Skewing the T-Cell Repertoire by Combined DNA Vaccination, Host Conditioning, and Adoptive Transfer

Annelies Jorritsma,John B.A.G Haanen,Ton N.M Schumacher,Adriaan D Bins

doi:10.1158/0008-5472.can-07-5254

Annelies Jorritsma, John B.A.G Haanen + Show 2 more

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https://doi.org/10.1158/0008-5472.can-07-5254

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Abstract

Approaches for T-cell-based immunotherapy that have shown substantial effects in clinical trials are generally based on the adoptive transfer of high numbers of antigen-specific cells, and the success of these approaches is thought to rely on the high magnitude of the tumor-specific T-cell responses that are induced. In this study, we aimed to develop strategies that also yield a T-cell repertoire that is highly skewed toward tumor recognition but do not rely on ex vivo generation of tumor-specific T cells. To this end, the tumor-specific T-cell repertoire was first expanded by DNA vaccination and then infused into irradiated recipients. Subsequent vaccination of the recipient mice with the same antigen resulted in peak CD8(+) T-cell responses of approximately 50%. These high T-cell responses required the presence of antigen-experienced tumor-specific T cells within the graft because only mice that received cells of previously vaccinated donor mice developed effective responses. Tumor-bearing mice treated with this combined therapy showed a significant delay in tumor outgrowth, compared with mice treated by irradiation or vaccination alone. Furthermore, this antitumor effect was accompanied by an increased accumulation of activated and antigen-specific T cells within the tumor. In summary, the combination of DNA vaccination with host conditioning and adoptive transfer generates a marked, but transient, skewing of the T-cell repertoire toward tumor recognition. This strategy does not require ex vivo expansion of cells to generate effective antitumor immunity and may therefore easily be translated to clinical application.

Highlights

Virus-induced tumors, such as human papillomavirus (HPV)induced cervical carcinoma, express foreign antigens that are potential targets for immunotherapy
Vaccination-induced responses were strongly enhanced in irradiated mice, amounting to 50% NP-tetramer+ CD8+ cells (Fig. 1B and C). These data show that a vaccination– conditioning–adoptive cell transfer (ACT)–vaccination (VCAV) protocol can be used to generate T-cell responses that are substantially more pronounced than those induced by vaccination alone
The more successful approaches for T-cell–based immunotherapy of cancer used to date have required ex vivo expansion of tumor-specific T cells to generate sufficiently high numbers for subsequent adoptive transfer

Summary

Introduction

Virus-induced tumors, such as human papillomavirus (HPV)induced cervical carcinoma, express foreign antigens that are potential targets for immunotherapy. Clinical trials that assess the efficacy of therapeutic vaccination against HPV oncoproteins E6 and E7 have shown only a limited therapeutic benefit for cervical cancer patients to date [1,2,3,4,5]. In line with the notion that the development of marked tumorspecific T-cell responses may be essential, a number of successful T-cell–based immunotherapy trials have been performed that involved the adoptive transfer of high numbers of virus- or tumorspecific T cells. The general application of these strategies for the treatment of cancer patients is hampered by the difficulty of expanding sufficient numbers of tumor-reactive T cells ex vivo. Our aim in this study was to develop an immunotherapeutic strategy that results in a marked skewing of the T-cell repertoire toward tumor reactivity and that is solely based on a combination of vaccination and host conditioning

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