Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1
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.
Full-textDOI: · Available from: Chyi-Chia Richard Lee, Aug 12, 2015
- SourceAvailable from: Reno Debets
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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). "
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 · 1.64 Impact Factor
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- "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. "
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
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- "Such techniques have been used to produce T cells specific to melanoma antigens, such as melanoma antigen recognized by T cells (MART-1)   and testis antigen NY-ESO-1, which are found in synovial cell sarcoma and metastatic melanoma   , and to general TAAs, such as p53   and survivin  . T cells expressing TAA-specific TCRs have successfully promoted clinical responses in patients, including complete responses (CRs) in 2 of 11 patients with metastatic melanoma treated with T cells expressing a NY- ESO-1-recognizing TCR  . However, there are drawbacks to this approach. "
ABSTRACT: The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors (TCRs) or chimeric antigen receptors (CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin’s lymphoma.Chinese journal of cancer 09/2014; Chin J Cancer(Vol.33 Issue 9):421-433. DOI:10.5732/cjc.014.10100