المؤلفون: Arielle Jacover, Yonaton Zarbiv, Keidar Haran Tal, Shira Klein, Shani Breuer, Ronen Durst, Batia Avni, Sigal Grisariu, Polina Stepensky, Michal Lotem, Ofra Maimon, Tamar Yablonski‐Peretz

المصدر: Cancer Reports, Vol 6, Iss 12, Pp n/a-n/a (2023)

مصطلحات موضوعية: adoptive cell therapy, triple negative breast cancer, tumor infiltrating lymphocyte, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is treated with chemotherapy. Recently, programmed death 1 (PD1) inhibition, as well as antibody‐drug conjugates, have been added to the available treatment regimen, yet metastatic disease is fatal. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TILs) has been well described in melanoma, but less data is available on other solid malignancies. Case Herein, we present a case of a 31‐year‐old patient diagnosed with Breast Cancer gene 1 (BRCA1) positive, TNBC. The patient's disease rapidly progressed while under standard treatment protocols. As a result, additional genetic testing of the tumor was carried out and revealed loss of BRCA1 heterozygosity, a double Tumor Protein 53 (TP53) mutation, and MYC amplification. Due to resistance to conventional therapy, an experimental approach was attempted using tumor‐infiltrating lymphocytes in November 2021 at Hadassah University Medical Center. While receiving this treatment, the patient exhibited a reported subjective clinical improvement including a month spent out of the hospital. However, the final result, presumably due to Interleukin 2 (IL‐2) toxicity, was the patient's passing. Conclusion This case is unique and peculiar regarding the treatment modality chosen, due to the extremely refractory disease the patient suffered from. After standard therapies rapidly failed, adoptive cell therapy was attempted with the infusion of TILs. This treatment has been shown effective in melanoma, however, there is an extreme paucity of data on other solid tumors, including TNBC. Although the patient ultimately demised presumably due to treatment side effects, brief clinical benefit was apparent. Further studies are warranted.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2573-8348Test

الوصول الحر: https://doaj.org/article/35069d56b7044ff99868e160fb5d34f0Test

المؤلفون: Irina Zaidman, Ehud Even-Or, Elroee Aharoni, Dina Averbuch, Yael Dinur-Schejter, Adeeb NaserEddin, Mordechai Slae, Bella Shadur, Polina Stepensky

المصدر: Frontiers in Pediatrics, Vol 11 (2023)

مصطلحات موضوعية: hematopoietic stem cell transplantation, survival, graft-vs.-host disease, pediatric nonmalignant diseases, outcome, Pediatrics, RJ1-570

الوصف: BackgroundHematopoietic stem cell transplantation (HSCT) is the only curative option for many nonmalignant hematopoietic-derived diseases in pediatric patients. Survival after HSCT has improved in recent years and resulted in a 90% survival rate and cure in some nonmalignant diseases. Graft-vs.-host disease (GVHD) remains a frequent and major complication of HSCT, and a leading cause of morbidity and mortality. Prognosis of patients with high-grade GVHD is dismal, with survival rates varying from 25% in the adult population to 55% in pediatric patients.MethodsThe main aim of this study is to evaluate the incidence, risk factors, and outcome of severe acute GVHD (AGVHD) in pediatric patients with nonmalignant diseases, following allogeneic HSCT. Clinical and transplant data were retrospectively collected for all pediatric patients who underwent allogeneic HSCT for nonmalignant diseases at the Hadassah Medical Center between 2008 and 2019. Patients who developed severe AGVHD were compared with those who did not.ResultsA total of 247 children with nonmalignant diseases underwent 266 allogeneic HSCTs at Hadassah University Hospital over an 11-year period. Seventy-two patients (29.1%) developed AGVHD, 35 of them (14.1%) severe AGVHD (grade 3–4). Significant risk factors for developing severe AGVHD were unrelated donor (p

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fped.2023.1194891/fullTest; https://doaj.org/toc/2296-2360Test

الوصول الحر: https://doaj.org/article/5686bde0f1354afe9f086434e02bf8c4Test

المؤلفون: Andrea Fracchia, Drirh Khare, Samar Da’na, Reuven Or, Amnon Buxboim, Boaz Nachmias, Claudine Barkatz, Regina Golan-Gerstl, Swasti Tiwari, Polina Stepensky, Yuval Nevo, Hadar Benyamini, Sharona Elgavish, Osnat Almogi-Hazan, Batia Avni

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 18, p 13689 (2023)

مصطلحات موضوعية: mesenchymal stem cells, small extracellular vesicles, T lymphocytes, next-generation sequencing, Ingenuity Pathway Analysis, gene set enrichment analysis, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Recent studies have highlighted the therapeutic potential of small extracellular bodies derived from mesenchymal stem cells (MSC-sEVs) for various diseases, notably through their ability to alter T-cell differentiation and function. The current study aimed to explore immunomodulatory pathway alterations within T cells through mRNA sequencing of activated T cells cocultured with bone marrow-derived MSC-sEVs. mRNA profiling of activated human T cells cocultured with MSC-sEVs or vehicle control was performed using the QIAGEN Illumina sequencing platform. Pathway networks and biological functions of the differentially expressed genes were analyzed using Ingenuity pathway analysis (IPA)® software, KEGG pathway, GSEA and STRING database. A total of 364 differentially expressed genes were identified in sEV-treated T cells. Canonical pathway analysis highlighted the RhoA signaling pathway. Cellular development, movement, growth and proliferation, cell-to-cell interaction and inflammatory response-related gene expression were altered. KEGG enrichment pathway analysis underscored the apoptosis pathway. GSEA identified enrichment in downregulated genes associated with TNF alpha and interferon gamma response, and upregulated genes related to apoptosis and migration of lymphocytes and T-cell differentiation gene sets. Our findings provide valuable insights into the mechanisms by which MSC-sEVs implement immunomodulatory effects on activated T cells. These findings may contribute to the development of MSC-sEV-based therapies.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/18/13689Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/71bdc765d92a40aa9656037325544fdcTest

المؤلفون: Irina Zaidman, Tamar Shaziri, Dina Averbuch, Ehud Even-Or, Yael Dinur-Schejter, Adeeb NaserEddin, Rebecca Brooks, Bella Shadur, Aharon Gefen, Polina Stepensky

المصدر: Frontiers in Pediatrics, Vol 10 (2022)

مصطلحات موضوعية: neurological complications, hematopoietic stem cell transplantation, survival, neurological sequelae, abnormal imaging, pediatric malignant and nonmalignant diseases, Pediatrics, RJ1-570

الوصف: BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is an efficient treatment for numerous malignant and nonmalignant conditions affecting children. This procedure can result in infectious and noninfectious neurological complications (NCs).ObjectiveThe objective of the study is to examine the incidence, risk factors, and outcomes of NCs in pediatric patients following allogeneic HSCT.MethodsWe performed a retrospective study of 746 children who underwent 943 allogeneic HSCTs in two large pediatric hospitals in Israel from January 2000 to December 2019.ResultsOf the pediatric patients 107 (14.3%) experienced 150 NCs. The median follow-up was 55 months. Noninfectious NCs were more common than infectious NCs (81.3% vs. 18.7%). Factors significantly associated with type of NC (infectious vs. noninfectious) were underlying disease (immunodeficiency vs. malignant and metabolic/hematologic disease) (p-value = 0.000), and use of immunosuppressive agent, either Campath or ATG (p-value = 0.041). Factors with a significant impact on developing neurological sequelae post-NC were number of HSCT >1 (p-value = 0.028), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.003), and infectious type of NC (p-value = 0.046). The overall survival rate of whole NC-cohort was 44%; one-third of all mortality cases were attributed to the NC. The strongest prognostic factors associated with mortality were older age at HSCT (p-value = 0.000), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.004), and the existence of neurological sequelae (p-value = 0.000). Abnormal central nervous system imaging (p-value = 0.013), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.019), and neurological sequelae (p-value = 0.000) had statistically significant effects on neurological cause of death.ConclusionInfectious and noninfectious NCs are a significant cause of morbidity and mortality following allogeneic HSCT in children. Further research is required to better understand the risk factors for different NCs and their outcomes regarding sequelae and survival.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fped.2022.1064038/fullTest; https://doaj.org/toc/2296-2360Test

الوصول الحر: https://doaj.org/article/22b74a28384544a5aeb9e1ca75d0bbfdTest

المؤلفون: Vladimir Vainstein, Batia Avni, Sigal Grisariu, Shlomit Kfir-Erenfeld, Nathalie Asherie, Boaz Nachmias, Shlomtzion Auman, Revital Saban, Eran Zimran, Miri Assayag, Kalman Filanovsky, Netanel A. Horowitz, Eyal Lebel, Adir Shaulov, Michal Gur, Chaggai Rosenbluh, Svetlana Krichevsky, Polina Stepensky, Moshe E. Gatt

المصدر: Cancers, Vol 15, Iss 13, p 3471 (2023)

مصطلحات موضوعية: multiple myeloma, myelodysplastic syndrome, CART therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/15/13/3471Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/4e10ec35b94641e099d8b3dcc636a5deTest

المؤلفون: Nathalie Asherie, Shlomit Kfir-Erenfeld, Batia Avni, Miri Assayag, Tatyana Dubnikov, Nomi Zalcman, Eyal Lebel, Eran Zimran, Adir Shaulov, Marjorie Pick, Yael Cohen, Irit Avivi, Cyrille Cohen, Moshe E. Gatt, Sigal Grisariu, Polina Stepensky

المصدر: Haematologica, Vol 108, Iss 7 (2022)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.

وصف الملف: electronic resource

العلاقة: https://haematologica.org/article/view/10819Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test

الوصول الحر: https://doaj.org/article/40a8d177594b49e183117e6a58b4f391Test

المؤلفون: Ehud Even-Or, Yael Dinur Schejter, Adeeb NaserEddin, Irina Zaidman, Bella Shadur, Polina Stepensky

المصدر: Frontiers in Immunology, Vol 13 (2022)

مصطلحات موضوعية: autoimmune cytopenia, hematopoietic stem cell transplantation, osteopetrosis, nonmalignant, immune thrombocytopenia, autoimmune hemolytic anemia, Immunologic diseases. Allergy, RC581-607

الوصف: Autoimmune cytopenia (AIC) is a rare complication post hematopoietic stem cell transplantation (HSCT), with a higher incidence in nonmalignant diseases. The etiology of post-HSCT AIC is poorly understood, and in many cases, the cytopenia is prolonged and refractory to treatment. Diagnosis of post-HSCT AIC may be challenging, and there is no consensus for a standard of care. In this retrospective study, we summarize our experience over the past five years with post-HSCT AIC in pediatric patients with osteopetrosis and other nonmalignant diseases. All pediatric patients who underwent HSCT for nonmalignant diseases at Hadassah Medical Center over the past five years were screened for post-HSCT AIC, and data were collected from the patient’s medical records. From January 2017 through December 2021, 140 pediatric patients underwent HSCT for osteopetrosis (n=40), and a variety of other nonmalignant diseases. Thirteen patients (9.3%) presented with post-HSCT AIC. Of these, 7 had osteopetrosis (17.5%), and 6 had other underlying nonmalignant diseases. Factors associated with developing AIC included unrelated or non-sibling family donors (n=10), mixed chimerism (n=6), and chronic GvHD (n=5). Treatment modalities included steroids, IVIG, rituximab, bortezomib, daratumumab, eltrombopag, plasmapheresis, and repeated HSCT. Response to treatment was variable; Seven patients (54%) recovered completely, and three patients (23%) recovered partially, still suffering from mild-moderate thrombocytopenia. Three patients died (23%), two following progressive lung disease and one from sepsis and multi-organ failure after a 3rd HSCT. In our experience, post-HSCT AICs in pediatric patients with nonmalignant diseases may pose a challenging post-transplant complication with a variable presentation and a wide spectrum of severity. A relatively high prevalence is seen in patients with osteopetrosis, possibly due to difficult engraftment and high rates of mixed chimerism. There is a dire need for novel treatment modalities for better management of the more severe and refractory cases.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2022.879994/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/8f0a78e716664e04a8aa1db505828ff0Test

المؤلفون: Ortal Harush, Nathalie Asherie, Shlomit Kfir-Erenfeld, Galit Adler, Tilda Barliya, Miri Assayag, Moshe E. Gatt, Polina Stepensky, Cyrille J. Cohen

المصدر: Haematologica, Vol 107, Iss 10 (2022)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T cells and could trigger cytokine production and cytotoxicity upon co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker expression and in vivo antitumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4-connecting regions, and/or a CD28-signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumoral activity both in vitro and long-term in vivo efficacy.

وصف الملف: electronic resource

العلاقة: https://haematologica.org/article/view/10592Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test

الوصول الحر: https://doaj.org/article/3af11b88505042039b68c3d69532886fTest

المؤلفون: Yael Dinur-Schejter, Irina Zaidman, Hagar Mor-Shaked, Polina Stepensky

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: adaptor molecules, ADAP, LAT, SLP-76, T-cell signaling, primary immune deficiency, Immunologic diseases. Allergy, RC581-607

الوصف: Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.701704/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/42efe452764e44919c57fb3f0a7f139eTest

المؤلفون: Ron Ram, Sigal Grisariu, Liat Shargian-Alon, Odelia Amit, Yaeli Bar-On, Polina Stepensky, Moshe Yeshurun, Batia Avni, David Hagin, Chava Perry, Ronit Gurion, Nadav Sarid, Yair Herishanu, Ronit Gold, Chen Glait-Santar, Sigi Kay, Irit Avivi

المصدر: Haematologica, Vol 107, Iss 5 (2021)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

وصف الملف: electronic resource

العلاقة: https://haematologica.org/article/view/10324Test; https://doaj.org/toc/0390-6078Test; https://doaj.org/toc/1592-8721Test

الوصول الحر: https://doaj.org/article/ee6304dbe547454693562f57a4f69b46Test