Human γδ+ T lymphocytes have in vitro graft vs leukemia activity in the absence of an allogeneic response

Abstract

Summary:Refractory acute lymphoblastic leukemia (ALL) is often incurable, and relapse rates following allogeneic bone marrow transplantation (BMT) remain high. We have reported that patients who develop increased numbers of ␥␦ + T cells soon after BMT are significantly less likely to relapse. We now show in seven donor/recipient pairs that donor-derived V␦1 + CD4 − CD8 − ␥␦ + T cells are activated and proliferate in response to recipient primary ALL blasts. In addition, these cells have been shown to bind and lyse the recipient ALL blasts. Separately, ␥␦ + T cells proliferate poorly or not at all in mixed lymphocyte culture against HLA-mismatched unrelated stimulator cells. These observations suggest that allogeneic ␥␦ + T cells could be an effective immunotherapeutic strategy against refractory disease without the risk of graft-versus-host disease. Bone Marrow Transplantation (2001) 27, 601-606.

Flow cytometric assessment of autologous γδ T cells in patients with acute myeloid leukemia: Potential effector cells for immunotherapy?

“…Ten of forty-three patients had increased peripheral blood gd T cell counts at 60-270 days after BMT, and all remained alive and free of disease at 2.5 years compared with a disease-free survival probability of 31% among patients with nonelevated gd T cell counts. The same group later showed that enrichment of the marrow graft with gd T cells decreases the incidence of relapse, and that gd T cells proliferate in vitro in response to acute lymphoblastic leukemia (ALL) blasts (61). Thus, they suggested a possible association between an increase in the number of gd T cells and improved disease-free survival.…”

“…AML relapse is assumed to arise from minimal residual disease (64). T cell immunosurveillance of residual leukemia may help to achieve durable remissions (61). Prolonging event-free survival of AML with immune cells, such as gd T cells, is therefore a promising concept and is under investigation by our group.…”

“…Data on the anti-leukemic effect of gd T cells in AML are scarce; no clinical trials have been reported, but based on in vitro lytic activity against leukemia cell lines (2,59) in vivo reactivity of peripheral blood gd T cells against lymphatic (60,61) and myeloid leukemias (62) has been hypothesized.…”

“…These observations are in line with a study of Poupot et al (2) in anaplastic large cell lymphoma, who confirmed by confocal microscopy and flow cytometry the ability of primary circulating human gd T cells to spontaneously bind and interact with lymphoma cells during coincubation. Similarly, Lamb et al also demonstrated binding (in a flow cytometric binding assay) and cytotoxicity of gd T cells against ALL (61).…”

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

“…Importantly, as for some other non-conventional T cell subsets, the antigenic activation process of Vg9Vd2 T cells is TCR-and contact-dependent, involving the expression of key molecules (eg., PAg and butyrophilins), 29 but not restricted by MHC class I/II molecules, then eliminating any risk of deleterious direct alloreactive responses toward non-transformed cells. 30,31 Therefore, the constitution of clinical allogeneic human Vg9Vd2 T cell banks, established from healthy donors, could represent a unique opportunity for designing adoptive transfer antitumor immunotherapies. Administration of effector T cells could be further hampered by the particular immunological status of the central nervous system, notably characterized by the presence of the bloodbrain barrier (BBB) and the absence of classical lymphatic drainage system, 32,33 then limiting T cell trafficking within the brain parenchyma and representing an additional obstacle to intravenous injections.…”