Immunologic and Clinical Effects of Injecting Mature Peptide-Loaded Dendritic Cells by Intralymphatic and Intranodal Routes in Metastatic Melanoma Patients

Lesimple, Thierry; Neidhard, Eve-Marie; Vignard, Virginie; Lefeuvre, Claudia; Adamski, H.; Labarrière, Nathalie; Carsin, A; Monnier, Delphine; Collet, Brigitte; Clapisson, Gilles; Birebent, Brigitte; Philip, I; Toujas, Louis; Chokri, Mohamed Ali; Quillien, Véronique

doi:10.1158/1078-0432.ccr-06-1879

Cited by 59 publications

(46 citation statements)

References 38 publications

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“…The frequency of antigen-specific CD8 ϩ T cells that are elicited by the combined administration of ␣CD40/TLR agonist and antigen is an order of magnitude higher than that observed with almost any other adjuvant or cell-based vaccine platform, such as antigen-pulsed DCs. [30][31][32] While the cellular and molecular basis for this striking response is incompletely understood, we have published that the expression of CD70 on DCs is critical for CD8 ϩ T-cell expansion. 9 Heightened expression of CD70 on CD8␣ Ϫ DCs is induced only when both CD40 and TLR agonists are coadministered.…”

Section: Discussionmentioning

confidence: 99%

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

Ahonen

Wasiuk

Fuse

et al. 2008

Blood

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Identification of Toll-like receptors (TLRs)and their ligands, and tumor necrosis factor-tumor necrosis factor receptor (TNF-TNFR) pairs have provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants to elicit potent cell-mediated immunity via activation of innate and adaptive immunity. However, isolated activation of one immune pathway in the absence of others can be toxic, ineffective, and detrimental to long-term, protective immunity. Effective engineered vaccines must include agents that trigger multiple immunologic pathways. Here, we report that combinatorial use of CD40 and TLR agonists as a cancer vaccine, compared with monotherapy, elicits high frequencies of selfreactive CD8 ؉ T cells, potent tumorspecific CD8 ؉ memory, CD8 ؉ T cells that efficiently infiltrate the tumor-burdened target organ; therapeutic efficacy; heightened ratios of CD8 ؉ T cells to FoxP3 ؉ cells at the tumor site; and reduced hepatotoxicity. These findings provide intelligent strategies for the formulation of multifactorial vaccines to achieve maximal efficacy in cancer vaccine trials in hu IntroductionThe molecular identification of Toll-like receptors (TLRs) and their ligands, as well as tumor necrosis factor (TNF)-tumor necrosis factor receptor (TNFR) pairs that control adaptive immunity, has provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants that elicit potent cell-mediated immunity. Paralleling TLRs in mobilizing the innate immune response, CD40 and its ligand represent the primary ligand-receptor pair essential for development of the adaptive immune response. Individually, TLR agonists 1 and CD40 agonists 2-4 have entered clinical trials as adjuvants for eliciting protective immune responses to cancer. Inherent in these monotherapeutic approaches are limited induction of immunity, lack of clinical efficacy and, in some cases, hepatotoxicity. 3,4 TLRs are widely expressed on both hematopoietic and nonhematopoietic cells and elicit proinflammatory responses upon receptor engagement. Indeed, use of TLR agonists as solitary adjuvants triggers dendritic cell (DC) maturation, leukocyte migration, and release of chemokines and cytokines, and enhances immunity. 5,6 Studies in which TLR agonists have been scrutinized for their ability to induce cross-presentation and antigen-specific CD8 ϩ responses in vivo 7 show some level of activity that is minimal compared with that observed when combined with a CD40 agonist. 8,9 TLR agonists as unitary adjuvants in murine tumor models have demonstrated marginal efficacy, as reviewed, 10 but have proven effective when combined with other vaccine modalities. [11][12][13] Finally, clinical use of a TLR9 agonist in lung cancer trials has been recently suspended due to lack of clinical response. 1Studies from animal models underscore the utility of anti-CD40 (␣CD40) as a unitary adjuvant. 14,15 We previously demonstrated that the magnitude of immune responses elicited by TLR or CD40 agonists alone is minimal compared with the magnit...

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Section: Discussionmentioning

confidence: 99%

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

Ahonen

Wasiuk

Fuse

et al. 2008

Blood

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“…The median survival was 10.5 months. The most common adverse events included local reactions at the site of injection, and only 1 grade 4 lymphopenia occurred [121]. A study of Speiser et al exploited another synthetic TLR ligand, CpG 7909.…”

Section: Tlrs As Anti-tumor Vaccinesmentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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“…23 Neither complete response nor partial response was observed and only two patients were stabilized for more than 3 months. They assumed that the particular type, the number and the mode of dendritic cells and the administration route might be the explanation for the limited success.…”

Section: Discussionmentioning

confidence: 92%

“…Two patients be a sign of clinical benefit. 23 Two other phase II clinical trials for metastatic melanoma reported the clinical efficiency of two different anti-CTLA-4 monoclonal antibodies, ipilimumab and tremelimumab. 24,25 The objective response rate was 4.6% (4 of 88 patients) using ipilimumab and 10% (8 of 84 patients) using tremelimumab, respectively.…”

Section: Demographicsmentioning

confidence: 99%