Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I–II trial

Driel, Willemien J. van; Ressing, Maaike E.; Kenter, Gemma G.; Brandt, R. M. P.; Krul, Eveline J. T.; Rossum, A.B. van; Schuuring, Ed; Offringa, Rienk; Bauknecht, Thomas; Tamm-Hermelink, A.; Dam, Peter van; Fleuren, Gert Jan; Kast, W. Martin; Melief, Cornelis J.M.; Trimbos, J. Baptist

doi:10.1016/s0959-8049(99)00048-9

Cited by 199 publications

(116 citation statements)

References 24 publications

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“…[3][4][5] The constitutive expression of the viral oncoproteins E6 and E7 by the tumor cells renders the transformed cells excellent targets for cytolytic attack by HPV E6-and E7-specific T cells. 11,[15][16][17][18] Recent studies strongly implicate that CD8ϩ T cell-mediated, cytolytic responses play an essential role in regression of precancerous lesions and tumors, with CD4ϩ T cells being important for the development of an efficient immune response. 5,12,[15][16][17][18][19][20] For the development of peptide-based vaccines and for monitoring of the induction of specific T cells via vaccination, the knowledge of cytolytic T cell epitopes of the E6 and E7 antigens is necessary.…”

Section: Discussionmentioning

confidence: 99%

“…Screening by the use of a long synthetic 20mer peptide library allowed us to identify an epitope that would not have been predicted with high priority by the computer program. The lack of response to the 20mer HPV18 E7 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] that includes the high affinity binding peptide HPV18 E7 7-15 described by Rudolf et al 24 would have excluded this potential epitope from further analysis as an irrelevant epitope. Consequently, we never found a response to this epitope.…”

Section: Discussionmentioning

confidence: 99%

“…In this library, consequently, all possible epitope sequences of the HPV18 E7 were represented. Sequences are: HPV18 E7 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] , p44 (MHGP-KATLQDIVLHLEPQNE); HPV18 E7 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] , p45 (VLHLEPQNE-IPVDLLCHEQL); HPV18 E7 , p46 (VDLLCHEQLSDSEEEN-DEID); HPV18 E7 34 -53 , p47 (SEEENDEIDGVNHQHLPARR); HPV18 E7 [45][46][47][48][49][50][51][52][53]…”

Section: Peptides and Proteinsmentioning

confidence: 99%

“…CD8ϩ T cell mediated, cytolytic responses were identified to play an essential role in regression processes, though CD4ϩ T cells may also be induced and important for an efficient immune response. 5,12,[15][16][17][18][19][20] For the development of vaccines and the monitoring of the immune response of the treated patients, knowledge of relevant CTL epitopes of E6 and E7 is indispensable.…”

mentioning

confidence: 99%

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Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Kather

Ferrara

Nonn

et al. 2003

Intl Journal of Cancer

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Immunotherapy of HPV-associated disease such as cervical cancer is moving from preclinical investigation to clinical trials. The viral oncoproteins E6 and E7 are ideal target antigens because their expression is mandatory in HPVtransformed tumor cells. T cells are the most important effector cells for therapeutic vaccination strategies. Therefore, the identification and characterization of HPV E6 and E7 T cell epitopes is necessary. Methods to date rely on screening for immunogenicity of peptides predicted by algorithms. Presentation of the identified peptides on tumor cells, however, needs to be confirmed. In our study, we have improved the method to identify peptide epitopes of HPV18 E7 that are actually presented by tumor cells. We induced allogeneic T-cell lines by stimulation with HPV18-positive, CD80 and HLA-A*0201 transfected cervical cancer cells. Sensitized T cells were probed against an array of a HPV18 E7 20mer peptide-library. We found specific reactivity to one of the 20mer peptides. This sequence was then screened via algorithms for putative epitopes. One putative HLA-A2 restricted epitope was confirmed to bind to HLA-A2, to be immunogenic and to induce IFN␥-release in ELISpot assays. Epitope-specific T cells were cytolytic toward autologous peptide pulsed targets and HPV18 transformed tumor cells. The identification of epitope-specific T cells in tumor infiltrating lymphocytes of a HPV18-positive HLA-matched cervical cancer patient suggests an in vivo relevance of the identified epitope. We suggest that our approach is advantageous over conventional methods, because it yields candidate peptides that are relevant CTL epitopes that are expressed, processed and presented by tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Peptides and Proteinsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Kather

Ferrara

Nonn

et al. 2003

Intl Journal of Cancer

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“…48 In a Phase I/II clinical trial, 19 terminally ill cervical cancer patients were immunized with HLA-A*0201-restricted HPV-16 E7 peptide, with confirmed tolerability but no detectable CTL response. 49 Another Phase II clinical trial in patients with end-stage cervical cancer used E6 or E7 HLA-A*0201-binding peptides pulsed onto cytokine-stimulated autologous peripheral blood mononuclear cells.…”

Section: Peptide and Protein-based Vaccinesmentioning

confidence: 99%

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

Eskander

Tewari

2015

Clinical Therapeutics

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Purpose: In 2014, the US Food and Drug Administration approved the first targeted agent, bevacizumab, in the treatment of advanced stage, persistent, or recurrent cervical cancer. This oncologic milestone has catalyzed interest in the investigation of alternate therapies, including immunotherapy, in an effort to extend life and possibly cure patients with advanced stage disease.Methods: This review article focuses on the evolving paradigm of immunotherapy in the treatment of cervical cancer, describing the biologic basis of this treatment modality and discussing applicable Phase I to II clinical trials.Findings: To date several trials have been conducted exploring vaccine-based therapies, adoptive T-cell therapy, and immune-modulating agents in patients with cervical cancer with promising results.Implications: Immunotherapy represents a promising therapeutic paradigm in the treatment of advanced cervical cancer. Additional investigation is warranted to try and identify alternate immune targets and predictors of response, allowing for the selection of patients most likely to benefit from immune-based treatments. (Clin Ther. 2015;37:20-38) & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Vaccination With Human Papillomavirus Type 16 E7 Peptide With CpG Oligonucleotides for Prevention of Tumor Growth in Mice

Gendron

Rodriguez²,

Sewell³

2006

Arch Otolaryngol Head Neck Surg

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Objective: To test whether an E7 peptide/CpG vaccine is effective in preventing and treating human papillomavirus-positive tumors in a murine model. Intervention: First, an E7 peptide/CpG vaccine was administered systemically on days −14 and −7, and tumor cells were injected subcutaneously on day 0. Second, tumor cells were injected on day 0, and vaccine was administered on days 7, 14, and 21. Main Outcome Measures: Tumor size was measured 3 times per week. A tetramer assay was used to assess the presence of activated, E7-specific lymphocytes in spleen and tumor cells harvested from mice treated with a similar vaccination regimen. Results: In the prophylactic study, 75% of mice injected with E7 peptide/CpG resisted tumor formation. In the therapeutic setting, tumors initially regressed and experienced delayed progression when compared with controls. Survival rates improved in E7/CpGvaccinated mice. Tetramer analysis detected increased numbers of activated, E7-specific lymphocytes in the spleens and tumors of animals treated with the experimental vaccine when compared with controls. Conclusion: The use of CpG motifs as an adjunct to peptide-based immunotherapy has potential impact on the treatment of human papillomavirus-associated cancers.

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Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I–II trial

Cited by 199 publications

References 24 publications

Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

Vaccination With Human Papillomavirus Type 16 E7 Peptide With CpG Oligonucleotides for Prevention of Tumor Growth in Mice

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Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I–II trial

Cited by 199 publications

References 24 publications

Identification of a naturally processed HLA‐A*0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro vaccination

Identification of a naturally processed HLA‐A*0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro vaccination

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

Vaccination With Human Papillomavirus Type 16 E7 Peptide With CpG Oligonucleotides for Prevention of Tumor Growth in Mice

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Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination