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C H A P T E R 96

INVESTIGATIONAL NEW DRUG–ENABLING PROCESSES

FOR CELL-BASED THERAPIES

Robert Lindblad, Traci Heath Mondoro, Deborah Wood, and
Gillian Armstrong

The use of donated human cells as more than replacement therapy together funding from institutional or philanthropic sources. The
has become a reality over the course of the last several years. While National Heart, Lung, and Blood Institute (NHLBI) will accept grant
basic and clinical scientists are developing many new and promising applications for cell therapy studies that include manufacturing and
strategies to improve immune reconstitution and transplant outcome translational studies. The National Institute of Biomedical Imaging
at the manufacturing and individual patient level, they are dependent and Bioengineering (NIBIB) funds hypothesis-driven research related
on many others to implement these new therapies on a larger scale. to technologies, and some investigators have been able to utilize
Ultimately, implementation of procedures that were successful in the services provided by NIH Clinical and Translational Sciences Awards
laboratory can be expensive and difficult to scale up to a process that (CTSA) programs. Regardless of the source of funding, this chapter
will produce the required dosage while maintaining the consistent will provide general information about requirements during the
cellular product quality needed for clinical trials. To cope with these IND-enabling phase of the development of a cellular therapy before
issues, many institutions have established specialized cell-processing it is tested for safety in a clinical trial. Critical elements involved
centers; however, a specialized cell-processing laboratory and specially in the stages of cell therapy product development are outlined in
trained laboratory staff do not resolve all the problems associated with Fig. 96.1.
scaling a new procedure for a clinical trial. In some cases, equivalent
reagents and processes suitable for use in large-scale clinical trials are
not available. OVERVIEW OF THE CELL THERAPY PRODUCT
In addition to the technical challenges of producing clinical grade
cells in larger quantities, all of this work involving more than mini- Novel cell-based therapy offers great potential for treating a number
mally manipulated cell therapy products must be performed under of currently untreatable disorders and diseases including immune
the Investigational New Drug (IND) process through the US Food reconstitution, tissue repair and regeneration, and metabolic support.
and Drug Administration (FDA). The use of any cell product that is Cell-based therapies can be derived from a variety of human autolo-
more than minimally manipulated and is for a nonhomologous gous, allogeneic, or xenogeneic tissue sources such as blood, bone
indication in humans requires an IND, and even if the cellular marrow, adipose, umbilical cord blood, fetal, embryonic stem cell
therapy has been approved, a new IND may be needed if the agent lines, and induced pluripotent cells. Cellular engineering techniques
is being tested in new populations or a situation where the risks to such as selection, depletion, expansion, and genetic modification can
the patient are unknown (Table 96.1). An IND-enabling pre-clinical be applied to alter or modify a cell to achieve a desired therapeutic
program is geared toward generating and collecting critical safety/ effect. With these novel cell therapies, however, come development,
toxicology/pharmacology data required to allow first-in-human manufacturing, characterization, and testing challenges in consis-
studies. Appropriately designed pre-clinical studies are essential to the tently generating a safe and effective cell therapy product.
successful development and characterization of clinical scale manu-
facturing processes that will enable the filing of a well-supported IND
with the FDA for a clinical trial. After IND filing, the FDA will Challenges for Cell Therapy Product and
review the procedures in place for the procurement, storage, and Manufacturing Development
processing of the cells, as well as the proposed clinical trial design. A
clinical study that is not likely to yield interpretable results is consid- Current good manufacturing practices (cGMPs) govern manufactur-
ered an unethical study because it places participants at risk without ing processes to ensure consistent manufacture of safe, pure, and
1
the prospect of either direct or generalizable benefit. potent products. Current good tissue practices (cGTPs) govern the
As the field of cellular therapy moved beyond transfusion of methods used in, and the facilities used for, the manufacture of
blood components and bone marrow transplantation, it became human cells, tissues, and cellular and tissue-based products (HCT/
apparent that the processing and preparation of the cellular product Ps). cGTPs focus on the prevention of the introduction, transmission,
was becoming a science unto itself. The isolation and identification and spread of communicable diseases or other adverse events while
of the desired cell population could take months, and the optimi- preserving product function and integrity. 2
zation of this process could take years. This did not include the
development and validation of potency assays. All of this work is
expensive, labor intensive, and requires staff qualified to perform Biological Variability
at the highest technical level. Even though these tasks are vital to
the production process, they are not hypothesis driven, so this type Living biological products present unique challenges. With cell-based
of work does not meet the requirements for National Institutes of therapy there is inherent patient-to-patient biological variability and
Health (NIH) research project grants. One of the review criteria cellular heterogeneity. Cell therapy products are derived from tissue
for NIH grant applications and contract proposals is innovation. sources that contain multiple cell types. In addition to known “active
Work required to develop and validate scale-up procedures and components,” there are known and unknown cell subpopulations
potency assays is not considered innovative and therefore is not that may be considered “contaminants” or “inactive components,” or
eligible for discovery research that is typically funded through NIH could be critical to the biologic function of the product. Viability
grants. Many investigators perform this translational work by piecing alone is a poor marker of cell function. Evolving characterization and

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