High-Value Pathology
Safety Assessment
Julia Baker

High-Value Pathology

Five tips for optimizing the preclinical pathology applied to cellular therapeutics

Regulatory requirements for preclinical safety and efficacy studies of cellular therapeutic agents tend to be more fluid than those for standard toxicology studies. Instead of a predefined list of study design and species choice, the nature of the therapeutic may demand selection of a species based on its relevance to man, or on the practicality of cell administration. The US Food and Drug Administration’s Center for Biologics Evaluation and Research is open to working with scientists to customize their protocols. With that said, the cost of such studies can be prohibitive. Here are five tips that can help make the process more efficient.

  1. Get the most out of smaller-scale pilot studies. Develop appropriate species-specific surface markers, nuclear markers, or mitochondrial markers that are highly specific to your cell-line. Avoid the costly use of immunofluorescence in large-scale studies by using it with the same markers in smaller pilot studies; solid co-localization of staining will justify the use of identical markers for conventional immunohistochemical staining of adjacent serial sections in later studies. If the cellular therapeutic requires the use of a tissue scaffold, the biomaterial used must be carefully evaluated to determine how it will react in the proposed tissue processing flow.
  2. Triage your tissue. You can reduce the number of tissues examined by selecting the site of administration, regional lymph nodes, tissues directly connected to the administration site, highly perfused sentinel tissues, and any gross masses. The number of slides can be reduced by considering each group separately; no need to do an exhaustive search for cells in control animals that have not been cell-dosed.
  3. Adopt trimming strategies. Whenever possible, create multiple tissue levels at trimming rather than during microtomy; serial sectioning in these studies requires every intervening level to be taken to a sequentially numbered slide and retained.
  4. Use qPCR for biodistribution. This tool allows a larger volume of tissue to be examined. If a time point is reached where no cells are detected in a tissue, there is no rationale to repeat this test until the final time point.
  5. Conduct phased reads. Increased costs of performing histopathologic examination after each time point may be more than covered by savings IF early disappearance of the cells permits less extensive examination at subsequent time points.

With a little effort, these tips can help you design a study of high scientific integrity at minimal cost.