New Peer-Reviewed Publication Provides Further Insights into Mechanism of ISA Pharmaceuticals’ SLP® Immunotherapeutics

May 15, 2015

SLP®s modulate intratumoral macrophages required for tumor regression

Leiden, The Netherlands, May 12, 2015 – ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed immunotherapeutics against cancer and persistent viral infections, today announced the publication of a new peer-reviewed paper* demonstrating a beneficial effect of Synthetic Long Peptide (SLP®s) immunotherapeutics on intratumoral macrophages in cancers induced by human papilloma virus 16 (HPV16). ISA’s proprietary SLP® immunotherapeutics are rationally designed, off-the-shelf, synthetic peptides which ISA is developing as cancer immunotherapeutics. The company’s SLP® lead compound ISA101 is in clinical development for the treatment of early-stage, advanced and recurrent cancers induced by HPV16 infections.

Macrophages, a type of white blood cell, play a critical role in immunity by recruiting other immune cells and exerting effector functions, such as phagocytosis and cell or bacterial killing. They exist in two major and opposing types: The so-called M1 macrophages inhibit cell proliferation and cause tissue damage, while M2 macrophages promote cell proliferation and tissue repair. Cancer is often characterized by M2 activity, which facilitates tumor growth via angiogenesis, metastasis formation and suppression of Th1-type immune responses, among others. As a result, M2 macrophage infiltration of tumors commonly correlates with poor prognosis.

Based on these observations, the targeting of macrophages or inhibition of macrophage infiltration is considered a promising therapeutic option in cancer therapy. However, as part of an ongoing investigation into tumor immunotherapy, the authors of the paper cited below were able to demonstrate that skewing the macrophages towards M1 antitumor activity might be the optimal strategy instead. In animal studies, this skewing can be accomplished with ISA’s Synthetic Long Peptide (SLP®) immunotherapeutics.

The team of researchers used a mouse tumor model of HPV-induced cancers, such as cervical cancer, and HPV-positive head and neck cancer. Administration of an SLP® compound, among others, resulted in an influx of cytokine-producing CD8 T cells that strongly altered the numbers and phenotype of intratumoral macrophages from M2 to M1 activity. It was also demonstrated that complete regressions of large established tumors are dependent on the tumor-infiltrating macrophages induced by this immunotherapy: when a small molecule drug inhibitor diminished the number of intratumoral macrophages after SLP® administration, the complete remissions were abrogated and survival rates deteriorated.

“In sum, these results show that administration of SLP immunotherapeutics can induce cytokine-producing T cells with the strong macrophage-skewing capacity necessary for tumor shrinkage,” said Kees Melief, CSO of ISA Therapeutics and co-author of the study. “The findings strongly suggest that the development of macrophage-polarizing rather than macrophage-depleting strategies is warranted in oncology.”

“The study illustrates that our SLP immunotherapeutics can be instrumental in guiding intratumoral macrophages in the desired direction,” said Ronald Loggers, CEO of ISA. “We have also seen similar results in a recent clinical study in cervical cancer patients, and are very happy that this publication adds to the growing body of evidence that our SLP approach has very promising therapeutic potential.”

* van der Sluis TC et al. (2015), Therapeutic peptide vaccine-induced CD8 T cells strongly modulate intratumoral macrophages required for tumor regression. Cancer Immunol Res. 2015 Apr 17. pii: canimm.0052.2015

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 enable the generation of safe and effective drugs 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 as novel immunomodulators. SLP® immunotherapies are capable of fully harnessing and directing the body‘s own defenses towards fighting the disease.

ISA101, an SLP® immunotherapy targeting human papillomavirus (HPV)-induced diseases, is currently in clinical development in cervical cancer and anal intraepithelial neoplasia (AIN). Clinical proof-of-concept has been established with ISA101 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.