Abstract

Development of DC vaccines for antitumour immunotherapy

Clinical trials of DC vaccination

DC vaccination studies in endocrine malignancies

Conclusions

References

Glossary

Copyright

 

Dendritic cells (DCs) are antigen-presenting cells that are involved in the induction of primary immune responses. The unique ability of DCs to activate naive and memory CD4⁺ and CD8⁺ T cells suggests that they could be used for the induction of a specific antitumour immunity. In the past few years, several in vitro and in vivo studies in rodents and humans have demonstrated that immunizations with DCs pulsed with tumour antigens result in protective immunity and rejection of established tumours in various malignancies. Here, we focus on recent results of how DCs regulate immune responses that are important for generating antitumour cytotoxic T cells, and summarize clinical vaccination trials for the treatment of endocrine and nonendocrine carcinomas. Preliminary results suggest that DC vaccines might be novel tools for antitumour immunotherapies to treat chemotherapy-resistant and radioresistant endocrine cancers, such as metastasized medullary thyroid carcinomas and other neuroendocrine carcinomas.

The initiation of a potent immune response depends on the interaction of the innate and adaptive immune systems. Over the past ten years, evidence has accumulated for a central role of a population of antigen-presenting cells (APCs; see also Glossary Box) termed dendritic cells (DCs) in the control and modulation of the cellular immune system. T cells are stimulated by two distinct signals: the first is provided by the binding of the T-cell receptor (TCR) to its specific antigen presented by molecules of the human major histocompatibility complex (MHC); the second is provided by the interaction of costimulatory molecules (e.g. CD28 with CD80 and CD86 molecules, or CD40 ligand with CD40) on the surface of APCs [1,2] . MHC molecules comprise two types, class I and class II, which stimulate CD8⁺ cytotoxic T lymphocytes (CTLs) and CD4⁺ T helper (Th) cells, respectively. Generally, endogenous antigens are presented on MHC class I molecules, whereas exogenous antigens are presented on class II molecules. Recent findings indicate that DCs are uniquely capable of presenting exogenous antigens not only on MHC class II, but also on class I molecules. This phenomenon is termed cross-presentation and leads to the cross-priming of CTLs and Th cells, which explains how DCs can induce both a strong Th-cell response and a class I-restricted immune response, as observed in viral infections and tumour immunology ( Fig. 1) [3–6] .
 

There is strong evidence from several animal experiments and human trials that both the innate and adaptive immune systems are capable of attacking tumour cells. Therefore, the key question is why the immune system fails to reject tumour cells in patients with established cancers. Infiltrating DCs isolated from tumour tissue or progressing metastatic lesions from patients with malignant melanoma, breast cancer or colon cancer were found to have low allostimulatory capacity or decreased costimulation by CD80 and CD86 [14]. This could partly be explained by the finding that some tumours can produce factors such as IL-10 and transforming growth factor (TGF)-, which are involved in the suppression of DC maturation, leading to a decreased T-cell-stimulatory capacity [15,16] . Several in vitro studies have shown that vaccination with IL-10-pretreated DCs prime Th2 cells, decrease the activation of CTLs and contribute to the induction of immunosuppressive regulatory T cells or tumour-antigen-specific T-cell anergy [17,18] . The immunostimulatory capacity of DCs can be recovered by generating and activating DCs in vitro [19].

In the past few years, several protocols have been generated to obtain large numbers of activated human DCs from CD34⁺ bone marrow cells, leukapheresis and peripheral blood monocytes, by culturing in media supplemented with granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-4, followed by stimulation with TNF- or monocyte-conditioned medium [20–24] . To obtain a tumour-specific immune response, DCs must be loaded with tumour antigens. In vitro studies have shown that cultured DCs can take up soluble antigen in the form of whole proteins, which need to be processed in the cell for presentation on MHC molecules, or as synthetic peptides, which can bind directly to MHC class I molecules. Alternatively, antigens can be delivered to DCs by: whole tumour lysates (TLs); undefined acid-eluted peptides from autologous tumours; tumour-cell-derived mRNA; transfection with antigen-specific mRNA or cDNA; fusion of DCs with tumour cells; or transduction of DCs with retroviral and adenoviral vectors encoding tumour antigens [25–30] . In animals, these strategies were used successfully to induce protective and therapeutic antitumour responses against various tumour types. These studies represent the rationale underlying analysis of the potential of using human DCs as antitumour vaccines.

The ability of in vitro-expanded human DCs to serve as efficient adjuvants has been shown by Dhodapkar et al., who demonstrated a specific Th1-cell and CTL response after a single injection of tetanus toxoid or influenza matrix peptide-pulsed mature DCs in healthy volunteers [31]. However, the successful treatment of patients with cancer requires other considerations. First, it might be necessary to generate fully matured, strongly activated DCs. Only DCs with a high level of expression of MHC and costimulatory molecules, as well as the ability to secrete bioactive IL-12, can elicit a strong Th1 and CTL response, whereas immature DCs are ineffective or can even silence T-cell immunity by the generation of regulatory T cells [13,32] . Second, both the number of DCs and the antigen dose might influence the vaccination outcome. Whereas a low DC/antigen concentration might fail to induce a specific immune response, a dose that was too high or a high frequency of immunization could induce anergy or tolerance [11]. Third, the route of DC administration might affect the number of DCs that migrate to the lymphoid organs and can interact with effector cells. Preliminary data suggest that subcutaneous (s.c.) or intradermal (i.d.) DC application, or direct injection into a regional lymph node, might be superior in inducing a Th1 response as compared with intravenous (i.v.) injection [33–36] . The fourth and most important consideration is the choice of tumour antigens. The use of a single tumour protein or peptide might induce a specific immune response against only a defined antigen. By contrast, tumour cell mRNA, a TL or cell fusion offer the possibility to widen the immune response against several tumour-associated or mutated antigens, which might reduce the risk that the tumour cells can escape the immune attack, but in turn bears the risk of inducing a harmful autoimmune response against self-antigens.

The nature of the tumour cells and the immune status of the patient could both have a major impact on the efficiency of DC vaccination. Thus, the optimal conditions for DC treatment need to be established for each cancer type. Several clinical trials have been performed to assess the benefit and side effects of this novel therapy.

 

The aim of cancer immunotherapy is to deliver a vaccine that specifically overcomes the apparent failure of the immune system to eradicate tumour cells. In humans, most tumours are poorly immunogenic and the mechanisms involved in their evasion of immune systems are not well understood. There are only a few tumours, such as papilloma-associated tumours, myeloma or melanoma, in which tumour-specific antigens or shared antigens have been identified [37]. To overcome this problem, several studies have used antigens that are expressed only in cells from which the tumour has been derived (i.e. tumour-associated antigens) or from whole tumour preparations ( Table 1).