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


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.

Download full-text


Available from: Chyi-Chia Richard Lee,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This unit describes protocols for developing tumors in mice, including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modification of mouse T cells for adoptive transfer by using retrovirus-expressing genes of interest are provided. Additional sections, including growing B16 melanoma, enumerating pulmonary metastases, tumor imaging technique, and use of recombinant viruses for vaccination, are discussed together with safety concerns. © 2015 by John Wiley & Sons, Inc. Copyright © 2015 John Wiley & Sons, Inc.
    Current protocols in immunology / edited by John E. Coligan ... [et al.] 02/2015; 108:20.1.1-20.1.43. DOI:10.1002/0471142735.im2001s108
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for Carbonic Anhydrase IX (CAIX) we observed toxicities which (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have re-defined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or post gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8+,CD27+,CD62L+,CD45RA+ T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors.
    Human Gene Therapy Methods 11/2014; 25(6). DOI:10.1089/hgtb.2014.051 · 2.44 Impact Factor
  • Source
    • "TCR (Robbins et al., 2011) or CAR redirected T cells (Porter et al., 2011; Kochenderfer et al., 2012; Brentjens et al., 2013) have been successful implemented in several clinical trials. However adverse events including autoimmunity or off-target effects have been reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adoptive T-cell therapy can involve donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte (TILs) expanded ex-vivo, or more recently the use of T cell receptor (TCR) or chimeric antigen receptor (CAR) redirected T cells. However cellular therapies can pose significant risks, including graft-versus-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase (HSV-TK) and inducible-caspase-9 (iCasp9).
    Frontiers in Pharmacology 10/2014; 5(524). DOI:10.3389/fphar.2014.00254 · 3.80 Impact Factor
Show more