MODIFICATION OF CYTOTOXIC LYMPHOCYTES WITH T CELL RECEPTOR SPECIFIC FOR MINOR HISTOCOMPATIBILITY ANTIGEN ACC-1Y
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for hematopoietic malignancies. The graft-derived donor lymphocytes are capable of eliminating the residual recipient malignant cells in the course of allogeneic immune response thus decreasing the chances of the disease relapse. Immunologically foreign peptides of the recipient presented in the MHC molecules are able to elicit the immune response. These polymorphic peptides are known as Minor Histocompatibility Antigens (MiHAs). MiHAs are derived from the nonsynonymous single nucleotide polymorphisms. Transfusion of T cells specific to MiHAs presented predominantly in the cells of hematopoietic origin will allow the targeted elimination of residual malignant clones avoiding the undesirable damage of the healthy tissues. To induce the immune response, the donor must be homozygous by the MiHA allele and the recipient must either be homozygous or heterozygous by the alternative MiHA allele. Under the optimal frequency of allelic variants, the therapeutic mismatch occurs in 25% of cases. Minor antigen ACC-1Y is derived from polymorphism in gene BCL-2A1 and its therapeutic mismatch occurrence approaches the theoretical maximum. In addition, ACC-1Y is overexpressed in cells of various lymphomas and it is presented on allele HLA-A*24:02 which is relatively frequent in the Russian population. Combination of these factors makes the minor antigen ACC-1Y a prospective target for immunotherapy. Transfusion of donor CD8+ lymphocytes modified with transgenic MiHA-specific TCR is one of the promising methods of posttransplant leukemia therapy and relapse prophylaxis. Here, we obtained a sequence of high-affinity ACC-1Y-specific TCR. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. CD8+ lymphocytes modified by the described method could be potentially transferred to recipients either simultaneously with alloHSCT or as a relapse therapy.