Eirini Chrysovalantou Giannokopoulou

• Douvlataniotis, Dimitrios Karolos; Titov, Aleksei; Zeun, Julia; Bilici, Merve; Palashati, Heyilimu & Loh, Waywen [Vis alle 23 forfattere av denne artikkelen] (2026). TCR T cells targeting IgA- and IgG-expressing multiple myeloma∗. Blood. ISSN 0006-4971. doi: 10.1182/blood.2025031897. Fulltekst i vitenarkiv Vis sammendrag

  T cell-based therapies have shown remarkable efficacy in multiple myeloma (MM), yet the disease remains largely incurable. Here, we investigated the constant domains of the immunoglobulin heavy chain (IgH) as novel targets for therapeutic T cell receptors (TCRs), after confirming high and homogeneous IGH expression in >95% of MM patients. MM cells secrete excessive monoclonal immunoglobulins (M-proteins) that drive complications but are inaccessible to CAR T-cell or antibody targeting. Peptides from IgA and IgG constant regions were eluted from HLA-A*02:01, and reactive TCRs were isolated from healthy donors using allo-HLA-A*02:01 presentation to circumvent self-tolerance. T cells engineered with two TCRs specific for IgA or IgG passed a stringent multi-tier safety screen and selectively eliminated MM cells from 20 HLA-A*02:01+ patients secreting the relevant IgH in vitro. In vivo, IgA-TCR T cells eradicated IgA+HLA-A*02:01+ MM cells in xenograft models and reduced circulating IgA in humanized mice. These findings establish immunoglobulin constant domains as viable TCR targets in MM, potentially making ~40% of patients of European descent eligible for TCR T cell therapy, and extension to additional HLA alleles could further broaden eligibility. The approach may also be applicable to lymphoma and antibody-mediated autoimmune diseases.

• Giannakopoulou, Eirini Chrysovalantou; Lehander, Madeleine; Culleton, Stina Virding; Yang, Weiwen; Li, Yingqian & Kärpänen, Terhi Hannele [Vis alle 29 forfattere av denne artikkelen] (2023). A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo. Nature Cancer. 4(10). doi: 10.1038/s43018-023-00642-8. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCR FLT3D/Y ). TCR FLT3D/Y -redirected T cells selectively eliminated primary human AML cells harboring the FLT3 D835Y mutation in vitro and in vivo. TCR FLT3D/Y cells rejected both CD34 + and CD34 − AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34 + AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.

• Ali, Muhammad; Giannakopoulou, Eirini Chrysovalantou; Li, Yingqian; Lehander, Madeleine; Culleton, Stina Virding & Yang, Weiwen [Vis alle 33 forfattere av denne artikkelen] (2021). T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes. Nature Biotechnology. ISSN 1087-0156. doi: 10.1038/s41587-021-01089-x. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

• Muhammad, Ali; Földvári, Zsofia; Giannakopoulou, Eirini Chrysovalantou; Bøschen, Maxi-Lu; Strønen, Erlend & Yang, Weiwen [Vis alle 11 forfattere av denne artikkelen] (2019). Induction of neoantigen-reactive T cells from healthy donors. Nature Protocols. ISSN 1754-2189. 14(6), s. 1926–1943. doi: 10.1038/s41596-019-0170-6. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Giannakopoulou, Eirini Chrysovalantou (2023). Unleashing the power of T-cell receptors for adoptive immunotherapy. Fulltekst i vitenarkiv
• Giannakopoulou, Eirini Chrysovalantou (2023). A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimiation of primary human acute myeloid leukemia in vivo. Fulltekst i vitenarkiv

Se alle arbeider i NVA