ZYC101a for Treatment of High-Grade Cervical Intraepithelial Neoplasia

García, Francisco; Petry, Karl Ulrich; Muderspach, Laila I.; Gold, Michael A.; Braly, Patricia S.; Crum, Christopher P.; Magill, Marianne; Silverman, Michael H.; Urban, Robert G.; Hedley, Mary Lynne; Beach, Kathleen J.

doi:10.1097/01.aog.0000110246.93627.17

Cited by 175 publications

(125 citation statements)

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“…[7][8][9][10][11][12][13] However, to date, the clinical translation of these approaches has met little success. 14,15 Recently, we developed a novel DNA vaccination strategy named DNA tattoo vaccination that can potentially overcome this translational block. This strategy was shown to lead to the rapid induction of cellular immunity when compared to conventional methods of DNA vaccination in mice.…”

mentioning

confidence: 99%

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis

Öhlschläger

Berg

et al. 2011

Intl Journal of Cancer

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To allow vaccination irrespective of HLA type, DNA vaccines encoding full-length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full-length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic ''gene-shuffled" variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full-length and geneshuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full-length and the gene-shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein-70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T-cell responses. The E7-specific CD8 1 T cells induced by TTFC fusion vaccines were functional in terms of IFN-c production,formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene-shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full-length and gene-shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV-positive carcinomas in future studies.Persistent infection with ''high-risk'' human papillomavirus (HPV) genotypes is strongly associated with the development of anogenital cancers. 1,2 Of the ''high-risk'' genotypes, HPV 16 alone is known to be responsible for about half of the cervical cancer cases worldwide.3 Because persistent expression of the oncogenic HPV proteins E6 and E7 is required for carcinogenesis, these viral antigens are ideal targets for immunotherapeutic interventions. As E6 and E7 are solely expressed intracellularly, such therapeutic interventions should induce cellular immune responses to control existing HPV-induced lesions. 3,4 DNA vaccination forms an attractive approach for the induction of cellular immune responses as the DNA-encoded antigens are by definition produced intracellularly. Furthermore, DNA vaccines are safe, easy to produce, stable and do not suffer from the drawback of preexisting immunity or induction of antivector immunity. 5,6 In murine models, numerous DNA vaccines directed against either HPV 16 E6 or E7 have been tested with promising results.7-13 However, to date, the clinical translation of these approaches has met little success.14,15 Recently, we developed a novel DNA vaccination strategy named DNA tattoo vaccination that can potentially overcome this translational block. This strategy was shown to lead to the rapid induction of...

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confidence: 99%

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis

Öhlschläger

Berg

et al. 2011

Intl Journal of Cancer

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“…8 Adding to the challenge of assessing noncorrelating histopathologic follow-up findings after HSIL Paps, many high-grade lesions spontaneously regress, especially in younger adults. [9][10][11][12][13][14] With the advent of Food and Drug Administration (FDA) -cleared routine Pap and high-risk (hr) human papillomavirus (HPV) DNA cotesting for women 30 and older, 15,16 an increasing number of women with HSIL Pap test results now also have hrHPV DNA test results available to further assess histopathologic follow-up findings and to potentially help inform follow-up management decisions. 17 Nonetheless, reports on the range of expected histopathologic follow-up outcomes for large numbers of patients with HSIL Pap results based on widely used FDA-cleared liquid-based cytology (LBC) and from-the-vial hrHPV DNA testing remain limited.…”

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confidence: 99%

Histopathologic follow‐up and human papillomavirus DNA test results in 290 patients with high–grade squamous intraepithelial lesion papanicolaou test results

Gao

Austin

Zhao

2011

Cancer Cytopathology

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BACKGROUND:The study documents histopathologic outcomes and high‐risk (hr) human papillomavirus (HPV) test results in a large cohort of patients with high‐grade squamous intraepithelial lesion (HSIL) liquid‐based cytology (LBC) Pap test results.METHODS:A total of 352 patients with HSIL results (338 cervical and 14 vaginal) who had hrHPV testing and 290 patients with biopsy follow‐up were studied. hrHPV detection rates were compared at different ages, with or without an endocervical/transformation zone sample (EC/TZS), and for cervical and vaginal HSIL Pap smears. Histopathologic follow‐up findings were also compared. hrHPV‐negative HSIL slides were re‐evaluated in a blinded manner.RESULTS:A total of 325 of 338 (96.2%) cervical HSIL and 12 of 14 (87.5%) vaginal HSIL tested hrHPV‐positive. A total of 271 of 281 (96.4%) EC/TZS‐positive cervical HSIL and 54 of 57 (94.7%) EC/TZS‐negative cervical HSIL tested hrHPV‐positive. The percentage of hrHPV‐positive HSIL declined slightly with increasing age. 197 of 273 (72.3%) hrHPV‐positive cervical HSIL had histopathologic cervical intraepithelial neoplasia (CIN) 2/3+ follow‐up, including 8 squamous carcinomas, compared with 4 of 12 (33.3%) hrHPV‐negative HSIL with CIN2/3 (no carcinomas). 167 of 241 (69.2%) EC/TZS‐positive HSIL had CIN2/3+ follow‐up, compared with 34 of 44 (77.3%) EC/TZS‐negative HSIL. Equivocal HSIL morphology characterized some HPV‐negative HSIL without CIN2/3+ follow‐up.CONCLUSIONS:hrHPV was detected in LBC vials from 96.2% of 338 cervical HSIL and 85.7% of 14 vaginal HSIL. CIN2/3+ was significantly more likely with hrHPV‐positive cervical HSIL than with hrHPV‐negative cervical HSIL. Presence or absence of an EC/TZS did not significantly impact HSIL hrHPV or CIN2/3+ rates. Some hrHPV‐negative HSIL cases may represent HSIL cytologic mimics. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.

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“…In the results reported below, we describe a safety and feasibility study of vaccination with ZYC300, a plasmid encoding an inactivated form of the CYP1B1 DNA formulated within biodegradable poly-DL-lactide-coglycolide microparticles, a strategy previously shown to elicit T-cell -mediated responses (17,18). Seventeen patients with advanced-stage cancer were vaccinated for up to 12 vaccinations.…”

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confidence: 99%

Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Gribben¹,

Ryan

Boyajian³

et al. 2005

Clinical Cancer Research

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147

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Purpose: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1–specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy. Experimental Design: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-dl-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 μg every other week for up to 12 doses. Results: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year. Conclusions: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.

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ZYC101a for Treatment of High-Grade Cervical Intraepithelial Neoplasia

Abstract: I

Cited by 175 publications

References 20 publications

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Histopathologic follow‐up and human papillomavirus DNA test results in 290 patients with high–grade squamous intraepithelial lesion papanicolaou test results

Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

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