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).

 

Owing to their low chemo- and radiosensibility, many endocrine carcinomas remain incurable by conventional therapies, and it is therefore of particular importance to develop new approaches for the treatment of such cancers. Because of the lack of specific tumour antigens in endocrine cancers, there are two alternatives for DC vaccination: first, preparations of autologous tumour cells could be used, as performed in patients with melanoma and renal cell cancers [40,48] ; second, cell-specific antigens, such as specific enzymes involved in the synthesis of hormones or the polypeptide hormones themselves, might be used to induce a cytotoxic immune response against hormone-secreting carcinomas.

The first approach was applied for the treatment of two patients with rare endocrine malignancies in advanced disease stages to minimize the growth of metastatic lesions or to control the hormone activity, respectively. One patient suffered from a parathyroid hormone (PTH)-secreting carcinoma, which caused hypercalcaemic symptoms, including severe bone pain, profound weight loss and extreme muscle weakness. A second patient had a metastasized neuroendocrine pancreas carcinoma, which was strongly positive for chromogranin A (ChA). After repeated vaccinations, both patients showed a dose-dependent proliferation of PBMCs towards antigen(s) that are as yet unidentified within the TL, and a strong erythema and induration at the TL–DC challenge site, suggesting the induction of TL-specific T cells [54,55] . In the patient with the (PTH)-secreting carcinoma, vaccination with TL-pulsed DCs had no clinical effect. After administration of DCs loaded with a synthetic PTH peptide in combination with the Th antigen keyhole limpet haemocyanin (KLH), a significant decrease of serum PTH was observed, suggesting a partial destruction of tumour cells [56,57] . However, this was not associated with an objective reduction of tumour masses and the patient died of pneumonia. In spite of the outcome, this case demonstrated for the first time the ability to induce cytotoxic immunity in an endocrine carcinoma by using a polypeptide hormone as antigen. In the patient with the neuroendocrine tumour, the therapy was accompanied by a steady decrease of the tumour marker ChA and a slight tumour regression [55].

On the basis of these results, a novel protocol for DC vaccination was designed for the treatment of patients with metastasized medullary thyroid carcinoma (MTC). MTC, arising from the parafollicular, calcitonin-producing C-cells of the thyroid gland, represents an aggressive yet usually slow-growing tumour occurring in both sporadic and familial forms, such as multiple endocrine neoplasia type 2 (MEN 2) [58]. The tumour cells express and secrete the polypeptide hormone calcitonin and carcinoembryonic antigen (CEA), which are both established tumour markers to monitor metastatic MTC. For vaccination, seven MTC patients were treated with s.c. injections of 2–5×10⁵ DCs in intervals of four weeks. Because recent studies have demonstrated that autologous DCs loaded with CEA peptide or CEA–RNA can induce CTLs in patients with metastatic malignancies expressing CEA [59–61] , DCs were pulsed with 100 µg ml^-1 calcitonin alone (n=1) or, in HLA-A2⁺ patients (n=6), with calcitonin and the CEA peptide YLSGANLNL (10 µg ml^-1) to widen the immunoreactivity to two tumour-associated antigens [62]. After DC vaccination, all patients developed a DTH reaction mediated by infiltration with CD4⁺ and CD8⁺ T cells. Three patients showed a significant T-cell proliferation against calcitonin and CEA [63]. Analysis of post-treatment cytokine secretion (IFN-, IL-4) demonstrated a Th1-dominated cellular immune response against calcitonin (five out of seven patients) and CEA (four out of six patients). Clinical follow-up of seven treated patients revealed that: one developed a clinical response with a decrease of the serum levels of calcitonin and CEA, and a significant regression of liver and pulmonary metastases; five had a stable disease; and one, who failed to develop a T-cell response to either calcitonin or CEA, developed further tumour progression [62]. Recently, another study reported on the activation of CTLs after in vitro stimulation with TL-pulsed DCs in patients with MTC; in all three patients, significant cytotoxic activity of T cells was observed against autologous tumour cells [64]. In addition, DC vaccination of four patients with advanced MTC with TL-pulsed DCs resulted in a T-cell response in all, accompanied by a significant reduction of tumour masses in two patients [65].

Thus far, immunization with DCs in humans has been performed to assess the feasibility and safety of DC vaccination. Most studies in non-endocrine and endocrine malignancies were performed with few patients over a limited period of time, and it is still unknown whether or not DC vaccination provides a significant, long-term clinical benefit in cancer patients. However, the results from the above-mentioned pilot studies are encouraging enough to perform controlled, prospective clinical trials where the DC-based immunotherapy is compared with a standard chemo- or radiotherapy or with DCs pulsed with irrelevant antigens such as KLH or virus-derived peptides. Further studies should include novel methods to measure the quality and quantity of a cellular immune response. It has been shown that intracytoplasmic FACS analysis of T cells or ELISpot assays provide valuable information on the patterns of cytokine secretion (Th1 or Th2) after antigen challenge [13,47,66] . Recently, detection of antigen-specific T cells has been demonstrated using peptide–MHC class I tetramer technology, which allows quantification of the number of CTLs against a specific peptide in the peripheral blood [13]. These techniques might be useful to select strongly immunogenic antigens and could help the development of an optimal immunization regimen by the variation of the antigen dose and the number of booster injections.

Further studies are also needed to solve the major problem of immunotherapies in endocrine carcinomas: the lack of defined tumour antigens. Analysis of peptide presentation on APCs after pulsing with TL, RNA or cDNA libraries from tumour cells or peptide libraries, as performed in malignant melanoma and prostate cancer, will be required in each cancer type to identify antigens that are recognized by human CD8⁺ or CD4⁺ T cells [47,67] . The availability of defined tumour antigens or peptides would substantially facilitate antigen loading and reduce the risk of inducing potentially harmful autoimmunity.

Further progress in human DC immunotherapy is expected from ongoing studies on DC biology in the near future ( Table 2). As observed in the MTC studies, it is known that tumour immunotherapies frequently face the problem of only transient tumour regression. This is partially explained by the downregulation of MHC molecules on the tumour cells, the induction of apoptosis in T cells when encountering the tumour, or an active suppression or tolerance induction in T cells [14–18,68] . To overcome these problems, it is important to understand the molecular mechanisms that are involved in the immunosurveillance of cancer cells and the essential signals that are required for highly efficient antigen presentation and a strong CTL and/or NK-cell activation. Using the combination of strong immunogenic antigens and highly pre-activated DCs, it might be possible to generate high-level antitumour CTLs similar to those observed in virus infections [69]. In the setting of an established tumour, it might be that only high numbers of high-affinity CTLs have the capacity to resist tolerance mechanisms and mediate efficient tumour destruction. It has been proposed that DC treatment may be combined with additional adjuvants (e.g. immunostimulatory cytokines, double-stranded DNA including bacterial CpG motifs) to mimic an appropriate environment for T-cell activation [23,30,67] . However, this has to be confirmed in clinical trials. Collectively, recent advances in our understanding of the innate immunity and tumour cell biology could provide the key for the development of novel approaches to improve current strategies of DC vaccination and offers new hope for an effective antitumour immunotherapy in endocrine malignancies.

 

Although DC treatment has been performed in only a few patients, and clinical endpoints are still missing in most studies, the current efficiency and safety data indicate that DC-based vaccines could have beneficial effects in patients suffering from a wide variety of malignancies. Despite the lack of defined tumour antigens, tissue-specific polypeptide hormones or TLs can be used as targets to induce a strong immune response associated with the elimination of endocrine carcinoma cells. It is important to note that DC vaccination is still not an established treatment modality and should be performed only in controlled clinical trials. Such studies will help to develop generally accepted standards in the treatment protocols and allow a better definition of patients who might benefit from this novel therapeutic strategy.

 

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APCs:
Antigen-presenting cells
CEA:
Carcinoembryonic antigen
ChA:
Chromogranin A
CR:
Complete remission
CTLs:
Cytotoxic T lymphocytes
DCs:
Dendritic cells
DTH:
Delayed-type hypersensitivity
GM-CSF:
Granulocyte–macrophage colony-stimulating factor
IFN:
Interferon
IL:
Interleukin
KLH:
Keyhole limpet haemocyanin
LPS:
Lipopolysaccharide
MHC:
Major histocompatibility complex
MTC:
Medullary thyroid carcinoma
NK cells:
Natural killer cells
PBMCs:
Periperal blood mononuclear cells
PR:
Partial remission
PSA:
Prostate-specific antigen
PSMA:
Prostate-specific membrane antigen
PTH:
Parathyroid hormone
Th cells:
T helper cells
TL:
Tumour lysate
TGF-:
Tumour growth factor-
TNF-:
Tumour necrosis factor-
 

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