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A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed/refractory multiple myeloma.

ABSTRACT: Electron microscopy is the gold standard to characterize centrosomal ultrastructure. However, production of significant morphometrical data is highly limited by acquisition time. We therefore developed a generalizable, semi-automated high-throughput electron tomography strategy to study centrosome aberrations in sparse patient-derived cancer cells at nanoscale. As proof of principle, we present electron tomography data on 455 centrioles of CD138^pos plasma cells from one patient with relapsed/refractory multiple myeloma and CD138^neg bone marrow mononuclear cells from three healthy donors as a control. Plasma cells from the myeloma patient displayed 122 over-elongated centrioles (48.8%). Particularly mother centrioles also harbored gross structural abnormalities, including fragmentation and disturbed microtubule cylinder formation, while control centrioles were phenotypically unremarkable. These data demonstrate the feasibility of our scalable high-throughput electron tomography strategy to study structural centrosome aberrations in primary tumor cells. Moreover, our electron tomography workflow and data provide a resource for the characterization of cell organelles beyond centrosomes.

SUBMITTER: Dittrich T

PROVIDER: S-EPMC9701608 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed/refractory multiple myeloma.

Dittrich Tobias T Köhrer Sebastian S Schorb Martin M Haberbosch Isabella I Börmel Mandy M Goldschmidt Hartmut H Pajor Gabor G Müller-Tidow Carsten C Raab Marc S MS Hegenbart Ute U Schönland Stefan O SO Schwab Yannick Y Krämer Alwin A

Cell reports methods 20221101 11

Electron microscopy is the gold standard to characterize centrosomal ultrastructure. However, production of significant morphometrical data is highly limited by acquisition time. We therefore developed a generalizable, semi-automated high-throughput electron tomography strategy to study centrosome aberrations in sparse patient-derived cancer cells at nanoscale. As proof of principle, we present electron tomography data on 455 centrioles of CD138<sup>pos</sup> plasma cells from one patient with r ...[more]

PMID: 36452870

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Project description:BackgroundTeclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Dataset Information

A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed/refractory multiple myeloma.

Publications

A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed/refractory multiple myeloma.

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