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 We excluded studies with the status withdrawn.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
ReviewClinical use of dendritic cells for cancer therapy
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
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