Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Abstract

One fourth of women with HER-2+ metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human γδ T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20+ B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated γδ lymphocytes increases the efficacy of trastuzumab against HER-2+ breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2+ mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2+ cells and tumor infiltration by γδ lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant γδ T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated γδ cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2+ breast cancer.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134]. Such a licensing pathway to boost cross-presentation of tumor-derived antigens could be exploited by using monoclonal antibodies specifically targeting tumor cells, such as rituximab (anti-CD20), trastuzumab (anti-HER2/neu) or ch14.18 (anti-GD2), and contribute to the effectiveness of combination therapies [135][136][137].…”

“…In this context, Himoudi et al [130] proposed a role for opsonizing antibodies in the efficient 'licensing' of Vc9/Vd2 T-APCs, by enhancing uptake of antibody-bound material via Fc receptors like CD16, which is expressed by Vc9/Vd2 T cells under certain stimulation conditions and on distinct subsets [133,134]. Such a licensing pathway to boost cross-presentation of tumor-derived antigens could be exploited by using monoclonal antibodies specifically targeting tumor cells, such as rituximab (anti-CD20), trastuzumab (anti-HER2/neu) or ch14.18 (anti-GD2), and contribute to the effectiveness of combination therapies [135][136][137].Irrespective of this progress in our understanding of cd T-APC triggered responses in vitro, there is a paucity of data on the relevance of Vc9/Vd2 T cells acting as APCs in vivo, be it under homeostatic conditions in healthy tissues or in acute and chronic inflammatory scenarios including microbial infections. Naturally, local access to inflamed tissues and draining lymph nodes in humans is very limited, thereby severely compromising investigations into the APC function of Vc9/Vd2 T cells -or, as a matter of fact, into the APC function of any human immune cell.…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…[7][8][9][10] Nasopharyngeal carcinoma patients carry Vc9Vd2 cd T lymphocytes that are functionally impaired in blood 11 but are able to infiltrate and reduce xenografted nasopharyngeal tumors in mice. 12 Likewise, orthotopic xenografts of breast tumors 13 or bladder carcinomas 14 in mice infused with human TCRVc9Vd2 1 lymphocytes also show strong tumor infiltration by cd TILs and subsequent arrest of tumor growth. In a B-cell depletion assay from cynomolgus monkeys treated with a phosphoantigen plus interleukin-2 (IL-2) and rituximab, endogenous cytotoxic cd T cells were enriched in lymph nodes in which CD20 1 B cells had been depleted.…”

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

“…Ex vivo-expanded NK cells (6,7) and gd-T cells (8) have been tested in adoptive cell transfer cancer therapy alone or in combination with tumor antigen-specific mAbs. However, no reliable clinical procedure has yet been established for ex vivo expansion of autologous effector cells to the numbers that are therapeutically sufficient (9).…”