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ddn Cancer Research Portal Exclusive: Adjuvants--The Heroes of Immunotherapy
by Dr. Garo Armen, Agenus Inc.  |  Email the author

For most people, the word "vaccination" brings to mind prevention of disease. Vaccines for smallpox and polio have virtually eradicated these diseases with a benefit to society that has been unprecedented by any other breakthrough in healthcare. Preventive vaccines, dating back to the era of Jenner and Pasteur, work by boosting the body's resilience to prevent infections.
Over the last century, immunologists have taken a much broader view of vaccination. These scientists have explored the possibility that vaccines may also be used to treat pre-existing infections and even cancer, in addition to their established role in preventing infectious diseases. While the development path for therapeutic cancer vaccines has proven slow, 2012 could be a breakout year for the field with 40 unique agents presently being tested in over 60 clinical trials. A dozen readouts from randomized Phase II or Phase III trials are expected during the next 12 months.  
For these and other next-generation therapeutic as well as prophylactic vaccines, the cumulative evidence points to success being largely dependent on activation of T cells and/or a broader range of antibody responses. Compounds called adjuvants agents that boost and prolong the effect of an antigen-specific vaccine play an essential and central role in the ability to achieve these responses. In fact, a number of antigen-specific vaccines have proven ineffective when the right adjuvant is removed from an otherwise potent vaccine formulation.  
The use of the adjuvants or adjuvant systems has created new opportunities for therapeutic vaccines. Such vaccines can now be powered to play a central role in the treatment of cancer, viral illnesses and many other diseases, including autoimmune disorders. Given that vaccines work in a much more targeted manner than most drugs and use a natural pathway of the body, upon success we are likely to see efficacy and safety profiles not achieved with most current medicines.  
During the last 80 years, many adjuvants have been used in experimental settings, but only three have made it into routine clinical practice: alum, MF59 and MPL. Of these three adjuvants, only alum and MPL have been used in vaccines licensed by the U.S. Food and Drug Administration (FDA). Alum was first introduced in the 1930s and MPL, the first and only toll-like receptor (TLR) ligand currently approved in a human vaccine, was approved 80 years later.
The paucity of licensed adjuvants can be explained in part by the fact that they do not receive FDA approval as stand-alone products, but rather as part of a registered vaccine adjuvant-antigen combination.  In other words, both the adjuvant and the antigen components of a vaccine must prove safe and effective together for a successful registration. Further, since most preventative vaccines are for prophylactic use in infants or children, more complex safety considerations have slowed adjuvant development. However, these considerations may be less of an issue in the (adult) cancer setting for therapeutic vaccines targeting life-threatening illnesses.  
The new generation immunologic adjuvants have the added benefit of reducing the amount of antigen and/or number of vaccine doses needed, thus potentially lowering costs to patients and payers. This antigen-sparing benefit of adjuvants could allow for the expansion of vaccine supply to meet the necessary global demands during a pandemic. Such interests are supported by grants from the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services. If an influenza pandemic were to occur, such as the 2009-10 H1N1 pandemic, the potential vaccine supply using the old adjuvant technologies would fall several billion doses short of the amount needed to provide protection to the global population.
This is an exciting time in the field of vaccine development. Just as the approval of rituximab (Rituxan by Biogen) in 1997 was a watershed event for therapeutic monoclonal antibodies, the pathway for cancer vaccines and new generation cancer immunotherapeutics has been opened with the recent FDA approval of Dendreon's Provenge and Bristol-Myers Squibb's Yervoy. The critical enablers of new generation targeted vaccines are adjuvants an essential part of effective vaccines for the prevention and treatment of many of the serious diseases for which effective and safe therapies simply do not exist today.



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