Three Peer-Reviewed Papers By ISA Pharmaceuticals Introduce Strategies To Improve Immunotherapy Against Cancer
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of three peer-reviewed papers that demonstrate the benefit of local delivery of a checkpoint control antibody targeting CTLA-4 (cytotoxic T lymphocyte antigen-4) for the successful eradication of cancer and the reduction of side effects. The papers include a review that underlines the importance of strategies for combinatorial treatments to improve further the immunotherapy of cancer. ISA Pharmaceuticals is developing cancer immunotherapies along those lines, in particular its Synthetic Long Peptide (SLP®) vaccine ISA101 for the treatment of HPV-induced diseases, such as cervical cancer and head and neck cancer, and ISA203 for the treatment of various tumors including lung cancer, head and neck cancer, breast cancer and melanoma.
In a paper just published in Clinical Cancer Research(1), a team of scientists from Leiden University Medical Center (LUMC) and ISA Pharmaceuticals report that in preclinical mouse models of cancer, the injection of a CTLA-4 blocking antibody in a slow-release formulation close to the tumor is very effective in activating a systemic anti-tumor (CD8+) T cell response. CTLA-4 is a crucial immune checkpoint protein that down-regulates the body’s immune response. The low-dose local treatment (50μg subcutaneously in a slow-release vehicle) eradicates tumors, including distant tumors, as effectively as a high-dose systemic treatment (2×200μg intraperitoneally). The method also leads to a 1000-fold decrease of antibody levels in the serum, thereby reducing adverse events and the risk of autoimmunity.
These findings are supported by an increasing number of studies demonstrating that local targets, mainly present in the microenvironment of tumors and draining lymph nodes, are key players in tumor progression. As published in a second paper by researchers from LUMC and ISA, a review in the International Journal of Cancer(2), local immunotherapies have clear advantages over systemic treatments, both in their ability to shift tumor-promoting mechanisms towards effective tumor-eradicating immunity and in terms of reducing the risks of systemic administration.
In the third publication in Seminars in Immunology(3), current cancer immunotherapy approaches are reviewed, concluding that most standalone immunotherapeutic strategies either fail to affect progressive diseases and survival significantly – or only do so in a minority of patients. The authors support combinations of synthetic vaccines that stimulate tumor-specific T cell responses and adjuvants, immune-modulating antibodies, cytokines, or chemotherapy.
“Cancer immunotherapy will benefit from further enhancing the potency of cancer vaccines while simultaneously counteracting the tumor’s evasion strategies,” said Cornelis Melief, Chief Scientific Officer of ISA and co-author of the three papers. “With this study, we have demonstrated that checkpoint control antibodies targeting CTLA-4, the target of Ipilimumab, can be further improved by local delivery to the tumor microenvironment and especially tumor-draining lymph nodes. This results in effective tumor eradication at a much lower dose and a greatly reduced risk of side effects. A combination of this approach with our SLP® vaccines is feasible.”
“These publications reemphasize the importance of ISA’s approach of carefully analyzing the underlying mechanisms and pharmacology of immunotherapeutics,” said Ronald Loggers, Acting Chief Executive Officer of ISA. “Our team has published many peer-reviewed papers on various aspects of immunotherapy. This insight allows us to develop rationally designed immunotherapeutics and to pick the most promising strategies for combination therapies based on our product candidates.”
(1) Fransen MF et al. (2103), Clin Cancer Res, Published Online First June 20, 2013; doi: 10.1158/1078-0432.CCR-12-0781
(2) Fransen MF et al. (2013), Int. J. Cancer, 132: 1971–1976; doi: 10.1002/ijc.27755
(3) Arens R et al., (2013), Sem Immunol, Published Online First May 21, 2013; doi: 10.1016/j.bbr.2011.03.031