– ISA101 clinically effective against HPV-induced vulvar / vaginal lesions and cervical cancer

– Optimum immunotherapy window in cancer identified

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[1] and Science Translational Medicine[2], 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 https://www.isa-pharma.com/clinical-studies.

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About ISA Pharmaceuticals

ISA Pharmaceuticals B.V. is an immunotherapy company developing rationally designed, fully synthetic immunotherapeutics against cancer and persistent viral infections. The company has built a proprietary immunotherapy platform based on the Synthetic Long Peptide (SLP^®) concept and AMPLIVANT^® technology, which have the potential to generate safe and effective immunologic responses with a known mechanism of action. Synthetic long peptides are broadly applicable to multiple targets and ideally suited for monotherapy, as essential components in combination with conventional cancer treatments, and with novel immunomodulators such as Nivolumab. SLP^® immunotherapies are designed to fully harness and direct the body’s own defenses towards fighting the disease. In addition, ISA has begun to develop personalized SLP^® immunotherapies targeting tumor-specific, mutation-derived neo-antigens. These SLP^®s are based on the analysis of specific DNA mutations in a tumor sample, and designed and synthesized for each individual patient.

ISA´s most advanced clinical-stage immunotherapeutic is ISA101, an SLP^® immunotherapy targeting human papillomavirus (HPV)-induced diseases. It is currently in clinical development in advanced and recurrent cervical cancer, incurable HPV16-postive solid tumors and anal intraepithelial neoplasia (AIN). Moreover, a clinical Phase II combination trial with ISA101 and Nivolumab is being conducted at the MD Anderson Cancer Center in the US. Clinical proof-of-concept has been established in vulvar intraepithelial neoplasia (VIN), a pre-cancerous disease caused by HPV.

The company was founded in 2004 by Aglaia Oncology Fund and is based in Leiden, The Netherlands. For more information, please visit www.isa-pharma.com

SLP^® and AMPLIVANT^® are registered trademarks in Europe.

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[1] Van Poelgeest MIE et al. 2016. “Vaccination against oncoproteins of HPV16 for non-invasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-cell response.” Clin Cancer Res Published Online First on January 26, 2016; DOI: 10.1158/1078-0432.CCR-15-2594.

[2] Welters MJ et al. 2016. “Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T-cell responses.” Sci Transl Med 13 April 2016; DOI: 10.1126/scitranslmed.aad8307.

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