Potency assays for therapeutic live whole cell cancer vaccines.

Therapeutic cancer vaccines are under development with the goal of enhancing the body's immune response to cancer cells sufficient to arrest cancer cell growth. Among the various approaches being used are those based on whole tumor cells. Developing a suitable measure of the potency of such vaccines presents a significant challenge because neither cellular associated markers nor in vivo biological responses that are correlated with efficacy have been identified; nevertheless, manufacturers and regulatory agencies will need to develop methods to evaluate these products. At this moment, the challenge for manufacturers who are developing whole cell vaccines is to demonstrate batch-to-batch consistency for the vaccine used in clinical studies and to show that comparable vaccine batches have the same capacity to achieve an acceptable level of biological activity that may be related to efficacy. This is particularly challenging in that animal models to test that activity do not exist and direct serological or immunological correlates of clinical protection are not available because protection has not yet been established in clinical trials. In the absence of well-defined biological markers and tests for manufacturing consistency, manufacturers and regulators will need to rely heavily on a highly reproducible manufacturing process--the consistency of the process therefore becomes critical. In developing regulatory approaches to whole cell cancer vaccines, the experience from the field of infectious disease vaccines should be examined for general guidance. A framework that draws heavily on the field of infectious disease vaccines is presented and suggests that at this point in the development of this new class of products, it is reasonable to develop data on quantitative antigen expression as a measure of potency with the expectation that when clinical efficacy has been established it will confirm the appropriateness of this approach. But because this will not be known until the end of a pivotal trial, a bioassay should be considered and run in parallel. Several examples of bioassays are presented along with their advantages and disadvantages. The final selection of a potency assay for use in lot release of a commercializable therapeutic whole cell vaccine ultimately will depend on the totality of the data available at the time of approval by regulatory agencies. Based on information currently available, it is likely that quantitative antigen expression or a bioassay could be used to measure potency. If both are determined to be acceptable, the use of quantitative antigen expression could be considered for routine lot release, while the bioassay could be reserved for use as one of the elements in establishing comparability when manufacturing changes are being considered after approval.

Transgenic mice as an alternative to monkeys for neurovirulence testing of live oral poliovirus vaccine: validation by a WHO collaborative study.

OBJECTIVE: Extensive WHO collaborative studies were performed to evaluate the suitability of transgenic mice susceptible to poliovirus (TgPVR mice, strain 21, bred and provided by the Central Institute for Experimental Animals, Japan) as an alternative to monkeys in the neurovirulence test (NVT) of oral poliovirus vaccine (OPV). METHODS: Nine laboratories participated in the collaborative study on testing neurovirulence of 94 preparations of OPV and vaccine derivatives of all three serotypes in TgPVR21 mice. FINDINGS: Statistical analysis of the data demonstrated that the TgPVR21 mouse NVT was of comparable sensitivity and reproducibility to the conventional WHO NVT in simians. A statistical model for acceptance/rejection of OPV lots in the mouse test was developed, validated, and shown to be suitable for all three vaccine types. The assessment of the transgenic mouse NVT is based on clinical evaluation of paralysed mice. Unlike the monkey NVT, histological examination of central nervous system tissue of each mouse offered no advantage over careful and detailed clinical observation. CONCLUSIONS: Based on data from the collaborative studies the WHO Expert Committee for Biological Standardization approved the mouse NVT as an alternative to the monkey test for all three OPV types and defined a standard implementation process for laboratories that wish to use the test. This represents the first successful introduction of transgenic animals into control of biologicals.