Validating various QC tests for release of cancer vaccines may be difficult. Cell number and viability may be used to determine
the dose of killed tumor cell or DC vaccines. Manual cell count and viability methods can be highly variable and automated
methods can be difficult to establish. Identity and purity tests will likely be based on analysis of TAAs and cell surface
markers expressed by tumor cell lines or TAA-loaded DC. For TAAs proteins and peptides, validated physical or chemical methods
are known, e.g., HPLC or ELISA. Microscopy and flow cytometric methods can be validated to quantify TAA and cell marker expression
on tumor cell lines and DC. Cell surface markers, such as CD1, CD14, CD80, CD83 and HLA-DR, are frequently used to identify
and quantify DC in a vaccine. Antigen loading can be analyzed if reagents are available that recognize TAAs within the various
antigen-processing cellular compartments or as epitopes associated with MHC on the surface of DC. Determining the correct
proportion of specific DC subpopulations required for an effective vaccine must be established in clinical studies and is
likely to result in a broad specification for DC vaccines. Potency, defined in 21 CFR 600.3(s) as the specific ability or capacity of the product to effect a given result, is a more difficult parameter to address
for the release of cancer vaccines. Since the mechanism of action of a vaccine is to elicit an effective immune response,
it is a daunting, if not impossible, task to develop and validate a practical in vitro immunological potency assay for QC release. Although mixed lymphocyte response assays can measure proliferation of allogeneic
or autologous T-cells stimulated by APCs in a vaccine, validation of these complex biological assays is unlikely. Thus, most
sponsors may seek to release product based on potency assays using surrogate markers. For example, increased expression of
CD54 by TAA-loaded APCs is the potency assay used by Dendreon to release the Provenge vaccine. The reliability of a surrogate
marker as an indication of vaccine potency will depend on a strong correlation with nonclinical analyses and clinical data
gathered during product development.
The commercial manufacturing and regulatory approval pathways for cancer vaccines will become clearer as several of these
products move closer to licensure. However, for "personalized" vaccines, extensive clinical data may be required to demonstrate
that the manufacturing process is well controlled and produces a consistent product. Although cancer vaccines under development
have proven safe and well tolerated, establishing clinical efficacy remains a challenge. For a cancer vaccine, it is imperative
to establish a correlation between immunological endpoints and clinical responses, and to demonstrate a survival advantage
over the standards of care in randomized Phase III clinical trials. Successful commercial development of cancer vaccines may
in fact require new approaches to the design of clinical trials,21 as well as the manufacture and release of pharmaceutical products.
Thanks to Dr. Karen Auditore-Hargreaves, CEO of ODC Therapy, Inc., for her helpful comments on the preparation of this article.
My sincerest apologies to all those companies and investigators whose work in this field I was not able to mention due to
space constraints. Your efforts are recognized as important contribution to the eventual successful development of effective
Lee K. Roberts, PhD, is the vice president of operations at ODC Therapy, Inc., Dallas, TX, 214.370.6181, email@example.com
1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature
2. Proleukin is marketed by Novartis Pharmaceuticals Corporation and information about this product can be found at:
3. Schering-Plough webpage;
http://www.schering-plough.com/. See cancer therapies under Products & Care for description of Intron A.
4. Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nature Reviews/Drug Discovery.