Induction of Tumor-Specific Cytotoxic T Lymphocytes in Cancer Patients by Autologous Tumor RNA-Transfected Dendritic Cells

Nair, Smita K.; Morse, Michael A.; Boczkowski, David; Cumming, R. Ian; Vasovic, Ljiljana V.; Gilboa, Eli; Lyerly, H. Kim

doi:10.1097/00000658-200204000-00013

Cited by 189 publications

(99 citation statements)

References 26 publications

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“…However, in most trials, the reactivity to unloaded DCs have not been measured in the in vitro T-cell assays 10,21,22,[31][32][33] or have been measured in cytotox-assays only. 14,26 Further, some trials have made use of immature DCs. 18,[27][28][29] Interestingly, responses to unloaded matured DCs were recently published in a lung cancer DC vaccine trial.…”

Section: Discussionmentioning

confidence: 99%

“…The experience with tumor-RNA vaccines is also limited in other cancer forms. To date have been reported a pilot vaccination of a patient with lung cancer 26 followed by three phase I trials, in renal cancer, 27 pediatric brain cancer 28 and neuroblastoma. 29 The phase I studies all applied vaccination with immature DCs that were transfected by simple coincubation with tumor-RNA.…”

Section: Introductionmentioning

confidence: 99%

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Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

et al. 2006

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We have developed an individualized melanoma vaccine based on transfection of autologous dendritic cells (DCs) with autologous tumor-mRNA. Dendritic cells loaded with complete tumor-mRNA may generate an immune response against a broad repertoire of antigens, including unique patient-specific antigens. The purpose of the present phase I/II trial was to evaluate the feasibility and safety of the vaccine, and the ability of the DCs to elicit T-cell responses in melanoma patients. Further, we compared intradermal (i.d.) and intranodal (i.n.) vaccine administration. Twenty-two patients with advanced malignant melanoma were included, each receiving four weekly vaccines. Monocyte-derived DCs were transfected with tumor-mRNA by electroporation, matured and cryopreserved. We obtained successful vaccine production for all patients elected. No serious adverse effects were observed. A vaccine-specific immune response was demonstrated in 9/19 patients evaluable by T-cell assays (T-cell proliferation/interferon-g ELISPOT) and in 8/18 patients evaluable by delayed-type hypersensitivity (DTH) reaction. The response was demonstrated in 7/10 patients vaccinated intradermally and in 3/12 patients vaccinated intranodally. We conclude that immuno-gene-therapy with the described DC-vaccine is feasible and safe, and that the vaccine can elicit in vivo T-cell responses against antigens encoded by the transfected tumor-mRNA. The response rates do not suggest an advantage in applying i.n. vaccination. Cancer Gene Therapy (2006) 13, 905-918.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

et al. 2006

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“…4,5 Preclinical experiments and human clinical trials testing administration of autologous DCs loaded in vitro with RNA as well as direct injection of RNA via different routes to reach DCs in situ showed feasibility, lack of toxicity and induction of the expected antigen-specific immune response. [6][7][8][9][10][11] Improvement of immunobioavailability of RNA-based vaccines in DCs has been a recurrent subject of our research, because the dose of the antigen may be one of the critical factors for generating strong and sustained antigen-specific immune responses. 12 In previous work, we have developed plasmid templates for in vitro transcription of RNA-encoded antigen with modified 3 0 structures (3 0 UTR and poly(A)tail) stabilizing the RNA and optimizing its translational performance.…”

Section: Introductionmentioning

confidence: 99%

Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immature dendritic cells and induce superior immune responses in vivo

et al. 2010

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Vaccination with in vitro transcribed RNA coding for tumor antigens is considered a promising approach for cancer immunotherapy and has already entered human clinical testing. One of the basic objectives for development of RNA as a drug is the optimization of immunobioavailability of the encoded antigen in vivo. By analyzing the effect of different synthetic 5 0 mRNA cap analogs on the kinetics of the encoded protein, we found that m 2 7,2 0 ÀO Gpp S pG (b-S-ARCA) phosphorothioate caps, in particular the D1 diastereoisomer, profoundly enhance RNA stability and translational efficiency in immature but not mature dendritic cells. Moreover, in vivo delivery of the antigen as b-S-ARCA(D1)-capped RNA species is superior for protein expression and for efficient priming and expansion of naïve antigen-specific T cells in mice. Our findings establish 5 0 mRNA cap analogs as yet another module for tuning immunopharmacological properties of recombinant antigen-encoding RNA for vaccination purposes.

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“…To circumvent these limitations, other strategies for antigen loading have been tried. They include loading with necrotic/apoptotic tumor cells [21,22], tumor lysate [11,[23][24][25], idiotype proteins [26], or transfection of tumor antigen mRNA [27][28][29][30]. In particular, DC loaded with necrotic/apoptotic tumor cells are able to induce CD8 + T cells as well as CD4 + T cells specific for tumor antigens in vitro [31][32][33] and in vivo [34,35].…”

Section: Introductionmentioning

confidence: 99%

Both Langerhans cells and interstitial DC cross‐present melanoma antigens and efficiently activate antigen‐specific CTL

et al. 2007

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Dendritic cells (DC) have a unique capacity to present external antigens to CD8 + T cells, i.e. cross-presentation. However, it is not fully established whether the ability to crosspresentation is restricted to a unique subset of DC in humans. Here, we show that two major myeloid DC subsets, i.e. Langerhans cells (LC) and interstitial DC (Int-DC), have the ability to cross-present antigens to CD8 + T cells in vitro. LC and Int-DC were obtained from DC generated by culturing human CD34 + -hematopoietic progenitor cells with GM-CSF, FLT3-L, and TNF-a (CD34-DC). Both DC subsets were able to capture necrotic/apoptotic allogeneic melanoma cells and present antigens to CD8 + T cells, resulting in efficient priming of naive CD8 + T cells into CTL capable of killing melanoma cells. Strikingly, a single stimulation with either subset (LC or Int-DC) or total CD34-DC loaded with necrotic/apoptotic melanoma cells was sufficient to activate melanomaspecific memory CD8 + T cells obtained from patients with metastatic melanoma to become effective CTL. Thus, this study provides the rationale to use CD34-DC loaded with necrotic/apoptotic allogeneic melanoma cells in a clinical trial.

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Induction of Tumor-Specific Cytotoxic T Lymphocytes in Cancer Patients by Autologous Tumor RNA-Transfected Dendritic Cells

Cited by 189 publications

References 26 publications

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immature dendritic cells and induce superior immune responses in vivo

Both Langerhans cells and interstitial DC cross‐present melanoma antigens and efficiently activate antigen‐specific CTL

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