المؤلفون: Katja Seipel, Harpreet Mandhair, Ulrike Bacher, Thomas Pabst

المصدر: Current Issues in Molecular Biology, Vol 46, Iss 4, Pp 2946-2960 (2024)

مصطلحات موضوعية: acute myeloid leukemia (AML), B-cell lymphoma 2 (BCL2), BCL2 homology domain 3 (BH3), interleukin-1 receptor-associated kinase 4 (IRAK4), leukocyte integrin CD11B, cell surface glycoprotein CD34, Biology (General), QH301-705.5

الوصف: Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells. Emavusertib in combination with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in MOLM-13 cells. In primary AML cells, the response to emavusertib was associated with the presence of the FLT3 gene mutation with an allelic ratio >0.5 and the presence of NPM1 gene mutations. S63845 was effective in all tested AML cell lines and primary AML samples. Blast cell percentage was positively associated with the response to CA4948, S63845, and venetoclax, with elevated susceptibility of primary AML with blast cell fraction >80%. Biomarkers of the response to venetoclax included the blast cell percentage and bone marrow infiltration rate, as well as the expression levels of CD11b, CD64, and CD117. Elevated susceptibility to CA4948 combination treatments with S63845 or PU-H71 was associated with FLT3-mutated AML and CD34 < 30%. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1467-3045/46/4/184Test; https://doaj.org/toc/1467-3037Test; https://doaj.org/toc/1467-3045Test

الوصول الحر: https://doaj.org/article/ab41290b58f549f1851ded0efc64d10fTest

المؤلفون: Katja Seipel, Michèle Frey, Henning Nilius, Dilara Akhoundova, Yara Banz, Ulrike Bacher, Thomas Pabst

المصدر: Current Oncology, Vol 30, Iss 12, Pp 10463-10476 (2023)

مصطلحات موضوعية: Diffuse Large B-cell Lymphoma (DLBCL), Chimeric Antigen Receptor T-cell (CAR T), Clonal Hematopoiesis (CH), Protein Phosphatase Mg/Mn-dependent 1D (PPM1D), Wild-type p53-induced phosphatase 1 (Wip1), Next-Generation Sequencing (NGS), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of PPM1D mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency PPM1D mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of PPM1D gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without PPM1D mutations. Clinical outcomes were globally worse in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months (p = 0.07) and median overall survival (OS) was 5 vs. 37 months (p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1718-7729/30/12/762Test; https://doaj.org/toc/1198-0052Test; https://doaj.org/toc/1718-7729Test

الوصول الحر: https://doaj.org/article/2c44c5cc352f41dea481d90c3b1060c3Test

المؤلفون: Katja Seipel, Scarlett Kohler, Ulrike Bacher, Thomas Pabst

المصدر: Current Issues in Molecular Biology, Vol 45, Iss 9, Pp 7011-7026 (2023)

مصطلحات موضوعية: acute myeloid leukemia (AML), B-cell lymphoma 2 (BCL2), cell surface glycoprotein CD34, stem cell factor receptor c-KIT (CD117), heat-shock protein 90 (HSP90), fms-like tyrosine kinase 3 (FLT3), Biology (General), QH301-705.5

الوصف: Targeting the molecular chaperone HSP90 and the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The HSP90 inhibitor PU-H71, MCL1 inhibitor S63845, and BCL2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and TP53 mutant AML cell lines and a variety of patient-derived AML cells. Results: PU-H71 and combination treatments with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in susceptible AML cell lines and primary AML. The majority of the primary AML samples were responsive to PU-H71 in combination with BH3 mimetics. Elevated susceptibility to PU-H71 and S63845 was associated with FLT3 mutated AML with CD34 < 20%. Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1467-3045/45/9/443Test; https://doaj.org/toc/1467-3037Test; https://doaj.org/toc/1467-3045Test

الوصول الحر: https://doaj.org/article/e9fd06a271dc4970ac830749cb3a1183Test

المؤلفون: Christian Messerli, Gertrud Wiedemann, Naomi Porret, Michael Nagler, Katja Seipel, Barbara Jeker, Urban Novak, Sacha Zeerleder, Ulrike Bacher, Thomas Pabst

المصدر: Turkish Journal of Hematology, Vol 40, Iss 3, Pp 187-196 (2023)

مصطلحات موضوعية: non-hodgkin lymphoma, lymphomas, neoplasia, transplant-related toxicity, stem cell transplantation, molecular biology, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are significant complications in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy. However, it remains unclear whether CAR-T cell expression itself is clinically relevant. We assessed CAR-T cell mRNA expression and DNA concentration by digital droplet PCR in peripheral blood from 14 sequential CAR-T cell recipients. Patients were grouped according to CAR-T cell peak expression. Patients with high CAR-T cell peak expression (8 patients; 57%) had higher rates of ICANS (p=0.0308) and intensive care unit admission (p=0.0404), longer durations of hospitalization (p=0.0077), and, although not statistically significant, a higher rate of CRS (p=0.0778). There was a correlation of CAR-T cell mRNA expression with DNA concentration, but CAR-T cell expression levels failed to correlate to response or survival. Our data suggest that higher CAR-T cell peak mRNA expression is associated with increased risk for ICANS and possibly CRS, requiring further investigation in larger studies.

وصف الملف: electronic resource

العلاقة: https://jag.journalagent.com/z4/download_fulltext.asp?pdir=tjh&un=TJH-63625Test; https://doaj.org/toc/1308-5263Test

الوصول الحر: https://doaj.org/article/9a24576f2c1a4135973771d15a06c133Test

المؤلفون: Dilara Akhoundova Sanoyan, Katja Seipel, Ulrike Bacher, Marie-Noelle Kronig, Naomi Porret, Gertrud Wiedemann, Michael Daskalakis, Thomas Pabst

المصدر: BMC Cancer, Vol 23, Iss 1, Pp 1-10 (2023)

مصطلحات موضوعية: Myeloma, CAR-T, Relapsed, Outcome, Ide-cel, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients. Methods We performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels. Results We identified 16 consecutive RRMM patients treated with ide-cel between 06–10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3–12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders. Conclusions We report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/ce5dbc4f39da4c5390e1ce06849fd0f3Test

المؤلفون: Katja Seipel, Naomi Porret, Gertrud Wiedemann, Barbara Jeker, Vera Ulrike Bacher, Thomas Pabst

المصدر: Current Issues in Molecular Biology, Vol 44, Iss 4, Pp 1463-1471 (2022)

مصطلحات موضوعية: B-cell maturation antigen (BCMA), soluble BCMA (sBCMA), multiple myeloma (MM), anti-BCMA CAR-T cell therapy, Biology (General), QH301-705.5

الوصف: BACKGROUND: Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine. METHODS: Plasma levels of soluble BCMA (sBCMA) and anti-BCMA CAR-T cell copy numbers were monitored in the blood, following CAR-T cell infusion in patients with relapsed multiple myeloma. sBCMA peptide concentration was determined in the plasma, applying a human BCMA/TNFRS17 ELISA. ddPCR was performed using probes targeting the intracellular signaling domains 4-1BB und CD3zeta of the anti-BCMA CAR-T construct. RESULTS: We report responses in the first five patients who received anti-BCMA CAR- T cell therapy at our center. Four patients achieved a complete remission (CR) in the bone marrow one month after CAR-T infusion, with three patients achieving stringent CR, determined by flow cytometry techniques. Anti-BCMA CAR-T cells were detectable in the peripheral blood for up to 300 days, with copy numbers peaking 7 to 14 days post-infusion. sBCMA plasma levels started declining one to ten days post infusion, reaching minimal levels 30 to 60 days post infusion, before rebounding to normal levels. CONCLUSIONS: Our data confirm a favorable response to treatment in four of the first five patients receiving anti-BCMA CAR-T at our hospital. Anti-BCMA CAR-T cell expansion seems to peak in the peripheral blood in a similar pattern compared to the CAR-T cell products already approved for lymphoma treatment. sBCMA plasma level may be a valid biomarker in assessing response to BCMA-targeting therapies in myeloma patients.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1467-3045/44/4/98Test; https://doaj.org/toc/1467-3037Test; https://doaj.org/toc/1467-3045Test

الوصول الحر: https://doaj.org/article/184a772a47644dd891b18adfd9875798Test

المؤلفون: Laura Rüegsegger, Urs Schanz, Katja Seipel, Thomas Pabst, Jürg Schwegler, Elisabeth Schmidt, Adrian Schmidt

المصدر: healthbook TIMES. Oncology Hematology, Vol 14, Iss 4 (2022)

مصطلحات موضوعية: Medicine

الوصف: # Introduction Haploinsufficiency of _GATA2_ leads to impaired genesis and function of hematopoietic stem and progenitor cells, resulting in impairment of all subsequent blood cell lineages. Germline mutations in _GATA2_ are transmitted by autosomal-dominant inheritance. Leading clinical symptoms of _GATA2_ deficiency syndromes are immunodeficiency, infections (mainly nontuberculous mycobacteria and human papillomavirus), predisposition to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), pulmonary alveolar proteinosis (PAP) and primary lymphedema. _GATA2_ mutations underlie not only Emberger syndrome (primary lymphedema and MDS), but also other syndromes like monocytopenia and mycobacterial infections syndrome (MonoMAC), dendritic cell/monocytopenia/natural killer (NK)-cell/B-cell lymphoid deficiency (DCML) and familial MDS/AML syndrome. We report the history of a Swiss family with Emberger syndrome extending over three generations. In addition, a review of the literature on _GATA2_ deficiencies is provided. # Methods Based on a general practitioner's observation of father and son sharing similar declined blood values and lymphedema, we examined the whole family for the presence of _GATA2_ mutation and a possible genotype-phenotype correlation. Publications on _GATA2_ deficiencies were researched on the PubMed database. # Results Six family members were diagnosed with _GATA2_ mutation, demonstrating individually variable penetrance and diversity of leading symptoms. # Conclusion Careful investigation of personal and family history, as well as meticulous examination, led to suspicion of the rare diagnosis of familial Emberger syndrome. Early diagnosis is mandatory for appropriate disease management.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2673-2092Test; https://doaj.org/toc/2673-2106Test

الوصول الحر: https://doaj.org/article/072363942cba421aa3edf768ce07c95fTest

المؤلفون: Katja Seipel, Mariesol Abbühl, Ulrike Bacher, Henning Nilius, Michael Daskalakis, Thomas Pabst

المصدر: Cancers, Vol 15, Iss 11, p 3058 (2023)

مصطلحات موضوعية: B-lymphocyte antigen CD19, single nucleotide polymorphism (SNP), minor allele frequency (MAF), CAR-T cell therapy, FMC63-chimeric antigen receptor (FMC63-CAR), Tisagenlecleucel (Kymriah©), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63–84% and complete response observed in 43–54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/15/11/3058Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/df6fda3249ee4f86aa89469d7124be61Test

المؤلفون: Cédric Gillich, Dilara Akhoundova, Michael Hayoz, Yolanda Aebi, Carlo R. Largiadèr, Katja Seipel, Michael Daskalakis, Ulrike Bacher, Thomas Pabst

المصدر: Cancers, Vol 15, Iss 10, p 2699 (2023)

مصطلحات موضوعية: multiple myeloma (MM), treosulfan, pharmacokinetics, efficacy, response rate, overall survival (OS), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: (1) Background: Upfront treatment consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to achieving durable remissions following induction treatment in multiple myeloma (MM) patients. The optimization of HDCT regimens can, therefore, essentially contribute to improving the depth and duration of tumor remissions. To date, melphalan at 200 mg/m2 is the standard HDCT regimen for fit MM patients. In our previous work, we showed promising efficacy and safety results for treosulfan (14 g/m2) and melphalan (200 mg/m2) (TreoMel) in acute myeloid leukemia (AML) patients receiving ASCT. Based on these data, TreoMel became the standard of care for fit MM patients at our institution. (2) Methods: We identified 115 consecutive MM patients who underwent consolidation with TreoMel between 01/2020 and 08/2022 at the University Hospital of Bern. We analyzed the safety and efficacy data, as well as the treosulfan pharmacokinetics, correlating them with tumor responses. (3) Results: A complete response (CR) rate of 84% was achieved, which is comparable to the CR rate reported for the quadruplet combination. The median PFS was 30 months (95% CI: 20.4—not reached), and the 31-month OS rate was 83%. The median area under the curve (AUC) for treosulfan was 952.5 mg*h/L (range: 527.4–1781.4), and the median peak level was 332.3 mg/L (range: 168–554). The treosulfan pharmacokinetics showed no significant correlation with MM responses after HDCT and ASCT. However, female patients had a significantly higher AUC (p = 0.007) and peak value (p = 0.001), and the higher values were associated with longer hospitalizations. (4) Conclusions: Treatment consolidation with TreoMel HDCT demonstrated a promising efficacy and safety profile in our cohort of MM patients and deserves further investigation in prospective studies.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/15/10/2699Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/1f61e063760147fc85cb211182d9861aTest

المؤلفون: Valerie Wittibschlager, Ulrike Bacher, Katja Seipel, Naomi Porret, Gertrud Wiedemann, Claudia Haslebacher, Michèle Hoffmann, Michael Daskalakis, Dilara Akhoundova, Thomas Pabst

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 6, p 5688 (2023)

مصطلحات موضوعية: CAR T-cell persistence, CAR T-cell therapy, B-cell lymphoma, ddPCR, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to investigate the correlation between CAR T-cell persistence in the peripheral blood (PB) at 6 months, assessed by droplet digital PCR (ddPCR), with CAR T-cell treatment outcome. 92 patients with r/r B-cell lymphomas were treated with CD19-targeting CAR T-cell therapies at our institution between 01/2019–08/2022. Six months post-treatment, 15 (16%) patients had no detectable circulating CAR-T constructs by ddPCR. Patients with CAR T-cell persistence had a significantly higher CAR T-cell peak (5432 vs. 620 copies/ug cfDNA, p = 0.0096), as well as higher incidence of immune effector cell-associated neurotoxicity syndrome (37% vs. 7%, p = 0.0182). After a median follow-up of 8.5 months, 31 (34%) patients relapsed. Lymphoma relapses were less frequent among patients with CAR T-cell persistence (29% vs. 60%, p = 0.0336), and CAR T-cell persistence in the PB at 6 months was associated with longer progression-free survival (PFS) (HR 2.79, 95% CI: 1.09–7.11, p = 0.0319). Moreover, we observed a trend towards improved overall survival (OS) (HR 1.99, 95% CI: 0.68–5.82, p = 0.2092) for these patients. In our cohort of 92 B-cell lymphomas, CAR T-cell persistence at 6 months was associated with lower relapse rates and longer PFS. Moreover, our data confirm that 4-1BB-CAR T-cells have a longer persistence as compared to CD-28-based CAR T-cells.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/6/5688Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/5bb361d861fe49e081e8578bba9bfc69Test