Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen

Gilliet, Michel; Kleinhans, Martin; Lantelme, Erica; Schadendorf, Dirk; Burg, G.; Nestle, Frank O.

doi:10.1182/blood-2002-07-2274

Cited by 58 publications

(36 citation statements)

References 43 publications

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“…Similar observations have been made in two normal donors injected with immature DCs loaded with influenza peptide (41). Nevertheless, immune responses have been observed previously with immature or semimature DCs, particularly if injected intranodally (40,47). One explanation for these findings has been that mature, but not immature, DCs are migratory and capable of reaching draining lymph nodes (42).…”

Section: Discussionsupporting

confidence: 82%

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Vonderheide

Domchek

Schultze

et al. 2004

Clinical Cancer Research

226

133

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Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT؉ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT؉ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth.Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells.Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERTspecific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramerguided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC-restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8؉ tumor infiltrating lymphocytes.Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.

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Section: Discussionsupporting

confidence: 82%

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Vonderheide

Domchek

Schultze

et al. 2004

Clinical Cancer Research

226

133

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“…Mailliard et al (23) described a maturation mixture composed of TNF-a, IL-1b, IFN-a, IFN-g, and the TLR3 agonist poly(I:C), which enhanced the production of bioactive IL-12(p70) in 7-d mDCs but gave only low cell yields. This could be a limiting factor in obtaining sufficient numbers of mDCs for clinical studies if vaccination protocols do not entail direct intralymphatic injection (clinical trial ID UPCI 03-118; http://clinicaltrials.gov/ct2/show/NCT00390338) but rely instead on migration of a small proportion of mDCs to neighboring lymph nodes after s.c. or intradermal injection (39,40). An alternative approach included only the TLR7/8 ligand resiquimod (R848) for stimulation of iDCs; however, this yielded DCs lacking several phenotypic characteristics of fully mature DCs desired for clinical use (41).…”

Section: Discussionmentioning

confidence: 99%

Generation of Th1-Polarizing Dendritic Cells Using the TLR7/8 Agonist CL075

Spranger¹,

Javorovic²,

Bürdek³

et al. 2010

The Journal of Immunology

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“…Recombinant IL-2 (50 U/ml, aldesleukin, Proleukin; Chiron) was added at day 5, and T cell lines were analyzed at day 20 (47).…”

Section: Klh-specific T Cell Linesmentioning

confidence: 99%

“…Given the limited possibility to repeatedly draw large amounts of blood from rhesus monkeys, which is required to generate DCs, we chose a protocol published for the analysis of immune responses induced by KLH-loaded DCs in humans that does not require repeated restimulation with DCs (47). While the percentages of IFN-␥-secreting cells differed at the various time points of establishing the cell lines, the pattern of cytokine secretion was identical in all four animals; that is, we detected considerable percentages of IFN-␥-secreting cells in cell lines from the animals 12741 and 12743, and less IFN-␥ producing cells in those from animals 12744 and 12745 (Fig.…”

Section: Peripheral Cd4 ϩ T Cell Responses Induced By DC Immunizationmentioning

confidence: 99%

IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation

Jasny

Eisenblätter

Mätz‐Rensing

et al. 2008

The Journal of Immunology

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Experimental studies in monkeys on the basis of ex vivo-generated, reinjected dendritic cells (DCs) allow investigations of primate DC biology in vivo. To study in vitro and in vivo properties of DCs with a reduced capacity to produce IL-12, we adapted findings obtained in vitro with human cells to the rhesus macaque model. Following exposure of immature monocyte-derived monkey DCs to the immunomodulating synthetic polypeptide glatiramer acetate (GA) and to dibutyryl-cAMP (d-cAMP; i.e., a cAMP enhancer that activates DCs but inhibits the induction of Th1 immune responses), the resulting DCs displayed a mature phenotype with enhanced Ag-specific T cell stimulatory function, notably also for memory Th1 cells. Phosphorylation of p38 MAPK was not induced in GA/d-cAMP-activated DCs. Accordingly, these cells secreted significantly less IL-12p40 (p ≤ 0.001) than did cytokine-activated cells. However, upon restimulation with rhesus macaque CD154, GA/d-cAMP-activated DCs produced IL-12p40/IL-23. Additionally, DCs activated by proinflammatory cytokines following protocols for the generation of cells used in clinical studies secreted significantly more IL-23 upon CD154 restimulation than following prior activation. Two days after intradermal injection, GA/d-cAMP-activated fluorescence-labeled DCs were detected in the T cell areas of draining lymph nodes. When similarly injected, GA/d-cAMP as well as cytokine-activated protein-loaded DCs induced comparable Th immune responses characterized by secretion of IFN-γ, TNF, and IL-17, and transiently expanded FOXP3+ regulatory T cells. Reactivation of primate DCs through CD154 considerably influences their immmunostimulatory properties. This may have a substantial impact on the development of innovative vaccine approaches.

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Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen

Cited by 58 publications

References 43 publications

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Generation of Th1-Polarizing Dendritic Cells Using the TLR7/8 Agonist CL075

IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation

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