Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1

Abstract

A B S T R A C T PurposeAdoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of patients with synovial cell sarcoma and approximately 25% of patients with melanoma and common epithelial tumors, represents an attractive target for immune-based therapies. The current trial was carried out to evaluate the ability of adoptively transferred autologous T cells transduced with a T-cell receptor (TCR) directed against NY-ESO-1 to mediate tumor regression in patients with metastatic melanoma and synovial cell sarcoma. Patients and MethodsA clinical trial was performed in patients with metastatic melanoma or metastatic synovial cell sarcoma refractory to all standard treatments. Patients with NY-ESO-1-positive tumors were treated with autologous TCR-transduced T cells plus 720,000 iU/kg of interleukin-2 to tolerance after preparative chemotherapy. Objective clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). ResultsObjective clinical responses were observed in four of six patients with synovial cell sarcoma and five of 11 patients with melanoma bearing tumors expressing NY-ESO-1. Two of 11 patients with melanoma demonstrated complete regressions that persisted after 1 year. A partial response lasting 18 months was observed in one patient with synovial cell sarcoma. ConclusionThese observations indicate that TCR-based gene therapies directed against NY-ESO-1 represent a new and effective therapeutic approach for patients with melanoma and synovial cell sarcoma. To our knowledge, this represents the first demonstration of the successful treatment of a nonmelanoma tumor using TCR-transduced T cells.

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

“…This cutoff value was chosen to be consistent with criteria used in an ongoing clinical trial of NY-ESO-1 immunotherapy. 5 In addition, cross comparison of manual and autostaining revealed the manual method generated a weak background stain not seen with the automated platform. However, the scoring system, which considered weak (intensity 1) staining as negative meant that the cases defined as 'positive' were consistently categorized and equally discernible with both staining methods.…”

“…We employed a cutoff value for immunohistochemical positivity by reference to the eligibility of an antecedent clinical trial of immunotherapy targeting NY-ESO-1. 5 Myxoid liposarcoma represents 20-30% of all liposarcomas, mostly occurs in young adults, and is characterized by a translocation t(12;16)(q13;p11) or, in a few percent of the cases, a t(12;22)(q13;q12), leading to the chimeric fusion product FUS-DDIT3 or EWSR1-DDIT3, respectively. 25,26 According to the literature, one-third of myxoid liposarcoma patients develop distant metastases, 18,27,28 so effective systemic therapy is needed to improve the prognosis of many patients.…”

“…4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.Mesenchymal tumors arising from bone or soft tissues comprise many histologic subtypes, which even when taken together occur at a much lower rate than the more common carcinomas, creating a practical barrier to developing new drug therapies. However, the well-defined biology of many sarcomas suggests they may be particularly susceptible to appropriate targeted strategies.…”

“…4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…However, as endogenous TCR-mediated killing is MHC-restricted, this approach is limited to patients with certain common HLA types. Furthermore, despite encouraging responses in certain solid tumours(Robbins et al 2011), expanding the use of engineered αβ TCRs to treat haematological malignancies proved challenging given the low-level expression of TAAs on normal tissue, or ability of the TCR to recognize cross-reactive epitopes present on normal cells in some cases. (Arber et al 2015) The potential for “on-target, off-tumour” toxicities associated with certain TAA is another limitation of TCR-targeted approaches.…”