Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies

Le, Thuy T.; Gardner, Joy; Hoang-Le, Diem; Schmidt, Chris; MacDonald, Kelli P. A.; Lambley, Eleanore; Schroder, Wayne A.; Ogbourne, Steven M.; Suhrbier, Andreas

doi:10.1016/j.vaccine.2009.03.025

Cited by 36 publications

(38 citation statements)

References 51 publications

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“…The number of skin lesions outside the treatment areas was not significantly affected (Figure 1c), suggesting that the ingenol mebutate treatment did not induce effective systemic immunity against keratinocytes overexpressing mutated p53 (Le et al, 2009). This is consistent with the view that mutant p53 patches are not under immune control (Remenyik et al, 2003;de Graaf et al, 2008).…”

Section: Resultssupporting

confidence: 82%

Ingenol Mebutate Field-Directed Treatment of UVB-Damaged Skin Reduces Lesion Formation and Removes Mutant p53 Patches

Cozzi

Ogbourne²,

James

et al. 2012

Journal of Investigative Dermatology

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Skin cancer is the most prevalent cancer worldwide and is primarily caused by chronic UV exposure. Here, we describe the topical field-directed treatment of SKH1/hr mice with UVB-damaged skin with ingenol mebutate, a new topical drug shown to be effective for the treatment of actinic keratosis (AK). Application of 0.05% ingenol mebutate gel to photo-damaged skin resulted in a ≈70% reduction in the number of skin lesions that subsequently emerged compared with placebo treatment. Ingenol mebutate treatment also reduced the number of mutant p53 keratinocyte patches by ≈70%. The treatment resulted in epidermal cell death, acute inflammation, recruitment of neutrophils, hemorrhage, and eschar formation, all of which resolved over several weeks. Ingenol mebutate field-directed treatment might thus find utility in the removal of subclinical precancerous cells from UV-damaged skin. Field-directed treatment may be particularly suitable for patients who have AKs surrounded by UV-damaged skin.

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Section: Resultssupporting

confidence: 82%

Ingenol Mebutate Field-Directed Treatment of UVB-Damaged Skin Reduces Lesion Formation and Removes Mutant p53 Patches

Cozzi

Ogbourne²,

James

et al. 2012

Journal of Investigative Dermatology

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“…In addition, ingenol-3-angelate has been shown to regress untreated secondary tumors by inducing the generation of anti-cancer CD8 T cells after injection into primary tumors in mice [127].…”

Section: Effects On Tumorsmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

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Section: Possible T-cellemediated Antitumor Responsementioning

confidence: 99%

“…34 A single intratumoral injection of ingenol mebutate was able to cure B16 and Lewis lung tumors implanted subcutaneously in mice. 34 Treatment of the primary tumor resulted in regression of smaller distant untreated tumors secondary to the generation of anticancer CD8 T cells. This was demonstrated not only when secondary tumors had been established before treatment of the primary tumor with ingenol mebutate but also when secondary tumors were established after treatment of the primary tumor with ingenol mebutate.…”

Section: Possible T-cellemediated Antitumor Responsementioning

confidence: 99%

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Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response

Rosén¹,

Gupta²,

Tyring³

2012

Journal of the American Academy of Dermatology

149

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Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies

Cited by 36 publications

References 51 publications

Ingenol Mebutate Field-Directed Treatment of UVB-Damaged Skin Reduces Lesion Formation and Removes Mutant p53 Patches

Ingenol Mebutate Field-Directed Treatment of UVB-Damaged Skin Reduces Lesion Formation and Removes Mutant p53 Patches

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response

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