Vaccination against HPV-16 Oncoproteins for Vulvar Intraepithelial Neoplasia

Kenter, Gemma G.; Welters, Marij J.P.; Valentijn, A. Rob P. M.; Löwik, Margriet J.; Meer, Dorien M A Berends-van der; Vloon, Annelies P G; Essahsah, Farah; Fathers, Lorraine M.; Offringa, Rienk; Drijfhout, Jan W.; Wafelman, Amon R.; Oostendorp, Jaap; Fleuren, Gert Jan; Burg, Sjoerd H. van der; Melief, Cornelis J.M.

doi:10.1056/nejmoa0810097

Cited by 977 publications

(848 citation statements)

References 31 publications

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“…Hence, the multi-epitope vaccine targeting driver gene mutations met state-of-the-art requirements for TSA-based vaccines. Most of the latest and more advanced clinical trials for TSA-specific vaccines are based on the administration of Ag cocktails 47,66 . Another recent approach delivers multiple Ags as an individualized neo-antigen mRNA-polytope vaccine 67-69 which represents a promising alternative to administration of antigens via synthetic peptides.…”

Section: Discussionmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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Section: Discussionmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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“…Recently, different forms of immunotherapyvaccination to enhance the HPV16-specific T cells response, imiquimod to enhance the local innate immune response, and combination hereof-have been successful in the treatment of HPV16-induced lesions of the vulva. 19,20,43 Similar to HPV-induced lesions of the vulva, the HPV-induced HNSCC are relatively accessible and one could envisage that these strategies might be applicable to tumors of the oropharynx.…”

Section: Discussionmentioning

confidence: 99%

“…In all cultures, both CD8þ and CD4þ T cells grew out (CD4/CD8 ratio median 2.45, average 5.1 and range 0. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The composition of T cells was not clearly influenced by the culture conditions (Fig.…”

Section: Hpv-specific T Cells Can Be Isolated From Oropharyngeal Tumomentioning

confidence: 99%

“…[15][16][17] Recently, clinical success was achieved in the field of the immunotherapy of HPV16-induced (pre-) malignancies of the anogenital region, in particular with therapeutic vaccines. [18][19][20] Similar vaccine approaches are tested for the treatment of p53-overexpressing cancers. [21][22][23] There is a strong notion that the presence and type of preexisting circulating and local tumor-specific immunity influences the clinical outcome as well as that of immunotherapeutic approaches.…”

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confidence: 99%

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Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Heusinkveld

Goedemans

Briët

et al. 2011

Intl Journal of Cancer

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Squamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal carcinomas may express the HPV16 E6 and E7 oncoproteins and are associated with better survival, the nonvirally induced HNSCC are associated with overexpression of p53. In this study we assessed the presence of systemic and local T cells reactive against these oncoproteins in HNSCC. An exploratory study on the presence, type and function of HPV16-and/or p53-specific T cells in the blood, tumor and/or metastatic lymph node as measured by several immune assays was performed in an unselected group of 50 patients with HNSCC. Tumor tissue was tested for HPV DNA and the overexpression of p53 protein. Almost all HPV161 tumors were located in the oropharynx. Circulating HPV16-and p53-specific T cells were found in 17/47 and 7/45 tested patients. T cells were isolated from tumor cultures and/or lymph nodes of 20 patients. HPV16-specific T cells were detected in six of eight HPV1 tumors, but in none of the 12 HPV-tumors. Tumor-infiltrating p53-specific T cells were not detected. In depth analysis of the HPV16-specific T-cell response revealed that this response comprised a broad repertoire of CD41 T-helper Type 1 and 2 cells, CD41 regulatory T cells and CD81 T cells reactive to HPV16. The local presence of HPV16-specific T-cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and support the development of immunotherapy for HNSCC.

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“…[11][12][13][14] The incidence of VIN has increased 44-fold since the early 1970s. 15 Whereas classic VIN and its associated carcinoma are expected to decrease substantially in the future as the result of vaccination against high-risk papillomaviruses, 16 the incidence of differentiated VIN and its associated carcinoma is rising, likely owing to the increasing lifespan of our population. Immunohistochemical analysis for abnormal patterns of p16 INK4A , p53, and MIB1/Ki-67 expression, separately or as a panel, can distinguish classic from differentiated VIN but these markers often fail to identify the latter.…”

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confidence: 99%

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

et al. 2013

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As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin c 2 overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirusrelated 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin c 2 was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.

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Vaccination against HPV-16 Oncoproteins for Vulvar Intraepithelial Neoplasia

Abstract: Clinical responses in women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia can be achieved by vaccination with a synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7. Complete responses appear to be correlated with induction of HPV-16-specific immunity.

Cited by 977 publications

References 31 publications

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

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