TCR T cells targeting IgA- and IgG-expressing multiple myeloma
Abstract
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.
Article Details
Authors (23)
Karolos Douvlataniotis
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Aleksei Titov
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Julia Zeun
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Merve Bilici
Heyilimu Palashati
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Waywen Loh
University of Oxford, Oxford, United Kingdom
Even Holth Rustad
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Weiwen Yang
Oslo University Hospital Radiumhospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Trung T Tran
Oslo University Hospital Rikshospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Fridtjof Lund-Johansen
Ravi Chand Bollineni
The Precision Immunotherapy Alliance, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway, Norway
Jessica D. Kepple
University of Oxford, Oxford, United Kingdom
Luis P. Huth
BIH Center for Regenerative Therapies, Berlin Institute of Health, Germany
Ludvig A Munthe
Oslo University Hospital Rikshospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Thorstein Boxaspen
Oslo University Hospital Radiumhospitalet, The Precision Immunotherapy Alliance, University of Oslo and Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway, Norway
Fredrik Schjesvold
Anders Waage
Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Dimitrios L. Wagner
Katherine R. Bull
University of Oxford, Oxford, United Kingdom
Joanna Hester
Fadi Issa
Eirini Giannakopoulou
Oslo University Hospital Rikshospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway
Johanna Olweus
Oslo University Hospital Rikshospitalet and The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway, Norway