TY - JOUR
T1 - Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells
AU - Thiel, Uwe
AU - Schober, Sebastian J.
AU - Einspieler, Ingo
AU - Kirschner, Andreas
AU - Thiede, Melanie
AU - Schirmer, David
AU - Gall, Katja
AU - Blaeschke, Franziska
AU - Schmidt, Oxana
AU - Jabar, Susanne
AU - Ranft, Andreas
AU - Alba Rubío, Rebeca
AU - Dirksen, Uta
AU - Grunewald, Thomas G.P.
AU - Sorensen, Poul H.
AU - Richter, Günther H.S.
AU - von Lüttichau, Irene Teichert
AU - Busch, Dirk H.
AU - Burdach, Stefan E.G.
N1 - Publisher Copyright:
© 2017 Taylor & Francis Group, LLC.
PY - 2017/5/4
Y1 - 2017/5/4
N2 - 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.
AB - 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.
KW - Allorestricted T cells
KW - Ewing sarcoma
KW - T cell receptor transgenic T cells
KW - adoptive transfer
KW - immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85019046794&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2017.1312239
DO - 10.1080/2162402X.2017.1312239
M3 - Article
C2 - 28638739
AN - SCOPUS:85019046794
SN - 2162-4011
VL - 6
JO - OncoImmunology
JF - OncoImmunology
IS - 5
M1 - e1312239
ER -