We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Transgenic HA-1-Specific CD8 + T-Lymphocytes Selectively Target Leukemic Cells.
- Authors
Pilunov, Artem; Romaniuk, Dmitrii S.; Shmelev, Anton; Sheetikov, Savely; Gabashvili, Anna N.; Khmelevskaya, Alexandra; Dianov, Dmitry; Zornikova, Ksenia; Shakirova, Naina T.; Vagida, Murad; Bogolyubova, Apollinariya; Efimov, Grigory A.
- Abstract
Simple Summary: A relapse of the malignant disease frequently occurs after allogeneic hematopoietic stem cell transplantation. Immune recognition of minor histocompatibility antigens, the polymorphic peptides that differ between donor and recipient, often triggers a beneficial graft-versus-leukemia response. The transgenic donor-derived cytotoxic T cells, which recognize patient-specific minor histocompatibility antigens presented by hematopoietic cells, allow precise elimination of malignant recipient cells while sparing both donor and non-hematopoietic patient cells. We generated the MiHA-specific T cells by gene editing to knock out the endogenous T cell receptor, followed by lentiviral transduction of HA-1-specific T cell receptors. Modified T cells demonstrated cytotoxicity against leukemia cells from HA-1+ donors with acute myeloid leukemia, acute T-cell, and B-cell lymphoblastic leukemia. Transgenic T cells showed no cytotoxicity against donor cells lacking HA-1 surface presentation. The proposed therapeutic approach could be used after allogeneic hematopoietic stem cell transplantation to prevent and treat leukemia relapse. A significant share of allogeneic hematopoietic stem cell transplantations (allo-HSCT) results in the relapse of malignant disease. The T cell immune response to minor histocompatibility antigens (MiHAs) promotes a favorable graft-versus-leukemia response. The immunogenic MiHA HA-1 is a promising target for leukemia immunotherapy, as it is predominantly expressed in hematopoietic tissues and presented by the common HLA A*02:01 allele. Adoptive transfer of HA-1-specific modified CD8+ T cells could complement allo-HSCT from HA-1- donors to HA-1+ recipients. Using bioinformatic analysis and a reporter T cell line, we discovered 13 T cell receptors (TCRs) specific for HA-1. Their affinities were measured by the response of the TCR-transduced reporter cell lines to HA-1+ cells. The studied TCRs showed no cross-reactivity to the panel of donor peripheral mononuclear blood cells with 28 common HLA alleles. CD8+ T cells after endogenous TCR knock out and introduction of transgenic HA-1-specific TCR were able to lyse hematopoietic cells from HA-1+ patients with acute myeloid, T-, and B-cell lymphocytic leukemia (n = 15). No cytotoxic effect was observed on cells from HA-1- or HLA-A*02-negative donors (n = 10). The results support the use of HA-1 as a target for post-transplant T cell therapy.
- Subjects
CANCER relapse; ALLELES; BIOINFORMATICS; CANCER patients; RESEARCH funding; DESCRIPTIVE statistics; HEMATOPOIETIC stem cell transplantation; T cells; CELL lines; IMMUNOTHERAPY; HISTOCOMPATIBILITY antigens; ORGAN donors
- Publication
Cancers, 2023, Vol 15, Issue 5, p1592
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers15051592