Thiel Uwe, Schober Sebastian J, Einspieler Ingo, Kirschner Andreas, Thiede Melanie, Schirmer David, Gall Katja, Blaeschke Franziska, Schmidt Oxana, Jabar Susanne, Ranft Andreas, Alba Rubío Rebeca, Dirksen Uta, Grunewald Thomas G P, Sorensen Poul H, Richter Günther H S, von Lüttichau Irene Teichert, Busch Dirk H, Burdach Stefan E G
Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Technische Universität München, Munich, Germany.
Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Oncoimmunology. 2017 Apr 12;6(5):e1312239. doi: 10.1080/2162402X.2017.1312239. eCollection 2017.
: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8) T cells against ES. : Three refractory HLA-A2 ES patients were treated with HLA-A02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8 T cells. Patient #1 received up to 4.8 × 10/kg body weight HLA-A02:01 allorestricted donor-derived wild-type CD8 T cells. Patient #2 received up to 8.2 × 10/kg HLA-A02:01 donor-derived and patient #3 up to 6 × 10/kg autologous allorestricted TCR transgenic CD8 T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1). : HLA-A02:01/CHM1-specific allorestricted CD8 T cells showed specific lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1 TCR transgenic T cells could be tracked in his BM for weeks. : CHM1-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A02:01/antigen-specific allorestricted T cells proliferate without causing GvHD.
软骨调节素-I（CHM1）维持尤因肉瘤（ES）的恶性状态。难治性ES预后不佳，骨髓（BM）转移患者无论接受何种治疗均无法存活。我们评估了针对ES的HLA-A*02:01/CHM1特异性全限制T细胞受体（TCR）野生型和转基因细胞毒性（CD8）T细胞。
三名难治性HLA-A2 ES患者接受了HLA-A02:01/肽特异性全库来源（即全限制）的CD8 T细胞治疗。患者1接受了高达4.8×10⁶/kg体重的HLA-A02:01全限制供体来源野生型CD8 T细胞。患者2接受了高达8.2×10⁶/kg的HLA-A*02:01供体来源细胞，患者3接受了高达6×10⁶/kg的自体全限制TCR转基因CD8 T细胞。所有患者均接受针对CHM1肽319（CHM1）的相同TCR互补决定区3全识别序列治疗。
HLA-A*02:01/CHM1特异性全限制CD8 T细胞对所有患者来源的ES细胞系均表现出特异性裂解作用。治疗耐受性良好，未引起移植物抗宿主病（GvHD）。患者1和患者3病情进展缓慢，而患者2虽有BM受累，但出现部分转移灶消退，与T细胞归巢至受累病灶有关。可在患者2的BM中追踪CHM1 TCR转基因T细胞数周。
CHM1-TCR转基因T细胞归巢至受影响的BM，可能导致部分疾病消退。HLA-A*02:01/抗原特异性全限制T细胞增殖但不引起GvHD。
