Development of multi-epitope vaccines targeting wild-typesequence p53 peptides

DeLeo, Albert B.; Whiteside, Theresa L.

doi:10.1586/14760584.7.7.1031

Cited by 30 publications

(20 citation statements)

References 53 publications

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“…Historically, especially within the first 20 years of p53 research, the connection of p53 with host immune response and regulation had been mostly limited to employing fragments of p53 protein as tumor-associated antigens (TAAs) for tumor vaccines [20,21,22] because many forms of p53 mutation stabilize the p53 protein, resulting in elevated p53 level in tumors [1,3,23,24]. Recently, our studies and those of others have shown that p53 inactivation/dysfunction alters the immune landscape of the tumor microenvironment (TME) towards pro-tumor inflammation [25,26,27,28], whereas p53 reactivation or restoration changes the milieu of TME to promote antitumor immunity [29,30,31].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Cui

Guo

2016

IJMS

110

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The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence suggests that p53 mutation/inactivation also leads to gain-of-function or activation of non-autonomous pathways, which either directly or indirectly promote tumorigenesis. Experimental and clinical results suggest that p53 dysfunction fuels pro-tumor inflammation and serves as an immunological gain-of-function driver of tumorigenesis via skewing immune landscape of the tumor microenvironment (TME). It is now increasingly appreciated that p53 dysfunction in various cellular compartments of the TME leads to immunosuppression and immune evasion. Although our understanding of the cellular and molecular processes that link p53 activity to host immune regulation is still incomplete, it is clear that activating/reactivating the p53 pathway in the TME also represents a compelling immunological strategy to reverse immunosuppression and enhance antitumor immunity. Here, we review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and discuss how targeting the p53 pathway can be exploited to alter the immunological landscape of tumors for maximizing therapeutic outcome.

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Section: Introductionmentioning

confidence: 99%

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Cui

Guo

2016

IJMS

110

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“…The ex vivo comparison of vDC with DC1 matured in parallel from iDC of the same HNSCC patients by an alternative cytokine cocktail convincingly demonstrates that superior DC can be generated from monocytes derived from the blood of HNSCC patients using alternative maturation cocktails. Further, it has been determined that phenotypic and functional characteristics of vDC generated from patients with cancer differ from those of DC generated from normal donors (16). Since the vaccination outcome might depend on the quality of injected vDC, it is necessary to ensure that vDC are mature and functionally effective.…”

Section: Discussionmentioning

confidence: 99%

“…Although the study follows the design used for other wt p53-based DC vaccines (15, 16), it includes several novel aspects. First, to determine whether the addition of T helper (Th) peptides to the vaccine results in the improvements of TA-specific anti-tumor immunity, we included the HLA class II p53 helper peptide (p53 110-124 ref.…”

Section: Introductionmentioning

confidence: 99%

Phase I Dendritic Cell p53 Peptide Vaccine for Head and Neck Cancer

Schuler

Harasymczuk

Visús

et al. 2014

Clinical Cancer Research

134

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Background p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial. Methods Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1); additional T-helper(Th) tetanus toxoid peptide (Arm 2) or additional Th wt p53-specific peptide (Arm 3). Vaccine DC (vDC) were delivered to inguinal lymph nodes at 3 time points. Vaccine (vDC) phenotype, circulating p53-specific T-cells and regulatory T-cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared to those of DC1 generated with an alternative maturation regimen. Results No grade II-IV adverse events were observed. Two-year disease-free survival (DFS) of 88% was favorable. p53-specific T-cell frequencies were increased post vaccination in 11/16 patients (69%), with IFN-γ secretion detected in 4/16 patients. Treg frequencies were consistently decreased (p=0.006) relative to pre-vaccination values. The phenotype and function of DC1 were improved relative to vDC. Conclusion Adjuvant p53-specific vaccination of HNSCC patients was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients’ DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy.

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“…For this reason, multi-peptide anticancer vaccines are often advocated as the most logical solution to this issue [42,43], as discussed later. Over the past two decades, significant efforts have been made to enhance peptide immunogenicity and, based on our current understanding of peptide biology, several strategies have been adopted to improve the design of peptide-based vaccines, as below discussed.…”

Section: Peptide-based Anticancer Vaccinesmentioning

confidence: 99%

Peptides in Melanoma Therapy

Mocellin

2012

CPD

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Peptides derived from tumor associated antigens can be utilized to elicit a therapeutically effective immune response against melanoma in experimental models. However, patient vaccination with peptides - although it is often followed by the induction of melanoma- specific T lymphocytes - is rarely associated with tumor response of clinical relevance. In this review I summarize the principles of peptide design as well as the results so far obtained in the clinical setting while treating cutaneous melanoma by means of this active immunotherapy strategy. I also discuss some immunological and methodological issues that might be helpful for the successful development of peptide-based vaccines.

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Development of multi-epitope vaccines targeting wild-typesequence p53 peptides

Cited by 30 publications

References 53 publications

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Phase I Dendritic Cell p53 Peptide Vaccine for Head and Neck Cancer

Peptides in Melanoma Therapy

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