Final results of a phase 2 study using continuous 5% Imiquimod cream application in the primary treatment of high-grade vulva intraepithelial neoplasia

Le, Tien; Menard, Chantal; Hicks-Boucher, Wendy; Hopkins, Laura; Weberpals, Johanne I.; Fung-Kee-Fung, Michael

doi:10.1016/j.ygyno.2007.05.019

Cited by 48 publications

(54 citation statements)

References 26 publications

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“…In this study, treatment by 8 weeks of imiquimod followed by vaccination gave a lesion response rate of 63% at week 52. This compares very favourably with imiquimod alone treatment of 16 weeks assessed as histological regression to VIN1 or better as 64% soon after treatment (Le et al, 2007) or with no VIN at 2 months after treatment as 81% (Mathiesen et al, 2007) or 69% (van Seters et al, 2008).…”

Section: Discussionmentioning

confidence: 85%

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

et al. 2010

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BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure. METHODS: We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed. RESULTS: Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, nonresponders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens. CONCLUSION: The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.

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Section: Discussionmentioning

confidence: 85%

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

et al. 2010

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“…Overall, the initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular the increased proportions of T regulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. Other studies have implicated the importance of tumor CD8 to FOXP3 ratios in outcome in cervical cancer (20).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Immunologic Results of a Phase II Trial of Sequential Imiquimod and Photodynamic Therapy for Vulval Intraepithelial Neoplasia

Winters

Daayana

Lear

et al. 2008

Clinical Cancer Research

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Purpose: High-risk human papillomavirus (HPV)-associated vulval intraepithelial neoplasia (VIN) is difficult to treat by excision or ablation because of high recurrence rates. Small studies of photodynamic therapy (PDT) and imiquimod treatments have shown some success and function at least in part through stimulation of local immune responses. Indeed, there is evidence that immunosuppressed individuals have higher rates of VIN, suggesting immune control is relevant. Experimental Design: In the study, 20 women with high-grade VIN were treated with topical imiquimod and the PDT sequentially.Vulval biopsy and blood were taken pretreatment and, after imiquimod and PDT, with follow up for 1year. Clinical response was assessed by measuring lesion size. Biopsies were analyzed for HPV DNA and tumor-infiltrating lymphocytes including T regulatory cells. Results: The treatment was well-tolerated. There was an overall response rate of 55% by intention treat and 64% per protocol. The 52-week symptom response was 65% asymptomatic, compared with 5% at baseline. The nonresponders showed a significantly higher level of Tregulatory cells in the lesions after imiquimod treatment. Conclusions: The response rates are clinically relevant, and the treatment regimen was feasible for the majority. Initial nonresponders to imiquimod seem to be relatively refractory, and this may derive from their unfavorable local immune environment, in particular, the increased proportions of Tregulatory cells, possibly the limiting action and/or development of any HPV T-cell immunity. The potential benefit of this treatment is its ability to treat multifocal disease.

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“…38,39 Additionally, Imiquimod has been shown to exert proapoptotic activity toward tumor cells that is dependent on Bcl-2 and caspase activation. 40 Patients with VIN or AIN, lesions that can be easily accessed for cream or suppository-based treatments, who were treated with Imiquimod showed significant clinical responses as well as some HPV16-specific immune responses, 29,30,31,33 suggesting that induction of local inflammation and immunity is an important aspect of successful immunotherapy.…”

Section: Nonhpv-specific Tumor-directed Therapiesmentioning

confidence: 99%

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

Kanodia

Silva

Kast

2007

Intl Journal of Cancer

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Human papillomavirus (HPV)-induced lesions are distinct in that they have targetable foreign antigens, the expression of which is necessary to maintain the cancerous phenotype. Hence, they pose as a very attractive target for ''proof of concept'' studies in the development of therapeutic vaccines. This review will focus on the most recent clinical trials for the immunotherapy of mucosal and cutaneous HPV-induced lesions as well as emerging therapeutic strategies that have been tested in preclinical models for HPVinduced lesions. Progress in peptide-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune response modifiers, photodynamic therapy and T cell receptor based therapy for HPV will be discussed. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; immunotherapy; therapeutic vaccines; immunomodulation; animal models; clinical trialsThe human papillomaviruses (HPVs) are a family of sexually transmitted, double-stranded DNA viruses with over 100 different genotypes identified till date. HPV genotypes are divided into the low-risk and high-risk categories based on the spectrum of lesions they induce. Fifteen HPV types are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82); 3 are classified as probable high-risk types (26, 53 and 66) and 12 are classified as low-risk types (6,11,40,42,43,44,54,61,70,72, 81 and CP6108). 1 The low-risk types primarily induce benign genital condylomas and low-grade squamous intraepithelial lesions whereas the high-risk types are most frequently associated with the development of anogenital cancers and can be detected in 99% of cervical cancers, 2 with HPV16 found in about 50% of cases. 3 Infection by the low-risk types is not confined to the anogenital area and can cause other diseases such as recurrent respiratory papillomatosis. Similarly, infection by the high-risk types is also not confined to the anogenital area, since 18.3% of cancers of the oropharynx contain DNA from these types. 4 In the United States, an estimated 75% of the sexually active general population ages 15-49 years acquires at least one genital HPV type during their lifetime. 5 Though most individuals remain asymptomatic and spontaneously clear their infections, a small percentage of patients develop clinically or histologically recognizable lesions that develop into invasive cancer. The widespread use of cervical cytological screening using Papanicolaou (Pap) smear tests has reduced the mortality rate from cervical cancer in developed countries. However, in developing countries where screening programs are minimal, cervical cancer remains the second leading cause of cancer-related deaths among women. 6 Furthermore, Pap smear tests will not help identify HPV infection in males, where it can cause penile and anal cancers as well as cancers of the head and neck. Thus, it is essential to develop effective prophylactic and therapeutic strategies directed against HPV. Prophylactic vaccinesWhile therapeutic vaccines aim to develop a strong ...

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Final results of a phase 2 study using continuous 5% Imiquimod cream application in the primary treatment of high-grade vulva intraepithelial neoplasia

Cited by 48 publications

References 26 publications

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

Clinical and Immunologic Results of a Phase II Trial of Sequential Imiquimod and Photodynamic Therapy for Vulval Intraepithelial Neoplasia

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

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