A Pilot Trial Using Lymphocytes Genetically Engineered with an NY-ESO-1–Reactive T-cell Receptor: Long-term Follow-up and Correlates with Response

Abstract

Purpose Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70–80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial employing the adoptive transfer of autologous PBMC that were retrovirally transduced with an NY-ESO-1 reactive TCR to heavily pretreated patients bearing these metastatic cancers. Experimental Design HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report. Results Eleven of 18 patients with NY-ESO-1+ synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1 positive melanomas (55%) who received autologous T cells transduced with an NY-ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall three and five year survival rates for patients with synovial cell sarcoma were 38 and 14%, respectively, while the corresponding estimated survival rates for patients with melanoma were both 33%. Conclusions The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments.

T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

“…The simple tumors tend to have specific, reliably identifiable oncogenic alterations (such as translocations) and a limited number of mutated neoantigens 13, 14. Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) both are translocation‐driven malignancies and often express high levels of self‐antigens, notably NY‐ESO‐1,15, 16 which has been targeted with promising signals of efficacy 6, 17…”

PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy

“…al. already demonstrated favorable results with HLA-A*02:01 dependent NY-ESO1 specific TCR-gene therapy in this tumor 7 . We hypothesize that the low HLA-I expression in SS will be enough to initiate activation of T-cells.…”

“…10 The high and mostly homogeneous expression indicates that all HLA-A*02:01 positive SS patients could be treated with PRAME-specific T-cells, which might be favorable to the earlier used approach targeting NY-ESO-1. 7 NY-ESO-1 is expressed heterogeneously in SS, with only 56% of tumors expressing the antigen in more than 50% of the tumor cells. 11 PRAME-TCR engineered T-cells could be used for the treatment of other cancers as well, including medulloblastoma, since many tumor types express PRAME 8 – 10 , 12 – 14 .…”

“…5,6 T-cell receptor (TCR) gene therapy with NY-ESO-1 specific HLA-A*02:01 restricted T-cells resulted in objective responses in 11/18 patients including 1 complete response. 7 Recently, preferentially expressed antigen in melanoma ( PRAME) was identified as a potential target for immunotherapeutic approaches in sarcoma 8 , with SS expressing the highest levels of PRAME . We previously identified a PRAME-specific HLA-A*02:01 restricted TCR with potent anti-tumor potential.…”

Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.

“…15,16 In this field, a promising immunotherapy approach is based on the adoptive infusion of antitumor immune-effectors, with important results recently reported against selected cases of synovial sarcoma treated with anti-NY-ESO1 engineered T lymphocytes. 17-21 …”