1. What role do peptide vaccines play in the development of novel cancer therapies?
Therapeutic vaccines are administered to sick patients to cure or alleviate a diagnosed disease. The immune response is directed against self-antigens. From the peptide vaccines, cancer vaccines are the most investigated ones. They are designed to activate B-cells and killer T-cells to recognize cancer cells as foreign agents. Cancer cells differentiate from healthy cells by their surface protein modifications such as phosphorylations and glycosylations which make them a good target for the immune system. Fragments from these modified proteins (epitopes) are used to trigger the immune response. The concept of designing immunomodulating peptide cocktails and trigger the immune response has been mainly initiated by biotech companies who owns more than 80% of the current cancer vaccine pipeline. Multiple biotechnology companies are developing peptide vaccines (e.g. Ac Immune, Anergis, Ultimovacs, CellDex, Circassia, Immune Targeting Systems, Immatics, Gliknik, ISA Pharmaceuticals, etc). There are various cancer peptide vaccines in clinical trials and some of them reaching late stage clinical investigation, thus, the concept is now attracting big pharma players as well. Besides their low toxicity, peptide vaccines offer multiple advantages such as an increase in the specificity and longevity of the immune response, which leads to significant cost-saving compared to conventional therapies. Furthermore, cancer is a dynamic disease associated with mutations that render conventional drugs less effective. Vaccines could overcome the mutation barrier by using appropriate epitopes from proteins (over-)expressed in cancer cells, thus triggering the immune response against cancer cells despite the mutations.
2. What are the key regulatory challenges during the development and manufacturing of peptide vaccine "cocktails"?
Manufacturing cocktail peptide vaccines is not an easy task! The challenges are slightly different whether they relate to drug substance or drug product. At the drug substance level, producing multiple peptides at very small scale, sometimes only milligrams, under GMP and their release testing in parallel requires a substantial amount of resources. Furthermore, developing and validating the analytical methods for all of the peptides constituting the cocktail is time and resources consuming. Therefore, it is very important to identify synthetic and analytical synergies between each peptide to avoid duplicating the work. But in no case should the synergies jeopardize the reliability of the methods by willing to cut the development and the validation efforts. Obviously each peptide constituting the cocktail will be tested separately for stability and a CMC section will be written for each of them which add even more burden on the CMO manufacturing those peptide vaccines. From these perspectives, the CMO must have enough resources to dedicate to such a laborintensive and demanding product line. On the drug product front, one should keep in mind that all of the peptide constituents are usually mixed in one single vial or syringe. The physical and chemical stability of the vaccine may be influenced by mixing the individual peptides during the fill-finish process. In some cases aggregation can be triggered due to electrostatic interaction (intramolecular associations) or increase in hydrophobicity of the peptide cocktail mixture. Understanding the behaviour of the mix is taken into account during the development of the formulation. The analytical part is key, especially the HPLC method which must be robust enough to separate all the peptide constituents and the corresponding impurities. Furthermore, in order to monitor the stability, it is absolutely critical to trace back each impurity and associate it with the parent peptide it derives from. This requires a strong quality team with expertise in separation and mass spectrometry. In fact, in many cases the dose in each vial is very low and monitoring stability related impurities (limit of quantification) can be a real challenge that only strong analytical techniques can overcome.
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