دورية أكاديمية
T-Cell Characteristics Impact Response and Resistance to T-Cell-Redirecting Bispecific Antibodies in Multiple Myeloma.
| العنوان: | T-Cell Characteristics Impact Response and Resistance to T-Cell-Redirecting Bispecific Antibodies in Multiple Myeloma. |
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| المؤلفون: | Verkleij CPM; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., O'Neill CA; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Broekmans MEC; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Frerichs KA; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Bruins WSC; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Duetz C; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Kruyswijk S; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Baglio SR; Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Skerget S; Janssen Research & Development, Spring House, Pennsylvania., Montes de Oca R; Janssen Research & Development, Spring House, Pennsylvania., Zweegman S; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Verona RI; Janssen Research & Development, Spring House, Pennsylvania., Mutis T; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., van de Donk NWCJ; Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Jul 15; Vol. 30 (14), pp. 3006-3022. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Multiple Myeloma*/immunology , Multiple Myeloma*/drug therapy , Multiple Myeloma*/pathology , Antibodies, Bispecific*/pharmacology , Antibodies, Bispecific*/therapeutic use , Drug Resistance, Neoplasm*/immunology, Humans ; B-Cell Maturation Antigen/immunology ; T-Lymphocytes, Regulatory/immunology ; Female ; Male ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Middle Aged ; Aged ; Receptors, G-Protein-Coupled |
| مستخلص: | Purpose: Bispecific antibodies (BsAb) directed against B-cell maturation antigen (teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated patients with multiple myeloma. However, mechanisms underlying primary and acquired resistance remain poorly understood. Experimental Design: The anti-multiple myeloma activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from patients with multiple myeloma. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from patients with multiple myeloma who were treated with these BsAb. Results: In ex vivo killing assays with 41 BM samples from BsAb-naive patients with multiple myeloma, teclistamab- and talquetamab-mediated multiple myeloma lysis was strongly correlated (r = 0.73, P < 0.0001). Both BsAb exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/multiple myeloma cell ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab revealed that high frequencies of PD-1+ CD4+ T cells, CTLA4+ CD4+ T cells, and CD38+ CD4+ T cells were associated with primary resistance. Although this lack of response was linked to a modest increase in the expression of inhibitory receptors, increasing T-cell/multiple myeloma cell ratios by adding extra T cells enhanced sensitivity to BsAb. Further, treatment with BsAb resulted in an increased proportion of T cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired antitumor efficacy in ex vivo experiments. Conclusions: Primary resistance is characterized by a low T-cell/multiple myeloma cell ratio and Treg-driven immunosuppression, whereas reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to the development of acquired resistance. (©2024 American Association for Cancer Research.) |
| معلومات مُعتمدة: | Janssen Research and Development (JRD) |
| المشرفين على المادة: | 0 (Antibodies, Bispecific) 0 (B-Cell Maturation Antigen) 0 (GPRC5D protein, human) 0 (Receptors, G-Protein-Coupled) |
| تواريخ الأحداث: | Date Created: 20240430 Date Completed: 20240715 Latest Revision: 20240715 |
| رمز التحديث: | 20240715 |
| DOI: | 10.1158/1078-0432.CCR-23-3333 |
| PMID: | 38687588 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-23-3333 |