Leiden, The Netherlands, April 14, 2016 - ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company, has announced the publication of two peer-reviewed research manuscripts demonstrating the clinical efficacy of its lead product ISA101 in treating high-grade vulvar intraepithelial neoplasia (VIN), and synergy with chemotherapy in cervical cancer. In cervical cancer, the optimum window for treatment with ISA101 starts two weeks after the second chemotherapy cycle has been completed. The multi-center research was conducted in close collaboration with Leiden University Medical Center (LUMC). Publications appeared in Clinical Cancer Research* and Science Translational Medicine✝, respectively.
Infections with HPV are known to cause genital and, head & neck lesions which lead to cancer in a certain percentage of patients. While today selected high-risk HPV infections can be prevented by vaccination, this does not hold true for lesions and cancer formation once an HPV infection has occurred. To treat both pre-malignant (e.g. VIN) and malignant tissue damage (e.g. cervical cancer) in HPV-infected patients, ISA Pharmaceuticals has developed ISA101, a synthetic long peptide (SLP®) immunotherapeutic, to engage the immune system against these lesions.
In a combined analysis of animal and clinical studies in cervical cancer published in Science Translational Medicine, researchers discovered that a timed combination of ISA101 with standard carboplatin and paclitaxel chemotherapy can significantly improve immunity in advanced cervical cancer patients. Researchers also found that the most pronounced effect was seen if ISA101 was administered starting two weeks after the second cycle of chemotherapy.
"We looked into the mechanism of action," said Kees Melief, CSO of ISA. "In both mice and patients, the presence of a growing tumor was associated with abnormally high frequencies of circulating myeloid-derived suppressor cells. Administration of chemotherapy normalized the abnormal levels of these circulating myeloid cells and this was associated with increased T-cell reactivity to recall antigens. The effect was most pronounced starting two weeks after the second cycle of chemotherapy , providing an optimal immunological treatment window. We also observed that ISA101 treatment at this point resulted in unusually strong HPV16-specific T-cell responses, which were sustained after completing all cycles of chemotherapy. So one should consider chemotherapy as a treatment for the immune system rather than a mere treatment for the tumor."
The second paper in Clinical Cancer Research features a Phase I/II clinical study of ISA101 in 43 VIN patients demonstrating that advanced stages of VIN can be safely and effectively treated with the compound. All patients displayed drug-induced T-cell responses, which were significantly stronger in patients with complete clinical responses. Importantly, viral clearance occurred in all but one of the patients with complete histological clearance.
"The outcome of the VIN trial demonstrates once again the safety and efficacy of ISA101 in a premalignant setting," said Melief, who co-authored the study. "This study confirms the correlation between immune response and clinical outcome. It shows complete histopathological regressions and viral clearance, and the data demonstrate that the clinical efficacy of the immunotherapeutic is related to the strength of a drug-induced immune response. Rather than using post-hoc analyses for efficacy, we performed immunological assays and statistical analyses that were predefined."
"The results of these papers clearly emphasize the importance of our strategy in the cancer immunotherapy field, and prove that we have identified an effective, clinically relevant approach to engage the immune system against virus-induced cell damage," said Ronald Loggers, CEO of ISA. "They also demonstrate that our lead candidate ISA101 is a very effective treatment for both non-malignant and malignant diseases caused by HPV infections."
ISA101 is currently explored in two Phase I/II trials in anal intraepithelial neoplasia and HPV-positive cervical cancer, and in a Phase II Nivolumab combination trial in HPV-positive solid cancers. Further details can be found at http://www.isa-pharma.com/clinical-studies.
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