Vaccination with mRNA-Electroporated Dendritic Cells Induces Robust Tumor Antigen-Specific CD4+ and CD8+ T Cells Responses in Stage III and IV Melanoma Patients

Aarntzen, Erik H.J.G.; Schreibelt, Gerty; Bol, Kalijn F.; Lesterhuis, W. Joost; Croockewit, Alexandra J.; Wilt, Johannes H. W. de; Rossum, Michelle M. van; Blokx, Willeke A.M.; Jacobs, Joannes F M; Boer, Tjitske Duiveman-de; Schuurhuis, Danita H.; Mus, Roel; Thielemans, Kris; Vries, I. Jolanda M. de; Figdor, Carl G.; Punt, Cornelis J.A.; Adema, Gosse J.

doi:10.1158/1078-0432.ccr-11-3368

Cited by 85 publications

(72 citation statements)

References 43 publications

(46 reference statements)

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“…This response rate is similar to that of moDC-vaccinated stage IV melanoma patients in our previous studies (4). The high tumor burden in stage IV melanoma patients may hamper the induction of effective immune responses and cause the lack of response in the remaining patients, which is underscored by our observation that response rates in stage III melanoma patients are higher (32,33). Therefore, we hypothesize that DC vaccination may be more potent in the adjuvant setting.…”

Section: Discussionsupporting

confidence: 86%

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Schreibelt

Bol

Westdorp

et al. 2016

Clinical Cancer Research

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Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocytederived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c þ myeloid DCs, naturally circulating in the blood. Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c þ myeloid DCs, activated by only brief (16 hours) 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 (3-10 Â 10 6 ) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8þ T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNg as well as TNFa and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. Conclusions:We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155-66. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 86%

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Schreibelt

Bol

Westdorp

et al. 2016

Clinical Cancer Research

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196

171

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“…Variations in protocols included the type of DCs, route of administration, and method of antigen loading. For the exact details regarding the vaccination protocols, we refered to the following individual studies (20,21,(27)(28)(29)(30)(31).…”

Section: Vaccinationmentioning

confidence: 99%

T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines

et al. 2016

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Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3þ T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P ¼ 0.000026) and a validation cohort of 39 patients (P ¼ 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapytreated patients was observed for high (P ¼ 0.000566), but not low (P ¼ 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection.

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“…For the exact details regarding the vaccination protocols we refer to these individual studies. [35][36][37][38] Dendritic cell vaccine Monocytes were enriched from leukapheresis products by plastic adherence of peripheral blood mononuclear cells or by counterflow centrifugation using Elutra-cell separator (Gambro BCT) and single-use, functionally sealed disposable Elutra sets, as described before. 39 Monocytes were cultured in the presence of IL-4 (500 U/mL), GM-CSF (800 U/mL) (both Cellgenix) and KLH (10 mg/mL, Calbiochem).…”

Section: Treatment Schedulementioning

confidence: 99%

Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination

et al. 2015

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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 analyzed 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 (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo (p D 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 in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting.

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Vaccination with mRNA-Electroporated Dendritic Cells Induces Robust Tumor Antigen-Specific CD4+ and CD8+ T Cells Responses in Stage III and IV Melanoma Patients

Abstract: Purpose: Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients.

Cited by 85 publications

References 43 publications

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines

Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination

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