Many early-phase clinical trials have been done across a wide rage of tumor types, most often in patients with malignant melanoma, with more than 1250 patients treated, followed by prostate cancer (>750 patients), malignant glioma (>500 patients), and renal cell carcinoma (>250 patients). These malignant diseases are the only tumor types in which phase 3 clinical trials of these treatments have been done or are underway.
The safe of dendritic cell-based immunotherapy has been well documented in many phase 1 clinical studies. Local reactions at the injection sites are common, but these reactions are generally mild and self-limiting. Some systemic side effects including pyrexia, malaise and other influenza-like symptoms can occur. Immune-related adverse events have been reported in up to 60% of patients treated with anti cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody. In line with its low toxicity, dendritic cell-based immunotherapy is expected to preserve the quality of life of patients with cancer. This is an important outcome in assessment of novel anticancer agents, especially in the non-curative setting.
Antitumor Immune Responses
The main goal of cancer vaccine strategies involving dendritic cells is to stimulate tumor antigen- specific cytotoxic T lymphocytes that can recognize and eliminate cancer cells in an antigen- specific way. 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. This data indicate that dendritic cell-based immunotherapy can elicit adaptive and innate antitumor immunity in at least half of all patients.
Overall Objective Response
A systemic review of all published clinical trials to document the proportion of patients who had an objective response as defined by WHO criteria or by the Response Evaluation Criteria in Solid Tumors (RECIST) after dendritic cell vaccination in melanoma, prostate cancer, malignant glioma and renal cell carcinoma. From this review, it concludes that the clinical benefit of dendritic cell- based immunotherapy is terms of objective response is real, but small. With 8.5% of melanoma patients achieving an objective response, 7.1% of patients with prostate cancer, 15.6% of patients with malignant glioma and 11.5% of patients with advanced renal cell carcinoma.
The most important outcome measure of therapeutic benefit is the survival- particularly overall survival. A phase 3 randomized controlled trial, the dendritic cell-based therapeutic sipuleucel-T showed significantly larger median overall survival of patients with metastatic hormone-resistant prostate cancer than did placebo: median survival was 25.8 months in the experimental group versus 21.7 months in the control group. Sipuleucel-T was approved by the US Food and Drug Administration in 2010. Phase 3 trials are underway using overall survival as the primary endpoint in patients with advanced melanoma, glioma and renal cell carcinoma.
Dendritic cell-based immunotherapeutic approaches can positively affect clinical outcome in terms of increasing patient survival rather than by inducing objective tumor responses. Immunotherapies often produce different clinical response patterns, none of which are accurately captured by establishment of objective response. In patients with prostate cancer, theresponse profile changes in disease progression kinetics have been well documented, in results of many studies show that therapeutic cancer vaccines, including dendritic cell-based vaccines, can attenuate the PSA progression rate without significantly reducing PSA levels. For early-phase clinical trials, the immune-related response criteria might be a valid alternative to the classic WHO or RECIST criteria to assess antitumor responses, because they accommodate the atypical tumor response patterns recorded with immunotherapies.
Next Generation Dendritic cell Vaccines
Most published clinical trials have been done with early generation dendritic cell vaccines, including dendritic cell-enriched preparations. (For example, Sipuleucel-T- a crude preparation of prostate antigen-loaded, GM-CSF- activated blood mononuclear cells of which dendritic cells constitute only a small proportion) and interleukin-4 monocyte dendritic cells. The interleukin-4 monocyte dendritic cell-either used in its immature form or after activation or maturation with a pro-inflammatory cytokine cocktail composed of tumor necrosis factor (TNF) alpha, interleukin-1B, interleukin-6 and prostaglandin-E2- is by far the most commonly used dendritic cell type in clinical trials.
Interventions that enhance the strength of the immune effector response
Immune inhibitory pathways often dominate in patients with cancer and can affect the effectiveness of dendritic cell-based immunotherapy by preventing cytotoxic T lymphocytes and natural killer cells from exerting their effector function. The best understood molecules involved in the negative regulation of cytotoxic T-lymphocyte function are the immune checkpoint receptors CTLA-4 and programmed death-1 (PD-1). Several anti-PD-1 monoclonal antibodies have entered the clinical trial stage, one of which (pidilizumab) is being tested in combination with dendritic cell therapy in four clinical trials. Toll-like receptor agonist and cytokines have alsocome under intense scrutiny as dendritic cell vaccine adjuvants to harness the antitumor effector response. Interleukin-2 is the most extensively studied cytokine used in combination with dendritic cell vaccination.
Interventions that reverse tumor-associated immunosuppression
The translation of dendritic cell-induced antitumor immunity into clinical activity needs to overcome the immune suppressive barrier that is imposed by Tregs, MDSCs and other negative immune regulators. The best characterized cells that prevent the generation of effective antitumor responses are the Tregs. In dendritic cell-based immunotherapy protocols, there are two main strategies used to modulate Tregs. First, dendritic cells themselves can be harnessed to target Tregs, which can be achieved by loading dendritic cells with antigenic components of the Treg transcription factor forkhead box P3 (FoxP3) to mount a FoxP3-directed cytotoxic T- lymphocyte response. Second, dendritic cells can be combined with Treg-targeting drugs, such as the monoclonal antibodies Basiliximab and Daclizumab. The combination of dendritic cell therapy and Daclizumab has been examined in patients with metastatic melanoma. The addition of denileukin diftitox to dendritic cell vaccination resulted in a 16-fold increase in the frequency of tumor-specific cytotoxic T-lymphocytes in patients with advanced renal cell carcinoma. Also, Sunitinib is being tested in combination with dendritic cell-based immunotherapy in phase 3 clinical trials.
Interventions to reduce tumor burden and increase immune susceptibility of tumor cells
The level of tumor-induced immunosuppression is a function of the total burden of the tumor. In the context of high tumor burden, immunotherapies might function less. Patients with advanced or bulky disease are less likely to benefit from cancer immunotherapy, including dendritic cell therapy, than patients with less-advanced disease. In Haematology, dendritic cell therapy has shown little effectiveness in patients with relapsed or progressive acute myeloid leukemia, but strong antileukemic activity in patients with minimal residual disease. To bring the patient to a state of low tumor burden or minimal residual disease state, will take consideration of combining the dendritic cell therapy with cytoreductive cancer treatments like chemotherapy.
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Scientific article publishing date : 16/6/2014
Immucura identifier : BSC21_001EN