Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients

Abstract

Treatment of Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) with EBV-specific cytotoxic T cells (EBV-specific IntroductionNasopharyngeal carcinoma (NPC) arises from the epithelial cells of the nasopharynx, and almost all nonkeratinizing and undifferentiated forms of this tumor are associated with Epstein-Barr virus (EBV). 1,2 NPC patients with limited local disease have a good prognosis when treated with chemotherapy and intensitymodulated radiation therapy, but outcomes in patients with locoregional bulky or metastatic disease remain poor. 1,3,4 In addition, patients who do survive frequently face severe short-and long-term treatment-related complications. 5,6 Hence, there is a need for novel therapies to improve disease-free survival and reduce treatmentrelated complications. Targeted T cell-based immunotherapy clearly has the potential to meet these needs. 7,8 Treatment of EBV-positive NPC with polyclonal EBV-specific cytotoxic T cells (EBV-specific CTL) has been promising, producing disease stabilization and complete remissions in patients with relapsed disease with low disease burden. [9][10][11] One of the primary obstacles in the treatment of NPC with EBV-specific CTL is the lack of expansion of the cells in the peripheral blood after infusion, so that the numbers of effector T cells available may be sufficient only for patients without bulky disease. This failure of CTL expansion in the periphery contrasts with the greater than 1000-fold expansion seen when EBV-specific CTL are given to patients during the period of lymphopenia after hematopoietic stem cell transplantation (HSCT) 12 or to patients with lymphoid malignancies, who have a relative lymphopenia. 13,14 Lymphoid depletion as a strategy to create space for the expansion of adoptively transferred cells has already shown evidence of success; melanoma patients receiving cyclophosphamide and fludarabine before the adoptive transfer of ex vivo expanded, melanomaspecific tumor-infiltrating lymphocytes (TILs), showed enhanced repopulation and proliferation of the transferred cells as well as regression of metastatic melanoma. 15,16 However, some of these patients remained profoundly immunocompromised and failed to regenerate an effective immune system. This poor immune reconstitution resulted in part from the extensive and nonspecific destruction of the resident immune system by the lymphodepleting cytotoxic drugs.Monoclonal antibodies (mAbs) that are cytolytic for lymphocytes may be an alternative means of producing lymphodepletion. The ideal antibody for T-cell depletion before CTL infusion should be effective but short lived in vivo, to permit rapid infusion and repopulation with infused CTL. We have used rat mAbs directed to the common leukocyte antigen CD45, which can deplete all leukocyte lineages. 17 This depletion was prolonged only in lymphoid lineages, as neutrophils began to recover 48 hours after injection. For our clinical studies, we used a pair of rat immunoglobulin G2 (IgG2) mAbs, which have a short half-life in humans...

Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation

“…We cannot exclude that this lack of detection in peripheral blood may reflect the altered migration pattern of T cells specific for nonlymphoid tissues. 26,27,46 Nevertheless, the ability to detect a significant expansion of adenovirus-specific T cells in the periphery after adoptive T-cell transfer clearly requires the presence of antigen in vivo. 47 None of the treated patients developed a de novo adenovirus infection after infusion compared with an infection rate of 68% in pediatric patients who did not receive CTL therapy.…”

HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma

“…[3][4][5] Strategies to reverse the immune-suppression status in the HL microenvironment and to restore an effective anti-HRS immunity in vivo are currently being explored as novel treatments for patients with cHL. 4,6,7 OX40 ligand (OX40L), a member of the tumor necrosis factor (TNF) superfamily, is expressed predominantly by professional antigen-presenting cells such as dendritic cells, activated B cells, and macrophages, in addition to T cells and endothelial cells. 8,9 OX40 receptor (CD134) is transiently expressed as a costimulatory protein by activated T cells, natural killer T cells, and T-reg cells.…”

Current Status of Engineered T-Cell Therapy for Synovial Sarcoma

“…Preliminary data on dose reductions in pre-conditioning cyclophosphamide regimens in ovarian cancer show decreased response to ACT, although whether a similar effect would be seen in synovial sarcoma remains unclear. Lympho-depletion methods that avoid the use of chemotherapy are under development and include monoclonal antibodies that target CD45 and CD52 [13,28,39]. Other strategies to enhance T-cell expansion also being investigated involve expression of IL15 and IL7Rα in genetically modified T cells [13,[29][30].…”