A simple method to cure established tumors by inflammatory killing of normal cells

Daniels, Gregory A.; Sánchez-Pérez, Luis; Díaz, Rosa María; Kottke, Timothy; Thompson, Jill; Lai, Maoyi; Gough, Michael; Karim, Mahzuz; Bushell, Andrew; Chong, Heung; Melcher, Alan; Harrington, Kevin; Vile, Richard G.

doi:10.1038/nbt1007

Cited by 103 publications

(139 citation statements)

References 37 publications

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“…41 Indeed, the deliberate establishment of an autoimmune response against normal melanocytes has been proposed as a potential approach for promoting antimelanoma immunity. 42,43 Therefore, therapies that provoke immune activation in addition to direct tumour-specific cytotoxicity represent rational approaches to the treatment of MMM.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.

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Section: Discussionmentioning

confidence: 99%

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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“…Although our study was not effective in therapeutic models, some studies that develop rapid antitumor responses have shown to be effective against established B16 tumors. 34 The use of future vaccine strategies against MUC18 may lead to a more rapid induction of immune responses with the ability to overcome established tumors. There may be a potential for autoimmunity when vaccinating against murine MUC18 in mice.…”

Section: Discussionmentioning

confidence: 99%

Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis

et al. 2006

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Melanoma patients with metastases have a very low survival rate and limited treatment options. Therefore, the targeting of melanoma cells when they begin to invade and metastasize would be beneficial. An adhesion molecule that is upregulated at the vertical growth phase is the melanoma cell adhesion molecule (MCAM/MUC18). MUC18 is expressed in late primary and metastatic melanoma with little or no expression on normal melanocytes. We utilized the alphavirus-based DNA plasmid, SINCp, encoding murine MUC18 (SINCp c-muMUC18) for vaccination against B16F10 murine melanoma cells expressing murine MUC18. This vaccine effectively protected mice from lethal challenges with melanomaexpressing murine MUC18 in both primary and metastatic tumor models. Vaccination against MUC18 elicited effective humoral and CD8 + T-cell immune responses against melanoma. We propose that targeting molecules important in tumor invasion may be useful in the design of future strategies for the prevention and treatment of melanoma.

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“…23 Herein, we demonstrate that this antibody can also be employed as a vaccine adjuvant with a preferential effect on linked class I/II peptide vaccines to engender antitumor efficacy against poorly immunogenic intracranial tumor. However, it is worth noting that while αhCD27 dramatically elevated vaccine immunogenicity, that there was variability in these responses despite age- and gender-matched genetically identical recipients.…”

Section: Discussionmentioning

confidence: 96%

“…C57BL/6 mice were obtained from Charles River Laboratories (Wilmington, NC, USA), and transgenic OT-I and OT-II mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). Human CD27 transgenic (hCD27) mice, which express both murine and human CD27 molecules under the native murine CD27 promoter, 23 were obtained from Celldex Therapeutics (Hampton, NJ, USA) and bred at DUMC. Homozygous hCD27 males were bred with C57BL/6, OT-I, or OT-II females to generate heterozygous hCD27, hCD27xOT-I, or hCD27xOT-II mice, respectively, for use in experiments.…”

Section: Methodsmentioning

confidence: 99%

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

Riccione

Fecci

et al. 2018

OncoImmunology

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Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (αhCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of αhCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that αhCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant αhCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and αhCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with αhCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy.

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A simple method to cure established tumors by inflammatory killing of normal cells

Cited by 103 publications

References 37 publications

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

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