Elsevier

The Lancet Oncology

Volume 15, Issue 7, June 2014, Pages e257-e267
The Lancet Oncology

Review
Clinical use of dendritic cells for cancer therapy

https://doi.org/10.1016/S1470-2045(13)70585-0Get rights and content

Summary

Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. Dendritic cell-based immunotherapy is safe and can induce antitumour immunity, even in patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour response rates rarely exceeding 15%. Paradoxically, findings from emerging research indicate that dendritic cell-based vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical potency of dendritic cell-based vaccination. We review the clinical effectiveness of dendritic cell-based vaccine therapy in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated into clinical trials to leverage the clinical effectiveness of dendritic cell-based cancer immunotherapy. Specifically, we discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies.

Introduction

2013 marked the 40th anniversary of the discovery by Cohn and Steinman1 of a new type of immune cell: dendritic cells. Although our knowledge of their biology and function is incomplete, evidence shows that dendritic cells play a crucial part in the induction of antitumour immunity.2 Immunotherapeutic approaches involving dendritic cells aim to capitalise on the ability of the cells to direct cytotoxic T lymphocytes and natural killer cells to become potent antitumour effectors capable of eradicating malignant cells (figure).3 The basic immunological principles that provide a compelling rationale for use of dendritic cells in immunotherapy and the different ways to prepare these cells for clinical application have been reviewed elsewhere,2, 4 and are beyond the scope of this Review. In this Review, we first aim to examine the most important lessons gained from almost two decades of clinical studies of dendritic cell-based immunotherapy, particularly regarding the actual therapeutic usefulness of dendritic cells. We then describe how the specialty of dendritic cell-based immunotherapy is evolving, and provide an update of new models and approaches that are being adopted in clinical trials.

Since the first published clinical trials in the mid-1990s, many early-phase clinical trials have been done across a wide range of tumour types. Dendritic cell-based treatments have been tested most often in patients with malignant melanoma,5 with more than 1250 patients treated (appendix pp 2–3), followed by prostate cancer (>750 patients treated; appendix p 4), malignant glioma (>500 patients treated; appendix p 5), and renal cell cancer (>250 patients treated; appendix p 6). These malignant diseases are the only tumour types in which phase 3 clinical trials of these treatments have been done or are underway (table 1). Therefore, in this Review we focus on these four tumour types, and use them to summarise the conclusions that can be gathered about the clinical use of dendritic cells in cancer immunotherapy.

Section snippets

Safety

The safety of dendritic cell-based immunotherapy has been well documented in many phase 1 clinical studies.6 Local reactions at the injection sites (ie, pain, rash, and pruritus) are common, but these reactions are generally mild and self-limiting.6 Systemic side-effects, including pyrexia, malaise, and other influenza-like symptoms, can occur; however, systemic grade 3–4 (US National Cancer Institute-Common Terminology Criteria) toxicity is extremely uncommon when dendritic cell vaccination is

Antitumour immune responses

The main goal of cancer vaccine strategies involving dendritic cells is to stimulate tumour antigen-specific cytotoxic T lymphocytes that can recognise and eliminate cancer cells in an antigen-specific way.2 According to results of a meta-analysis of dendritic cell-based immunotherapy, such cellular immune responses can be elicited in 77% of patients with prostate cancer and 61% with renal cell carcinoma.6 In view of the fact that most of these patients have metastatic disease, this result

Overall objective response

Despite their favourable safety profiles and proven immunogenicity, cancer vaccine strategies have received a great deal of criticism, and even scepticism, because of their poor therapeutic efficacy in terms of inducing objective clinical responses.13 The same criticism has also been levied at dendritic cell-based cancer vaccine approaches.14 We did a systematic review of all published clinical trials to document the proportion of patients who had an objective response (achieving either a

Survival benefit

Whereas objective response is a rapid and direct parameter with which to assess the antitumour activity of an experimental treatment, survival—particularly overall survival—is generally thought of as the most important outcome measure of therapeutic benefit.19, 20 Table 2 provides an overview of all published trials5, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 of dendritic

Therapeutic effectiveness

The observed dissociation between objective response and survival indicates that alternative surrogate endpoints should be used to assess the therapeutic effectiveness of dendritic cell-based immunotherapy. As outlined, dendritic cell-based immunotherapeutic approaches can positively affect clinical outcome in terms of increasing patient survival rather than by inducing objective tumour responses. Although this notion might seem counterintuitive, for several tumour types and disease settings

Trends

Among the studies of dendritic cell cancer vaccines registered at http://www.clinicaltrials.gov, two main emerging trends in dendritic cell-based anticancer immunotherapy can be identified. The first revolves around the use of next-generation dendritic cell products with improved immunostimulatory activity. The second is to potentiate the effectiveness of dendritic cell immunotherapy through combination therapy.

Next-generation dendritic cell vaccines

Most published clinical trials have been done with early-generation dendritic cell

Conclusion

We conclude that dendritic cell therapy is a safe and well tolerated immunotherapeutic method that can elicit immunity even in patients with advanced-stage cancer. This work also confirms that dendritic cell-based interventions have only some capacity to produce objective tumour responses, as established by classic response assessment criteria such as RECIST. Although not all studies were designed primarily to measure survival, an increasing number indicate that dendritic cell therapy could

Search strategy and selection criteria

We selected references through a PubMed search with the terms “dendritic cells”, “cancer”, and “immunotherapy”. We retrieved data presented in table 1 and appendix pp 17–18 from the online clinical trial database http://www.clinicaltrials.gov with the search term “dendritic cells”. We excluded studies with the status withdrawn. We identified relevant records for the data presented in table 2, appendix pp 2–12, and appendix pp 14–15 by a systematic search of PubMed for all studies

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