In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

Abstract

Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8 þ cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigenpresenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4 þ or CD8 þ T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-c and TNF-a or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8 þ T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

“…However, because aGVHD and GVL are 2 tightly linked processes, any therapeutic strategy targeting aGVHD must not abrogate the GVL response of the donor allograft. To that end, maintenance of CTL function is critical for the beneficial antineoplastic immune response of the donor allograft (40,44). Using the P815 GVL model, we show that PRMT5 inhibition retains CD8 + CTL capacity, which might explain why PRMT5 inhibition still preserves the beneficial GVL effect.…”

A TLR5 Agonist Enhances CD8+ T Cell-Mediated Graft-versus-Tumor Effect without Exacerbating Graft-versus-Host Disease

“…Multiple cell types such as NK cells, CD4 + , and CD8 + T cells have been implicated in the GVT mechanisms (6)(7)(8). Among them, CD8 + T cells were shown to be a major contributor for GVT activity because of the strong alloantigen specificity (9,10).…”

Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

“…Not only the mouse mastocytoma cell line P815 was efficiently rejected but also primary Bcr-Abl transduced B cells, which are highly aggressive because injection of 40 tumor cells induced 100% mortality after 14 days. 7 Differences in the effect of APG101 on allogeneic T-cell effector functions, which induce host tissue destruction on the one hand and tumor cell eradication on the other hand, can probably be explained by the requirement of specific effector molecules for cell death in certain cell types. Tumor-cell destruction can be predominantly dependent on the presence of one cytotoxic mechanism but often CD95L and perforin-dependent killing can compensate for the absence of the other.…”

“…7 If indicated, APG101 at a concentration of 100 ng/mL was present during the whole stimulation time.…”

“…5,6 We recently found that even in vitro-generated alloantigen-specific cytotoxic T cells (CTLs) mediate antitumor cytotoxicity in the absence of GVHD. 7 Interfering with T-cell trafficking or cytokine production offers other treatment strategies. 8,9 The primary goal of most trials is the inhibition of host tissue destruction by attacking alloantigen-specific T cells.…”