Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Blood. 2012 Apr 12;119(15):3440-9. doi: 10.1182/blood-2011-06-357939. Epub 2012 Feb 27.
The hyaluronan-mediated motility receptor (HMMR/Rhamm) is overexpressed in numerous tumor types, including acute lymphoid leukemia and acute myeloid leukemia (AML). Several studies have reported the existence of T-cell responses directed against HMMR in AML patients that are linked to better clinical outcome. Therefore, we explored the use of HMMR-specific TCRs for transgenic expression in lymphocytes and their in vivo impact on HMMR(+) solid tumors and disseminated leukemia. We obtained TCRs via an in vitro priming approach in combination with CD137-mediated enrichment. Recipient lymphocytes expressing transgenic TCR revealed the specific tumor recognition pattern seen with the original T cells. Adoptive transfer experiments using a humanized xenograft mouse model resulted in significantly retarded solid tumor outgrowth, which was enhanced using IL-15-conditioned, TCR-transgenic effector memory cells. These cells also showed an increased potency to retard the outgrowth of disseminated AML, and this was further improved using CD8-enriched effector memory cells. To define a safe clinical setting for HMMR-TCR gene therapy, we analyzed transgenic T-cell recognition of hematopoietic stem cells (HSCs) and found on-target killing of HLA-A2(+) HSCs. Our findings clearly limit the use of HMMR-TCR therapy to MHC- mismatched HSC transplantation, in which HLA-A2 differences can be used to restrict recognition to patient HSCs and leukemia.
透明质酸介导的运动受体（HMMR/Rhamm）在许多肿瘤类型中过表达，包括急性淋巴细胞白血病和急性髓细胞白血病（AML）。几项研究报告了 AML 患者中针对 HMMR 的 T 细胞反应的存在，这些反应与更好的临床结果相关。因此，我们探索了使用 HMMR 特异性 TCR 进行淋巴细胞转基因表达及其对 HMMR(+)实体瘤和播散性白血病的体内影响。我们通过体外引发方法结合 CD137 介导的富集获得了 TCR。表达转基因 TCR 的受体淋巴细胞显示出与原始 T 细胞相同的特异性肿瘤识别模式。使用人源化异种移植小鼠模型进行的过继转移实验导致实体瘤生长明显延迟，使用 IL-15 条件化、TCR 转基因效应记忆细胞可增强这种延迟。这些细胞还显示出延迟播散性 AML 生长的增加效力，使用 CD8 富集的效应记忆细胞进一步改善了这种效力。为了定义 HMMR-TCR 基因治疗的安全临床环境，我们分析了转基因 T 细胞对造血干细胞（HSCs）的识别，发现 HLA-A2(+) HSCs 的靶向杀伤。我们的研究结果明确将 HMMR-TCR 治疗限制在 MHC 错配的 HSC 移植中，其中 HLA-A2 差异可用于将识别限制在患者 HSCs 和白血病上。
