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

Kyte, Jon Amund; Mu, Lijun; Aamdal, Steinar; Kvalheim, Gunnar; Dueland, Svein; Hauser, Markus; Gullestad, Hans Petter; Ryder, T. A.; Lislerud, Kari; Hammerstad, H.; Gaudernack, Gustav

doi:10.1038/sj.cgt.7700961

Cited by 172 publications

(108 citation statements)

References 43 publications

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“…The analysis suggests a difference in favor of this study treatment, reaching a borderline statistical significance. However, we have previously observed that human responses frequently do not follow a Th1/Th2 delineation (23,28,29). The present responses comprised high levels of key Th1-cytokines IFNg and TNFa, but also of hallmark Th2 cytokines, interleukin 5 (IL-5) and IL-13.…”

Section: Cytokine Profilesmentioning

confidence: 95%

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Kyte

Gaudernack

Dueland

et al. 2011

Clinical Cancer Research

101

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Purpose: The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients. Experimental Design: Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m2 orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination. Results: The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years. Conclusions: The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy. Clin Cancer Res; 17(13); 4568–80. ©2011 AACR.

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Section: Cytokine Profilesmentioning

confidence: 95%

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Kyte

Gaudernack

Dueland

et al. 2011

Clinical Cancer Research

101

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“…One is based on adoptive transfer of autologous dendritic cells (DCs) transfected ex vivo with antigen-encoding RNA. [5][6][7] The other employs direct injection of naked RNA. 8,9 Feasibility and safety of vaccination protocols based on intradermal administration of naked RNA have been shown in preclinical and clinical settings and partial protection from tumor challenge has been achieved in mice.…”

Section: Introductionmentioning

confidence: 99%

Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation

et al. 2011

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Even though it is known for more than one decade that antigen-encoding RNA can deliver antigenic information to induce antigen-specific immunity against cancer, the nature and mechanism of RNA uptake have remained enigmatic. In this study, we investigated the pharmacokinetics of naked RNA administered into the lymph node. We observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs). Furthermore, in vitro and in vivo studies revealed that the efficient internalization of RNA by human and murine DCs is primarily driven by macropinocytosis. Selective inhibition of macropinocytosis by compounds or as a consequence of DC maturation abrogated RNA internalization and delivery of encoded antigens. Our findings imply that bioavailability of recombinant RNA vaccines in vivo highly depends on the density and the maturation stage of DCs at the administration site and are of importance for the design of RNA-based clinical immunotherapy protocols. Gene Therapy (2011) Keywords: vaccination; dendritic cells; RNA; macropinocytosis INTRODUCTION Antigen-encoding RNA has emerged as an attractive new vaccine format. Major advantages of RNA are efficient delivery of the complete antigenic information, transient expression and lack of genome integration, as well as cost-efficient and easy production in large amounts and high purity. 1 Moreover, through activation of the immune system via TLR3, TLR7 and TLR8, 2,3 RNA supports the induction of immune responses against the encoded protein.Of several in vitro and in vivo strategies utilizing antigen-encoding RNA as a vaccine format, 4 two are in clinical stage. One is based on adoptive transfer of autologous dendritic cells (DCs) transfected ex vivo with antigen-encoding RNA. [5][6][7] The other employs direct injection of naked RNA. 8,9 Feasibility and safety of vaccination protocols based on intradermal administration of naked RNA have been shown in preclinical and clinical settings and partial protection from tumor challenge has been achieved in mice. 10,11 However, at present, neither in animals nor in men, systemic immune responses let alone therapeutic effects were unequivocally demonstrated. It is assumed that rapid degradation by ubiquitous RNAses constraining pharmacologically efficient dosing of unprotected RNA contributes to the still suboptimal clinical effects. Knowledge about the nature and pharmacokinetics of RNA uptake in vitro and in vivo as well as the cell-type specificity is still scarce. Recently, we discovered that the administration route of naked RNA has a crucial impact on its efficacy as a vaccine. By injecting RNA directly into lymph nodes of mice, we achieved for the first time strong systemic antigen-specific Th1 type immunity and cancer cure in preclinical animal models. 12

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“…Therapy with tumor RNA-loaded DC vaccines induces T cell responses specific for the transfected antigens in about 50% of melanoma patients [33]. Earlier studies have shown that activated human B cells can be loaded with RNA and efficiently lead to antigen-specific T cell responses against antigens present in vitro [13,14]; however, the ability of RNA-loaded B cells to activate T cells in vivo has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Efficient antitumor immunity in a murine colorectal cancer model induced by CEA RNA‐electroporated B cells

et al. 2008

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RNA electroporation as a gene delivery method is more feasible and safer as compared with viral vectors. RNA-loaded dendritic cells (DC) have been used to induce T cell responses against tumor rejection antigens and B cells can also act as antigen-presenting cells for cellular vaccines. In this study, we compared B cells and DC, after electroporation with carcinoembryonic antigen (CEA) RNA, for their capacity to generate cytotoxic T lymphocytes and antitumor immunity. Vaccination using these B cells induced levels of IFN-c-secreting T cells and cytotoxic T cells comparable to those induced by DC. Intravenous administration was the optimum route for the B cell vaccine, while subcutaneous administration was the optimum route for the DC vaccine. The B cell vaccine predominantly generated CEA-specific CD4 + T cells, whereas the DC vaccine generated CD8 + T cells. Moreover, the B cell vaccine induced higher levels of anti-CEA antibodies than the DC vaccine. A heterogeneous prime-boost using B cells and DC failed to show any synergistic effects; however, the B cell vaccine did inhibit tumor growth and prolonged survival to a similar extent as the DC vaccine. Such RNA-electroporated B cells may prove useful as cellular tumor vaccines with potential clinical application.

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

Cited by 172 publications

References 43 publications

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation

Efficient antitumor immunity in a murine colorectal cancer model induced by CEA RNA‐electroporated B cells

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