Antitumor Activity of EBV-specific T Lymphocytes Transduced With a Dominant Negative TGF-β Receptor

Abstract

SummaryTransforming growth factor (TGF)-β is produced in most human tumors and markedly inhibits tumor antigen-specific cellular immunity, representing a major obstacle to the success of tumor immunotherapy. TGF-β is produced in Epstein-Barr virus (EBV)-positive Hodgkin disease and nonHodgkin lymphoma both by the tumor cells and by infiltrating T-regulatory cells and may contribute the escape of these tumors from infused EBV-specific T cells. To determine whether tumor antigenspecific cytotoxic T lymphocytes (CTLs) can be shielded from the inhibitory effects of tumor-derived TGF-β, we previously used a hemagglutinin-tagged dominant negative TGF-βRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-β in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-β both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-β type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-β-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-β-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.

T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

“…DNR-transduced cytotoxic T lymphocytes were resistant to the anti-proliferative effects of TGFβ and adoptive transfer of TGFβ-DNR transduced T cells resulted in eradication of tumor cells in vivo. 79 Other current limitations of T-cell therapies are summarized in Table 1.…”

Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies

“…Much of this is mediated through release of TGF-b, which can attenuate T cell function. It has been shown recently that EBV-specific CTLs can be transduced with a retroviral vector carrying a dominant negative TGF-b type II receptor (DNRII) which functions to block the immunosuppressive effects of TGF-b while retaining the killing ability of the transduced cell, resulting in significant tumour regression [68]. However, TGF-b is pleiotropic in function and is required for other aspects of immune regulation, and although there are concerns that the introduction of a DNRII would result in uncontrolled immune responses, this has not been observed [68].…”

Role of the tumor microenvironment in mature B-cell lymphoid malignancies

“…One of the problems with CAR T-cell therapy is to overcome the immunosuppressive tumor microenvironment that includes M2 polarized macrophages, T regs , and myeloid-derived suppressor cells. 98 Investigators have approached this problem by modifying the CAR T-cell construct number in a number of customized ways, including the incorporation of proinflammatory cytokines such as IL-12, 99 expression of dominant negative TGF-β, 100 anti-apoptotic Fas-knockdowns 101 and the expression of survival signals such as Bclxl. 102 An alternate approach would be to combine CAR T cells with agents targeting the PD-1 axis to enhance the anti-tumor cytotoxicity.…”