Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

Background: 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-A*02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8⁺) T cells against ES. Patients and Methods: Three refractory HLA-A2⁺ ES patients were treated with HLA-A*02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8⁺ T cells. Patient #1 received up to 4.8 × 10⁵/kg body weight HLA-A*02:01^- allorestricted donor-derived wild-type CD8⁺ T cells. Patient #2 received up to 8.2 × 10⁶/kg HLA-A*02:01^- donor-derived and patient #3 up to 6 × 10⁶/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 (CHM1³¹⁹). Results: HLA-A*02:01/CHM1³¹⁹-specific allorestricted CD8⁺ T cells showed specific in vitro 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. CHM1³¹⁹ TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1³¹⁹-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen-specific allorestricted T cells proliferate in vivo without causing GvHD.