Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial (original) (raw)
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
PURPOSE Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c+ myeloid DCs, naturally circulating in the blood. EXPERIMENTAL DESIGN Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c+ myeloid DCs, activated by only brief (16h) ex vivo culture and loaded with tumor associated antigens of tyrosinase and gp100. RESULTS Our results show that therapeutic vaccination against melanoma with small amounts (3-10x106) of myeloid DCs is feasible and without substantial toxicity. Four out of fourteen patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8+ T cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity...
Vaccines, 2020
Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG1 monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)+ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 106 CD1c (BDCA-1)+ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumon...
Journal of Experimental Medicine, 2004
Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse. We have shown earlier, in 18 human histocompatibility leukocyte antigen (HLA)-A * 0201 patients with metastatic melanoma, that vaccination with peptide-loaded CD34-dendritic cells (DCs) leads to expansion of melanoma-specific interferon ␥ -producing CD8 ϩ T cells in the blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic CD8 ϩ T cell precursors specific for melanoma differentiation antigens. These precursors yield, upon single restimulation with melanoma peptide-pulsed DCs, cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific CTLs can be grown in vitro and can be detected in three assays: (a) melanoma tetramer binding, (b) killing of melanoma peptide-pulsed T2 cells, and (c) killing of HLA-A * 0201 melanoma cells. The cytolytic activity of expanded CTLs correlates with the frequency of melanoma tetramer binding CD8 ϩ T cells. Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen-expressing targets. These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.
Experimental Dermatology, 2009
Naturally occurring CD4 + CD25 + regulatory T-cell (Treg) activity is assumed to facilitate tumor development and progression. To elucidate the possible role of Tregs in the course of melanoma progression, we analysed the frequency of Tregs in the peripheral blood of patients at melanoma stages I-IV and in patients at melanoma stage IV that underwent dendritic cell (DC)-based immunotherapy. Using CD25, Foxp3, CD127 and HLA-DR as Treg associated markers, we observed increased Treg frequencies in patients at the late melanoma stage (stage IV) when compared to healthy donors. Accumulation of Tregs in patients with progressed melanoma correlated with a general reduction of T-cell responsiveness to the recall antigens tetanus toxoid and tuberculin-GT. However, DC-based immunotherapy not only restored antigen-specific immunity, but also decreased the frequency of Tregs in peripheral blood of patients with melanoma. These findings indicate that tumor progression in patients with melanoma result in general immunosuppression that is associated with Treg expansion in the periphery and can be overcome by DC-based vaccination.
Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination
OncoImmunology, 2015
Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analysed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival rate. Overall survival was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 months versus 31.0 months (p=0.018; hazard ratio 0.59; 95%CI 0.42-0.84). Five-year survival rate increased from 38% to 53% (p<0.01). In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses Downloaded by [Radboud Universiteit Nijmegen], [Jolanda de Vries] at 04:00 15 June 2015 3