HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial

Journal of Translational Medicine

Sjoerd H van der Burg³  Gemma G Kenter²  Cornelis J M Melief¹  Gert Jan Fleuren⁷  Jaap Oostendorp⁶  A Rob P M Valentijn⁶  Lorraine M Fathers⁶  Dorien M A Berends-van der Meer⁴  Margriet J G Löwik⁴  Muriel van den Hende⁴  Els L van Persijn van Meerten⁵  Gijs Kerpershoek⁴  Linda F M Stynenbosch³  Edith M G van Esch⁴  Marij J P Welters³  Mariette I E van Poelgeest⁴ 

[1] ISA Pharmaceuticals B.V., Leiden, The Netherlands;Center of Gynaecologic Oncology Amsterdam, Amsterdam, The Netherlands;Department of Clinical Oncology, Leiden University Medical Center, Building 1, K1-P, PO box 9600, 2300 RC Leiden, The Netherlands;Department of Gynaecology, Leiden University Medical Center, Leiden, The Netherlands;Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

关键词: Survival;    HPV;    Immunotherapy;    Immunomonitoring;    Cervical cancer;    Synthetic long peptides;    Therapeutic vaccine;   

Others  :  827815
DOI  :  10.1186/1479-5876-11-88

 received in 2013-01-07, accepted in 2013-03-23,  发布年份 2013

【 摘 要 】

Background

Human papilloma virus type 16 (HPV16)-induced gynecological cancers, in particular cervical cancers, are found in many women worldwide. The HPV16 encoded oncoproteins E6 and E7 are tumor-specific targets for the adaptive immune system permitting the development of an HPV16-synthetic long peptide (SLP) vaccine with an excellent treatment profile in animal models. Here, we determined the toxicity, safety, immunogenicity and efficacy of the HPV16 SLP vaccine in patients with advanced or recurrent HPV16-induced gynecological carcinoma.

Methods

Patients with HPV16-positive advanced or recurrent gynecological carcinoma (n = 20) were subcutaneously vaccinated with an HPV16-SLP vaccine consisting of a mix of 13 HPV16 E6 and HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant. The primary endpoints were safety, toxicity and tumor regression as determined by RECIST. In addition, the vaccine-induced T-cell response was assessed by proliferation and associated cytokine production as well as IFNγ-ELISPOT.

Results

No systemic toxicity beyond CTCAE grade II was observed. In a few patients transient flu-like symptoms were observed. In 9 out of 16 tested patients vaccine-induced HPV16-specific proliferative responses were detected which were associated with the production of IFNγ, TNFα, IL-5 and/or IL-10. ELISPOT analysis revealed a vaccine-induced immune response in 11 of the 13 tested patients. The capacity to respond to the vaccine was positively correlated to the patient’s immune status as reflected by their response to common recall antigens at the start of the trial. Median survival was 12.6 ± 9.1 months. No regression of tumors was observed among the 12 evaluable patients. Nineteen patients died of progressive disease.

Conclusions

The HPV16-SLP vaccine was well tolerated and induced a broad IFNγ-associated T-cell response in patients with advanced or recurrent HPV16-induced gynecological carcinoma but neither induced tumor regression nor prevented progressive disease. We, therefore, plan to use this vaccine in combination with chemotherapy and immunomodulation.

【 授权许可】

   
2013 van Poelgeest et al.; licensee BioMed Central Ltd.

【 图 表 】

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