Adoptive Transfer of Epstein-Barr Virus-Specific Cytotoxic T-Lymphocytes for the Treatment of Angiocentric Lymphomas

Abstract

Angiocentric lymphoma, known as natural killer (NK)/T-cell non-Hodgkin's lymphoma, has been reported to be associated with the Epstein-Barr virus (EBV). We performed adoptive transfer of EBV-specific polyclonal T-cell lines in 3 patients with extranodal NK/T-cell lymphoma, nasal type, and evaluated the treatment for safety, immunologic reconstitution, and clinical outcomes. The tissue samples collected from the 3 patients were confirmed by polymerase chain reaction analysis to be EBV positive. In the cases of the first and second patients, EBV-transformed B-lymphoblastoid cell lines (LCLs) and T-cell lines were generated from peripheral lymphocytes of HLA-matched sibling donors. The third patient's T-cell lines were induced with autologous lymphocytes. Polyclonal T-cell infusion was carried out after high-dose radiotherapy because active relapsed disease remained in all of the patients. The first patient received 4 weekly infusions of 2 3 10(7) cells/m(2), and the second and third patients underwent treatment with 2 cycles of infusions of the same dosage. All T-cell lines showed >60% NK activity, cytotoxic T-lymphocyte (CTL) responses of >40% against autologous LCLs, and no CTL activity against patient-derived lymphoblasts. The level of cytotoxicity increased substantially in all patients after cell infusion. The 2 patients who received T-cell therapy twice had stabilized disease for more than 3 years. These safe treatments exhibited no severe inflammatory response, and no serious toxicity developed during T-cell therapy. Our findings demonstrate that adoptively transferred cells may provide reconstitution of EBV-specific CTL responses in patients with active relapsed angiocentric lymphoma. These results provide a rationale for the immunotherapy of angiocentric lymphoma.

Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

“…The treatments were performed thrice at 5-day intervals and mice were monitored daily for tumor growth. Following treatment, the tumor volume (mm 3 ) was estimated in accordance with the formula (tumor width 2 (mm) Â tumor length (mm)/2). All animals were handled according to the local and national regulations, and the local ethics committee approved the protocol.…”

“…3,4 However, T cells reactive against tumor antigens cannot be generated in every case, due to individual antigen variation as well as to variation in the priming capacity of antigen-presenting cells. 5 The peripheral T-cell repertoire is usually without high-avidity tumor-specific cytotoxic T lymphocytes due to thymic selection.…”

“…6 Moreover, tumor-specific cytotoxic T lymphocytes are often anergic or show a limited life span. 3,7 Even if T cells with high avidity for antigens are generated, adoptive immunotherapy cannot be guaranteed to be successful because of the uncertainty of its persistency and reactivity in vivo. 5 Transgenic expression of T-cell receptor and chimeric immune receptors (CIR) aims to circumvent these constraints.…”

Adoptive cellular therapy with T cells specific for EBV-derived tumor antigens

“…33 Chua et al targeted patients with extranodal NK/T-cell lymphoma, nasal type and transferred EBV-specific polyclonal T-cell lines to 3 patients. 36 One patient received autologous cells while the other 2 received lines generated from HLA-matched sibling donors. One patient had no response but the other two patients had disease stabilization that persisted for over 3 years.…”

Adoptive cellular immunotherapy for childhood malignancies

“…The trial data demonstrate that prophylactic infusions of these viral-specific T cells can prevent clinically-significant EBV infection as well as treat bulky post transplant LPD/lymphoma, EBV-associated NK-cell malignancies (angiocentric lymphomas), and HIV-associated lymphomas. [17][18][19][20][21][22][23][24][25] The implications of clinical trials infusing EBV-specific T cells for adoptive immunotherapy of pediatric neoplasms are potentially far-reaching and five sequelae are described. (i) Bulk (nonclonal) populations of allogeneic T cells, enriched for specificity for EBV, can be safely infused without causing GVHD.…”