title: Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA.
abstract: T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20, including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast, a wide range of HLA-A2(pos)CD20(neg) cells representing different tissue origins, and HLA-A2(neg)CD20(pos) cells, were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2-specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos), these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells.
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Nadia
authors.initials: N
authors.lastname: Mensali
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Fan
authors.initials: F
authors.lastname: Ying
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vincent Oei Yi
authors.initials: VO
authors.lastname: Sheng
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet , Oslo, Norway.
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet , Oslo, Norway.
authors.forename: Lars-Egil
authors.initials: LE
authors.lastname: Fallang
authors.affiliation: K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Kolstad
authors.affiliation: Max Delbrück Center for Molecular Medicine and Institute of Biology, Humboldt University , Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karl Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Cell Therapy, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Johanna
authors.initials: J
authors.lastname: Olweus
keywords: B-cell malignancies; CD20; T-cell receptor; gene therapy; haploidentical allogeneic stem cell transplantation; immunotherapy