Bypassing tumor-specific and bispecific antibodies: triggering of antitumor immunity by expression of anti-FcγR scFv on cancer cell surface

Gruel, Nadège; Fridman, Wolf‐Herman; Teillaud, Jean‐Luc

doi:10.1038/sj.gt.3301575

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…Several chimeric surface proteins have recently been described including chimeric scFv receptors for T-cell activation 15,[24][25][26] or deactivation, 27 membrane-bound cytokines, 28,29 prodrug-activating enzymes 30 and artificial Fc receptors. 31,32 Expression of engineered proteins on the surface of cells therefore represents a rich source for the development of novel therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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Expression of CD80 or CD86 costimulatory molecules on tumor cells can produce rejection of immunogenic but not poorly immunogenic tumors. We have previously shown that anti-CD3 single-chain antibodies expressed on the surface of cells can directly activate T cells. We therefore investigated whether anti-CD3 ''receptors'' could enhance CD86-mediated rejection of poorly immunogenic tumors. Expression of anti-CD3 receptors on cells was increased by introduction of membrane-proximal ''spacer'' domains containing glycosylation sites between the single-chain antibody and the transmembrane domain of the chimeric receptors. Removal of glycosylation sites in the spacer reduced surface expression due to increased shedding of chimeric receptors from the cell surface. Induction of T-cell proliferation by anti-CD3 receptors did not correlate with the expression level of chimeric protein, but rather depended on the physical properties of the spacer. Anti-CD3 receptors effectively induced T-cell cytotoxicity, whereas coexpression with CD80 or CD86 was required for generating T-cell proliferation and IL-2 secretion. Although expression of CD86 did not significantly delay the growth of poorly immunogenic B16-F1 tumors, expression of anti-CD3 receptors with CD86 produced complete tumor rejections in 50% of mice and induced significant protection against wild-type B16-F1 tumor cells. Our results show that spacer domains can dramatically influence the surface expression and the biological activity of chimeric antibody receptors. The strong antitumor activity produced by anti-CD3 receptors and CD86 on tumor cells indicates that this strategy may be beneficial for the gene-mediated therapy of poorly immunogenic tumors.

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Section: Discussionmentioning

confidence: 99%

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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“…These studies underscore the importance of phagocytic cells such as macrophages, in tumor cell rejection. Thus, the action of IFN‐γ toward augmentation of phagocytic activity of macrophages may contribute to IFN‐γ‐mediated GVT effects following allo‐HCT.…”

Section: Mechanisms By Which Ifn‐γ Selectively Promotes Gvt Effects Imentioning

confidence: 99%

The complex and central role of interferon‐γ in graft‐versus‐host disease and graft‐versus‐tumor activity

Wang

Yang

2014

Immunological Reviews

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Summary Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly being performed to treat patients with hematologic malignancies. However, separating the beneficial graft-versus-tumor (GVT) or graft-versus-leukemia effects from graft-versus-host disease (GVHD) has been difficult and remains a significant challenge toward improving therapeutic efficacy and reducing toxicity of allo-HCT. GVHD is induced by donor T cells that also mediate potent anti-tumor responses. However, despite the largely shared effector mechanisms, extensive animal studies have demonstrated the potential of dissociating the GVT effect from GVHD. Also in many clinical cases, long-term remission was achieved following allo-HCT, without significant GVHD. A better mechanistic understanding of the immunopathophysiology of GVHD and GVT effects may potentially help to improve allo-HCT as well as maximize the benefit of GVT effects while minimizing GVHD. In this article, we review the role of IFN-γ in regulation of alloresponses following allo-HCT, with a focus on the mechanisms of how this cytokine may separate GVHD from GVT effects.

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“…An approach based on the expression of anti-FcyR scFv on tumour cel1s was therefore developed. The ability of tumourexpressed anti-FcyR scFv to activate immune cells in vitro and to prevent tumour growth in vivo was then examined (Gruel et al, 2001) (Fig. 9.3).…”

Section: Extrabodies On Tumour Cells: Recruiting Immune Cellsmentioning

confidence: 99%

“…1998) have been used to induce tumour regression in mice. Tumour cells have been also engineered to express scFv directed against activating receptors expressed on different cell types of the immune system (Kontermann and Muller, 1999;Gruel et al, 2001). Such antibodies have been termed extrabodies.…”

Section: Introductionmentioning

confidence: 99%

Antibodies

2004

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Bypassing tumor-specific and bispecific antibodies: triggering of antitumor immunity by expression of anti-FcγR scFv on cancer cell surface

Cited by 9 publications

References 36 publications

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

The complex and central role of interferon‐γ in graft‐versus‐host disease and graft‐versus‐tumor activity

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