introduction: The success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance. Methods: We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls. Results: In contrast to previous studies, our approach successfully stratifies noninfected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients. Discussion: These features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Human intestinal epithelial cells can internalize luminal fungi via LC3-associated phagocytosis.
- Author
-
Cohen-Kedar, Sarit, Barda, Efrat Shaham, Rabinowitz, Keren Masha, Keizer, Danielle, Abu-Taha, Hanan, Schwartz, Shoshana, Kaboub, Kawsar, Baram, Liran, Sadot, Eran, White, Ian, Wasserberg, Nir, Wolff-Bar, Meirav, Levy-Barda, Adva, and Dotan, Iris
- Subjects
PHAGOCYTOSIS ,EPITHELIAL cells ,INTESTINES ,BETA-glucans ,FUNGI - Abstract
Background: Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3-associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles via LAP. Methods: Colonic (n=18) and ileal (n=4) organoids from individuals undergoing bowel resection were grown as monolayers. Fluorescent-dye conjugated zymosan (β-glucan particle), heat-killed- and UV inactivated C. albicans were applied to differentiated organoids and to human IEC lines. Confocal microscopy was used for live imaging and immuno-fluorescence. Quantification of phagocytosis was carried out with a fluorescence plate-reader. Results: zymosan and C. albicans particles were phagocytosed by monolayers of human colonic and ileal organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases. Conclusions: Our results show that human IECs sense luminal fungal particles and internalize them via LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
19. Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases.
- Author
-
Rabinowitz, Keren Masha, Navon, Michal, Edelman-Klapper, Hadar, Zittan, Eran, Bar-Gil Shitrit, Ariella, Goren, Idan, Avni-Biron, Irit, Ollech, Jacob E., Lichtenstein, Lev, Banai-Eran, Hagar, Yanai, Henit, Snir, Yifat, Pauker, Maor H., Friedenberg, Adi, Levy-Barda, Adva, Segal, Arie, Broitman, Yelena, Maoz, Eran, Ovadia, Baruch, and Aharoni Golan, Maya
- Subjects
INFLAMMATORY bowel diseases ,COVID-19 vaccines ,IMMUNE response ,BOOSTER vaccines ,B cells - Abstract
Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
20. Detection of gene mutations and gene-gene fusions in circulating cell-free DNA of glioblastoma patients: an avenue for clinically relevant diagnostic analysis.
- Author
-
Palande, Vikrant, Siegal, Tali, Detroja, Rajesh, Gorohovski, Alessandro, Glass, Rainer, Flueh, Charlotte, Kanner, Andrew A., Laviv, Yoseph, Har-Nof, Sagi, Levy-Barda, Adva, Karpuj, Marcela Viviana, Kurtz, Marina, Perez, Shira, Shay, Dorith Raviv, and Frenkel-Morgenstern, Milana
- Abstract
Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene-gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng⋅mL
-1 ), as compared to healthy controls (1.4 ± 0.4 ng⋅mL-1 ) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene-gene fusion database, ChiTaRS 5.0, we identified gene-gene fusions in cfDNA and tumour DNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR-ABL1 (in 8% of patients), COL1A1-PDGFB (8%), NIN-PDGFRB (8%), and FGFR1-BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene-gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
21. Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer.
- Author
-
Massarweh, Amir, Eliakim-Raz, Noa, Stemmer, Amos, Levy-Barda, Adva, Yust-Katz, Shlomit, Zer, Alona, Benouaich-Amiel, Alexandra, Ben-Zvi, Haim, Moskovits, Neta, Brenner, Baruch, Bishara, Jihad, Yahav, Dafna, Tadmor, Boaz, Zaks, Tal, and Stemmer, Salomon M.
- Published
- 2021
- Full Text
- View/download PDF
22. 24: HUMAN INTESTINAL EPITHELIAL CELLS INTERNALIZE LUMINAL FUNGI VIA LC3-ASSOCIATED PHAGOCYTOSIS
- Author
-
Cohen-Kedar, Sarit, Barda, Efrat Shaham, Rabinowitz, Keren M., Keizer, Danielle, Schwartz, Shoshana, Kaboub, Kawsar, White, Ian D., Sadot, Eran, Wasserberg, Nir, Wolff-Bar, Meirav, Levy-Barda, Adva, and Dotan, Iris
- Published
- 2022
- Full Text
- View/download PDF
23. Sa448 THE JAK INHIBITOR-TOFACITINIB INHIBITS PRO-INFLAMMATORY RESPONSES IN EX-VIVO HUMAN INTESTINAL MUCOSA
- Author
-
Kaboub, Kawsar, Cohen-Kedar, Sarit, Wasserberg, Nir, Hayman-Manzur, Lucille, Berger, Yael, Levy-Barda, Adva, Yanai, Henit, Dotan, Iris, and Rabinowitz, Keren M.
- Published
- 2021
- Full Text
- View/download PDF
24. Su1894 – The Jak Inhibitor-Tofacitinib Inhibits Signaling Pathways and Cytokine Secretion in Human Intestinal Mucosa Ex-Vivo
- Author
-
Kaboub, Kawsar, Cohen-Kedar, Sarit, Wasserberg, Nir, Hayman-Manzur, Lucille, Berger, Yael, Levy-Barda, Adva, Yanai, Henit A., Dotan, Iris, and Rabinowitz, Keren M.
- Published
- 2019
- Full Text
- View/download PDF
25. Mo1586: A MICROBIOTA TARGETED, MEDITERRANEAN DIET-BASED NUTRITIONAL EDUCATION PROGRAM POSITIVELY MODIFIES THE INTESTINAL ECOSYSTEM OF HEALTHY INDIVIDUALS.
- Author
-
Godny, Lihi, Reshef, Leah, Fischler, Tali Sharar, Elial-Fatal, Sarine, Pfeffer-Gik, Tamar, Raykhel, Barbara, Rabinowitz, Keren M., Levy-Barda, Adva, Perets, Tsachi-Tsadok, Barken, Revital, Goren, Idan, Ollech, Jacob, Yanai, Henit A., Gophna, Uri, and Dotan, Iris
- Published
- 2022
- Full Text
- View/download PDF
26. Su1488: WITHIN 6 MONTHS FROM COVID-19 BNT162B2 VACCINE PATIENTS WITH INFLAMMATORY BOWEL DISEASES TREATED WITH ANTI-TNFα HAVE SIGNIFICANTLY LOWER SEROLOGIC RESPONSES.
- Author
-
Rabinowitz, Keren M., Navon, Michal, Edelman-Klapper, Hadar, Zittan, Eran, Shitrit, Ariella Bar-Gil, Goren, Idan, Avni-Biron, Irit, Ollech, Jacob, Lichtenstein, Lev, Banai, Hagar, Yanai, Henit A., Snir, Yifat, H.Pauker, Maor, Friedenberg, Adi, Levy-Barda, Adva, Segal, Arie, Broitman, Yelena, Maoz, Eran, Ovadia, Baruch, and Golan, Maya Aharoni
- Published
- 2022
- Full Text
- View/download PDF
27. Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks.
- Author
-
Levy-Barda, Adva, Lerenthal, Yaniv, Davis, Anthony J., Chung, Young Min, Essers, Jeroen, Shao, Zhengping, van Vliet, Nicole, Chen, David J., Hu, Mickey C-T., Kanaar, Roland, Ziv, Yael, and Shiloh, Yosef
- Published
- 2011
- Full Text
- View/download PDF
28. Discordant effects of Janus kinases inhibition ex-vivo on inflammatory responses in colonic compared to ileal mucosa.
- Author
-
Kaboub K, Abu-Taha H, Arrouasse J, Shaham-Barda E, Wasserberg N, Hayman-Manzur L, Friedenberg A, Levy-Barda A, Goren I, Levi Z, Banai-Eran H, Avni-Biron I, Ollech JE, Sharar-Fischler T, Yanai H, Cohen-Kedar S, Dotan I, and Rabinowitz KM
- Abstract
Background & Aims: Janus kinase (JAK) inhibitors are used for treating inflammatory bowel diseases (IBD). We aimed to identify molecular effects of JAK inhibition in human intestinal mucosa, considering IBD location and phenotype., Methods: Colonic and ileal explants from patients with ulcerative colitis (UC), Crohn's disease (CD), and non-IBD controls (NC) were assessed for phosphorylated signal transducers and activators of transcription (p-STAT) levels and Inflammatory genes expression panel in response to ex-vivo JAK inhibitor (tofacitinib). Cytokine production by lamina propria lymphocytes in response to tofacitinib was assessed. Human intestinal organoids were used to investigate JAK inhibitors' effects on iNOS expression., Results: Explants were collected from 68 patients (UC=20; CD=20; NC=28). p-STAT1\3\5 inhibition rates varied, being higher in colonic compared to ileal explants. p-STAT1\3 inhibition rates negatively correlated with CRP levels. While significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in 5 genes, including NOS2. JAK inhibition significantly decreased Th1\Th2\Th17-related cytokine production from lamina propria lymphocytes. Various JAK inhibitors reduced IFN-γ-induced increase in iNOS expression in organoids., Conclusions: Site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noticed, whereby the colon was more robustly affected than the ileum. Ex-vivo response to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression. Ex-vivo mucosal platforms may be a valuable resource for studying personalized drug effects in patients with IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
29. PVRIG is Expressed on Stem-Like T Cells in Dendritic Cell-Rich Niches in Tumors and Its Blockade May Induce Immune Infiltration in Non-Inflamed Tumors.
- Author
-
Alteber Z, Cojocaru G, Granit RZ, Barbiro I, Wool A, Frenkel M, Novik A, Shuchami A, Liang Y, Carmi VD, Sabath N, Foreman R, Petrenko N, He J, Kliger Y, Levy-Barda A, Eitan R, Raban O, Sadot E, Sulimani O, Nathan AA, Adewoye H, Ferre P, Levine Z, and Ophir E
- Subjects
- Humans, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Memory T Cells immunology, Memory T Cells metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Tumor Microenvironment immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms metabolism
- Abstract
Cancers that are poorly immune infiltrated pose a substantial challenge, with current immunotherapies yielding limited clinical success. Stem-like memory T cells (TSCM) have been identified as a subgroup of T cells that possess strong proliferative capacity and that can expand and differentiate following interactions with dendritic cells (DCs). In this study, we explored the pattern of expression of a recently discovered inhibitory receptor poliovirus receptor-related immunoglobulin domain protein (PVRIG) and its ligand, poliovirus receptor-related ligand 2 (PVRL2), in the human tumor microenvironment. Using spatial and single-cell RNA transcriptomics data across diverse cancer indications, we found that among the T-cell checkpoints, PVRIG is uniquely expressed on TSCM and PVRL2 is expressed on DCs in immune aggregate niches in tumors. PVRIG blockade could therefore enhance TSCM-DC interactions and efficiently drive T-cell infiltration to tumors. Consistent with these data, following PVRIG blockade in patients with poorly infiltrated tumors, we observed immune modulation including increased tumor T-cell infiltration, T-cell receptor (TCR) clonality, and intratumoral T-cell expansion, all of which were associated with clinical benefit. These data suggest PVRIG blockade as a promising strategy to induce potent antitumor T-cell responses, providing a novel approach to overcome resistance to immunotherapy in immune-excluded tumors., (©2024 American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
30. Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.
- Author
-
Menachem A, Alteber Z, Cojocaru G, Fridman Kfir T, Blat D, Leiderman O, Galperin M, Sever L, Cohen N, Cohen K, Granit RZ, Vols S, Frenkel M, Soffer L, Meyer K, Menachem K, Galon Tilleman H, Morein D, Borukhov I, Toporik A, Perpinial Shahor M, Tatirovsky E, Mizrachi A, Levy-Barda A, Sadot E, Strenov Y, Eitan R, Jakobson-Setton A, Yanichkin N, Ferre P, and Ophir E
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Killer Cells, Natural immunology, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Neoplasms immunology, Neoplasms drug therapy, Lymphocyte Activation immunology, Lymphocyte Activation drug effects, Female, Mice, Inbred C57BL, Intercellular Signaling Peptides and Proteins metabolism, Xenograft Model Antitumor Assays, T-Lymphocytes immunology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Interleukin-18 metabolism, Tumor Microenvironment immunology, Tumor Microenvironment drug effects
- Abstract
Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
31. Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.
- Author
-
Christopoulos P, Harel M, McGregor K, Brody Y, Puzanov I, Bar J, Elon Y, Sela I, Yellin B, Lahav C, Raveh S, Reiner-Benaim A, Reinmuth N, Nechushtan H, Farrugia D, Bustinza-Linares E, Lou Y, Leibowitz R, Kamer I, Zer Kuch A, Moskovitz M, Levy-Barda A, Koch I, Lotem M, Katzenelson R, Agbarya A, Price G, Cheley H, Abu-Amna M, Geldart T, Gottfried M, Tepper E, Polychronis A, Wolf I, Dicker AP, Carbone DP, and Gandara DR
- Subjects
- Humans, B7-H1 Antigen, Immune Checkpoint Inhibitors therapeutic use, Programmed Cell Death 1 Receptor therapeutic use, Proteome, Proteomics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Purpose: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions., Patients and Methods: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1., Results: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB ( R
2 < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424)., Conclusion: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.- Published
- 2024
- Full Text
- View/download PDF
32. Three-month follow-up of durability of response to the third dose of the SARS-CoV-2 BNT162b2 vaccine in adults aged 60 years and older: a prospective cohort study.
- Author
-
Eliakim-Raz N, Stemmer A, Leibovici-Weisman Y, Ness A, Awwad M, Ghantous N, Erez N, Bareket-Samish A, Levy-Barda A, Ben-Zvi H, Moskovits N, Bar-Haim E, and Stemmer SM
- Subjects
- Adult, Aged, Antibodies, Neutralizing, Antibodies, Viral, BNT162 Vaccine, COVID-19 Vaccines, Follow-Up Studies, Humans, Immunoglobulin G, Middle Aged, Prospective Studies, SARS-CoV-2, COVID-19 prevention & control
- Abstract
Objective: To evaluate the durability of response 3 months after the third BNT162b2 vaccine in adults aged 60 years and older., Design: Prospective cohort study., Setting: Single tertiary centre., Participants: Healthcare workers/family members aged ≥60 years old who received the third BNT162b2 dose., Interventions: Blood samples were drawn immediately before (T0), 10-19 days (T1) and 74-103 days (T2) after the third dose., Primary and Secondary Outcome Measures: Anti-spike IgG titres were determined using a commercial assay and seropositivity was defined as ≥50 arbitrary units (AU)/mL. Neutralising antibody titres were determined at T2. Adverse events, COVID-19 infections and Clinical Frailty Scale (CFS) levels were documented., Results: The analysis included 97 participants (median age, 70 years (IQR, 66-74), 58% CFS level 2). IgG titres, which increased significantly from T0 to T1 (median, 440 AU/mL (IQR, 294-923) and median, 25 429 AU/mL (IQR, 14 203-36 114), respectively; p<0.001), decreased significantly by T2, but all remained seropositive (median, 8306 AU/mL (IQR, 4595-14 701), p<0.001 vs T1). In a multivariable analysis, only time from the second vaccine was significantly associated with lower IgG levels at T2 (p=0.017). At T2, 60 patients were evaluated for neutralising antibodies; all were seropositive (median, 1294 antibody titres; IQR, 848-2072). Neutralising antibody and anti-spike IgG levels were correlated (r=0.6, p<0.001). No major adverse events or COVID-19 infections were reported., Conclusions: Anti-spike IgG and neutralising antibody levels remain adequate 3 months after the third BNT162b2 vaccine in healthy adults aged ≥60 years, although the decline in IgG is concerning. A third dose of vaccine in this population should be top priority., Competing Interests: Competing interests: SMS received research grants (to the institution) from CAN-FITE, AstraZeneca, BiolineRx, BMS, Halozyme, Clovis Oncology, CTG Pharma, Exelixis, Geicam, Incyte, Lilly, Moderna, Teva Pharmaceuticals and Roche, and owns stocks and options in CTG Pharma, DocBoxMD, TyrNovo, VYPE, Cytora and CAN-FITE. AB-S is employed by BioInsight., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
- View/download PDF
33. The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair.
- Author
-
Baranes-Bachar K, Levy-Barda A, Oehler J, Reid DA, Soria-Bretones I, Voss TC, Chung D, Park Y, Liu C, Yoon JB, Li W, Dellaire G, Misteli T, Huertas P, Rothenberg E, Ramadan K, Ziv Y, and Shiloh Y
- Subjects
- BRCA1 Protein genetics, Carrier Proteins genetics, DNA-Binding Proteins, HeLa Cells, Histone Chaperones, Humans, Nuclear Proteins genetics, Ubiquitin-Protein Ligases genetics, Ubiquitins genetics, Ubiquitins metabolism, BRCA1 Protein metabolism, Carrier Proteins metabolism, DNA Breaks, Double-Stranded, Nuclear Proteins metabolism, Recombinational DNA Repair physiology, Ubiquitin-Protein Ligases metabolism, Ubiquitination physiology
- Abstract
Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
34. Targeting the centriolar replication factor STIL synergizes with DNA damaging agents for treatment of ovarian cancer.
- Author
-
Rabinowicz N, Mangala LS, Brown KR, Checa-Rodriguez C, Castiel A, Moskovich O, Zarfati G, Trakhtenbrot L, Levy-Barda A, Jiang D, Rodriguez-Aguayo C, Pradeep S, van Praag Y, Lopez-Berestein G, David A, Novikov I, Huertas P, Rottapel R, Sood AK, and Izraeli S
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cell Cycle drug effects, Cell Cycle genetics, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, DNA Breaks, Double-Stranded, DNA Repair, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Histones metabolism, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Mice, Molecular Targeted Therapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, RNA Interference, RNA, Small Interfering genetics, Recombinational DNA Repair, Signal Transduction, Tumor Suppressor p53-Binding Protein 1 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, DNA Damage drug effects, Intracellular Signaling Peptides and Proteins antagonists & inhibitors
- Abstract
Advanced ovarian cancer is an incurable disease. Thus, novel therapies are required. We wished to identify new therapeutic targets for ovarian cancer. ShRNA screen performed in 42 ovarian cancer cell lines identified the centriolar replication factor STIL as an essential gene for ovarian cancer cells. This was verified in-vivo in orthotopic human ovarian cancer mouse models. STIL depletion by administration of siRNA in neutral liposomes resulted in robust anti-tumor effect that was further enhanced in combination with cisplatin. Consistent with this finding, STIL depletion enhanced the extent of DNA double strand breaks caused by DNA damaging agents. This was associated with centrosomal depletion, ongoing genomic instability and enhanced formation of micronuclei. Interestingly, the ongoing DNA damage was not associated with reduced DNA repair. Indeed, we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer.
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.