Review
Third generation dendritic cell vaccines for tumor immunotherapy

https://doi.org/10.1016/j.ejcb.2011.01.012Get rights and content

Abstract

This review summarizes our studies of the past several years on the development of third generation dendritic cell (DC) vaccines. These developments have implemented two major innovations in DC preparation: first, young DCs are prepared within 3 days and, second, the DCs are matured with the help of Toll-like receptor agonists, imbuing them with the capacity to produce bioactive IL-12 (p70). Based on phenotype, chemokine-directed migration, facility to process and present antigens, and stimulatory capacity to polarize Th1 responses in CD4+ T cells, induce antigen-specific CD8+ CTL and activate natural killer cells, these young mDCs display all the important properties needed for initiating good antitumor responses in a vaccine setting.

Introduction

Among the various types of antigen presenting cells (APCs), dendritic cells (DCs) are considered to be the most potent because they can efficiently prime naïve T cells during development of T cell-mediated immunity and stimulate adaptive immune responses. Particularly, immature DCs have an exceptional ability to internalize different forms of antigen that are subsequently processed and presented within major histocompatibility complex (MHC) class I and class II molecules at the DC cell surface. However, concerns have been raised regarding the use of immature DCs (iDCs) in clinical trials since antigen presentation by iDCs, in particular antigens representing self-proteins, is known to tolerize T cells rather than immunize hosts (Schuler et al., 2003). Exposure of iDCs to danger signals in the periphery leads to their differentiation to a mature state characterized by high expression of MHC and costimulatory molecules. Therefore, upon reaching the T-cell zones of secondary lymphoid organs, mature DCs (mDCs) are well equipped to activate antigen-specific T cells. Because of these properties, mDCs generated and transfected with tumor-associated antigens (TAAs) in vitro, in a environment free of tumor-associated inhibitory factors, have evolved as a powerful vaccination tool for tumor immunotherapy. Several clinical studies using mDCs as tumor vaccines have been implemented and T cell responses were elicited against TAA epitopes derived from self-proteins (Palucka et al., 2010).

Improved understanding of the biology of DCs has revealed that three interactive signals impinge on lymphocyte responses and are important for consideration in vaccine development in order to achieve optimal activation of both innate and adaptive antitumor immunity: (i) adequate DC presentation of MHC-peptide complexes for induction of antigen-specific T cells (signal 1), with simultaneous expression of activation ligands for stimulation of innate natural killer cells; (ii) dominant positive costimulation via molecules such as CD40, CD80, and CD86 (signal 2) and (iii) secretion of cytokines that polarize immune responses in a Th1/Tc1 direction to create optimal antitumor responses (signal 3) (Fig. 1).

Section snippets

Signal 1: reproducible and efficient expression of TAAs in mDCs after transfer of in vitro transcribed RNA

One of the most commonly used strategies of antigen delivery to DCs is exogenous loading with synthetic peptides that represent defined epitopes from known TAAs (Cerundolo et al., 2004, Schuler et al., 2003, Jager et al., 2002). The short half-life of peptide-MHC complexes (pMHC) and the MHC restriction of T cell recognition that limits this approach to patients with specific MHC allotypes are major disadvantages of providing DCs with this form of antigen. Furthermore, responses directed

Signal 2: optimal costimulatory profiles are displayed by young mDCs generated in 3 days in vitro

To date, many different protocols have been described for the preparation of mDCs, which vary both with respect to the signals used for maturation and the time periods used for induction of mDC in vitro. The most common methods require around 7 days of cell culture and frequently use a maturation cocktail that was developed by Jonuleit et al. (1997), which includes TNF-α, IL-1β, IL-6 and PGE2. Dauer and colleagues demonstrated that “fast DCs” could be rapidly generated from peripheral blood

Signal 3: TLR-activated mDCs show an optimized capacity to polarize Th1/Tc1 immune responses

Analyses of Toll-like receptor (TLR)-signaling in DCs demonstrated activation of the NF-kB pathway, with resultant modulation of their cytokine secretion (reviewed in Kaisho and Tanaka, 2008). For this reason, synthetic TLR agonists are of interest for inclusion in maturation mixtures for mDCs to enable them to optimally induce antitumor responses. Many different TLRs are expressed by human monocyte-derived DCs (Ito et al., 2002). Several immunomodulatory genes are induced following ligation of

Conclusions

In our DC vaccine strategy, we utilize young mDCs that are prepared within only three days in contrast to standard procedures that utilize a 7-day culture period. Other groups are exploring the properties of fast DCs (Jarnjak-Jankovic et al., 2007, Dauer et al., 2003, Dauer et al., 2005) but we are not aware of any ongoing clinical trials at this time employing these cells. Furthermore, we developed new maturation mixtures that include synthetic TLR agonists for TLR3 and TLR7/8. We could

Acknowledgments

The authors thank the German Research Foundation (SFB-455, SFB-TR36), the European Union under the 6th Framework Programme “Allostem”, the Helmholtz Society Alliance “Immunotherapy of Cancer” and the BayImmuNet Program for financial support and the members of the laboratory for many valuable contributions to the development of DC vaccines and helpful suggestions on this manuscript. We especially thank S. Spranger for preparation of figures.

References (53)

  • K. Palucka et al.

    Building on dendritic cell subsets to improve cancer vaccines

    Curr. Opin. Immunol.

    (2010)
  • G. Schuler et al.

    The use of dendritic cells in cancer immunotherapy

    Curr. Opin. Immunol.

    (2003)
  • S. Wilde et al.

    Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior anti-tumor activity and higher TCR functional avidity

    Blood

    (2009)
  • D.M. Ashley et al.

    Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors

    J. Exp. Med.

    (1997)
  • D. Boczkowski et al.

    Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo

    J. Exp. Med.

    (1996)
  • D. Boczkowski et al.

    Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells

    Cancer Res.

    (2000)
  • M. Bürdek et al.

    Three-day dendritic cells for vaccine development: antigen uptake, processing and presentation

    J. Transl. Med.

    (2010)
  • V. Cerundolo et al.

    Dendritic cells: a journey from laboratory to clinic

    Nat. Immunol.

    (2004)
  • M. Dauer et al.

    Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors

    J. Immunol.

    (2003)
  • G.J. Freeman et al.

    Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation

    J. Exp. Med.

    (2000)
  • G. Gautier et al.

    A type I interferon autocrineparacrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells

    J. Exp. Med.

    (2005)
  • C. Geiger et al.

    Harnessing innate and adaptive immunity for adoptive cell therapy of renal cell carcinoma

    J. Mol. Med.

    (2009)
  • E. Gilboa et al.

    Cancer immunotherapy with mRNA-transfected dendritic cells

    Immunol. Rev.

    (2004)
  • S.L. Goff et al.

    Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL

    J. Immunother.

    (2010)
  • K.B. Gorden et al.

    Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8

    J. Immunol.

    (2005)
  • A. Heiser et al.

    Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors

    Cancer Res.

    (2001)
  • Cited by (45)

    • Dendritic cell therapy in cancer treatment; the state-of-the-art

      2020, Life Sciences
      Citation Excerpt :

      Cellular vaccines have been utilized during the past decade. These vaccines are based on DCs, derived from peripheral blood of cancer patients, pulsed with tumor-associated antigen and activated by adjuvant and then reinjected into the same patient to boost T cell reactivity to defense against tumor cells [4,23]. Thus, the aim of the DC-based cancer immunotherapy is utilizing the advantages of these unique features of DCs to efficiently combat against cancer.

    • Synthetic tumor-specific antigenic peptides with a strong affinity to HLA-A2 elicit anti-breast cancer immune response through activating CD8<sup>+</sup> T cells

      2020, European Journal of Medicinal Chemistry
      Citation Excerpt :

      To date, many novel technologies to antagonize the growth of tumor are under widespread investigation [3–8]. Tumor immunotherapy has become a new type of therapeutic method with the development of biochemical and immunological technologies [7,9,10]. Tumor immunotherapy can avoid damage to normal cells, inhibit tumor metastasis and prevent recurrence via activating the patients’ own immune system which then automatically identify and kill the tumors [11].

    • 2003–2013, a valuable study: Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in stage IV breast cancer

      2017, Immunology Letters
      Citation Excerpt :

      The therapeutic alternatives for MBC are mainly based on the systemic administration of cytotoxic chemotherapeutic agents; their long-term impact on survival is, however, only around 20 months and the outcome depends heavily on the nature of the metastases and the tumour biology [3–5]. The dendritic cells (DCs) play a crucial role in the induction of antigen-specific T-cell responses to provide active immunotherapy [6,7]. Clinical studies using specifically designed DC-targeted cancer cell vaccines have demonstrated varying clinical benefits.

    • Enhancement of the immunostimulatory functions of ex vivo–generated dendritic cells from early-stage colon cancer patients by consecutive exposure to low doses of sequential-kinetic-activated IL-4 and IL-12. A preliminary study

      2015, Translational Oncology
      Citation Excerpt :

      In DC-based vaccination against cancer, cytokines play a critical role both ex vivo, to generate the cell populations used in vaccines, and in vivo, as adjuvants to these therapies, to augment the potency and duration of the antitumor response. It may be assumed that low doses of these SKA cytokines, which can be administered chronically over long periods without any deleterious side effects [70], could keep tumor growth under control by restoring and maintaining an effective immune response against tumor cells. Although the significance of the present ex vivo study is somewhat limited because of the small number of donor patients, it is nevertheless indicative.

    • Restoring immunosurveillance by dendritic cell vaccines and manipulation of the tumor microenvironment

      2015, Immunobiology
      Citation Excerpt :

      DCs are considered the master regulators in tuning the immune system toward either tolerance or immune activation. They are characterized as the professional antigen presenting cells and as such they are thought to play an important role in reactivating the immune system toward cancer by inducing B and T cells to produce tumor specific antibodies and cytotoxic activity, respectively (Tuettenberg et al., 2007; Lesterhuis et al., 2008; Frankenberger and Schendel, 2012). It is well known that malfunctioning cells including emerging tumor cells attract immune cells via cytokines (Ilkovitch and Lopez, 2008; Yigit et al., 2010), chemokines (Jordan et al., 2008; Maru et al., 2008; Qin et al., 2009) and alarmins (Chan et al., 2012).

    View all citing articles on Scopus
    View full text