Article

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

National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, MD 20892-1201, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2011; 29(7):917-24. DOI: 10.1200/JCO.2010.32.2537
Source: PubMed

ABSTRACT

Adoptive 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.
A 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).
Objective 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.
These 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.

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    • "Adoptive cellular therapy in which autologous tumour infiltrating lymphocytes (TILs) are harvested from human melanoma patients, expanded ex vivo and then re-infused intravenously postlymphodepletion has also resulted in some incredible effects in clinical trials with advanced stage melanoma patients (Rosenberg and Dudley, 2009). Engineering of autologous T-cells ex vivo to alter the T-cell receptor (TCR) has also been performed enabling T-cells to engage with tumour cells in patients where the unaltered autologous cells might be unable to bind to the appropriate targets (Robbins et al., 2011). Latterly T-cells with chimeric antigen receptors (CAR T-cells) have also been developed in pre-clinical melanoma models to enhance T-cell target recognition and killing (Zhang et al., 2014). "
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    • "Recently, a number of different laboratories have used immune-modulating antibodies [genetically engineered autologous T cells expressing tumor-antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR)] to treat a variety of human cancers other than melanoma and renal cell carcinoma. The list of cancer immunotherapies are now expanding to non-smallcell lung carcinoma (Brahmer et al., 2012; Topalian et al., 2012), metastatic hormonerefractory prostate cancer (Small et al., 2007), synovial sarcoma (Robbins et al., 2011), lymphoma, leukemia, breast cancer, colorectal cancer, ovarian cancer, and glioblastoma. "
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    • "Initial trials using gene-modified T cells to treat various tumor types did not show antitumor responses in a substantial number of patients (Kershaw et al., 2006; Morgan et al., 2006; Till et al., 2008; Johnson et al., 2009; Lamers et al., 2013a,b). Despite that some recent trials using either a CD19 CAR to treat B cell leukemias (Kalos et al., 2011; Davila et al., 2014; Lee et al., 2014; Maude et al., 2014) or an NY-ESO TCR to treat melanoma and synovial carcinoma (Robbins et al., 2011) showed significant clinical activities, the majority of the studies performed so far fail to demonstrate substantial antitumor effects (Gilham et al., 2012; Kunert et al., 2013). "
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