Combination of lentivector immunization and low‐dose chemotherapy or PD‐1/PD‐L1 blocking primes self‐reactive T cells and induces anti‐tumor immunity

Abstract

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8 1 T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumorinfiltrating lymphocytes revealed that specific anti-tumor CD8 1 T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity.Key words: Combination therapies . Immunotherapy . Lentiviral vector . Tumor Supporting Information available online IntroductionMany current therapeutic investigations in melanoma focus on vaccine-based immunotherapeutic strategies combined with targeted chemotherapeutic or immunomodulatory approaches [1,2]. Among the multiple melanoma-associated antigens (MAAs) that can be detected by the immune system, many are self-antigens, and eliciting strong and functional T-cell responses is challenging [3]. Overcoming immune tolerance is a major focus of current research and this includes the development of immunological strategies associating novel vaccines and new forms of adjuvants. 2217Cancer vaccines have yielded encouraging results in inducing systemic anti-tumor specific T cells [4][5][6]. However, this does not always correlate with protective tumor immunity. In spite of the relatively high number of tumor-specific CD8 1 T cells that can be primed through peptide immunization in melanoma patients, only marginal clinical efficacy has been observed [7][8][9]. The function of cells isolated from the blood or from the tumor site differs greatly, with tumor-infiltrating Melan-A-specific CD8 1 T cells displaying impaired functions [10]. The underlying mechanism for the dysfunction of tumor-infiltrating lymphocytes (TILs) is not well understood. Similar to what can be observed in chronic infectious diseases, chronic antigenic stimulation by tumor cells may result in exhaustion of tumor-specific CD8 1 T cells [11]. Factors influencing tumor-specific CD8 1 T-cell functions need to be better understood in order to design better treatments. Recent studies ha...

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