Pilunov A M, Kuchmiy A A, Sheetikov S A, Filkin S Y, Romaniuk D S, Rosov F N, Efimov G A
National Hematology Research Center, Moscow, 125167 Russia.
Biological Faculty, Moscow State University, Moscow, 119991 Russia.
Mol Biol (Mosk). 2019 May-Jun;53(3):456-466. doi: 10.1134/S0026898419030145.
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 a relapse of the disease. Foreign peptides of the recipient presented by the MHC molecules are able to elicit the immune response immunologically. These polymorphic peptides are known as minor histocompatibility antigens (MiHAs). MiHAs occur due to the nonsynonymous single nucleotide polymorphisms in human genome. 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 undesirable damage to 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. The therapeutic mismatch occurs in 25% of cases under the optimal frequency of allelic variants. Minor antigen ACC-1Y originates from polymorphism in the BCL-2A1 gene; its immunogenic mismatch occurrence approaches the theoretical maximum. In addition, BCL2A1 is overexpressed in cells of various lymphomas. ACC-1Y 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 promising 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. We obtained a sequence of high-affinity ACC-1Y-specific TCR after the antigen-specific expansion of T cells derived from a healthy ACC-IY^(-/-) donor. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the CD8^(+) lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. It is suggested that CD8^(+) lymphocytes modified by the described method could be potentially transferred to recipients as a therapy against relapse after allo-HSCT.
异基因造血干细胞移植(allo-HSCT)是治疗造血系统恶性肿瘤的唯一根治性疗法。移植来源的供体淋巴细胞能够在同种异体免疫反应过程中清除残留的受体恶性细胞,从而降低疾病复发的几率。主要组织相容性复合体(MHC)分子呈递的受体外来肽能够引发免疫反应。这些多态性肽被称为次要组织相容性抗原(MiHAs)。MiHAs是由于人类基因组中的非同义单核苷酸多态性而产生的。输注主要在造血起源细胞中呈递的MiHAs特异性T细胞将允许靶向清除残留的恶性克隆,同时避免对健康组织造成不良损害。为了诱导免疫反应,供体必须在MiHA等位基因上是纯合子,而受体必须在替代的MiHA等位基因上是纯合子或杂合子。在等位基因变体的最佳频率下,治疗性错配发生在25%的病例中。次要抗原ACC-1Y源自BCL-2A1基因的多态性;其免疫原性错配的发生率接近理论最大值。此外,BCL2A1在各种淋巴瘤细胞中过表达。ACC-1Y在等位基因HLA-A*24:02上呈递,该等位基因在俄罗斯人群中相对常见。这些因素的结合使得次要抗原ACC-1Y成为免疫治疗的一个有前景的靶点。用转基因MiHA特异性TCR修饰的供体CD8⁺淋巴细胞输注是移植后白血病治疗和复发预防的有前景的方法之一。我们在来自健康的ACC-IY⁻/⁻供体的T细胞进行抗原特异性扩增后获得了高亲和力ACC-1Y特异性TCR序列。我们将该序列克隆到慢病毒载体中并获得了组装好的病毒颗粒。此外,我们转导了CD8⁺淋巴细胞培养物并证明了其抗原特异性细胞毒性活性。有人认为,通过所述方法修饰的CD8⁺淋巴细胞有可能作为allo-HSCT后抗复发的疗法转移给受体。