Page 1742 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 97 Graft Engineering and Cell Processing 1547

the use of DCs pulsed with a tumor-associated antigen preparation FACT-JACIE International Standards for Cellular Therapy Product Collec-
and the use of the entire tumor cells as an immunogen, either tion: Processing and Administration. Foundation for Accreditation of
unmodified or transduced with immunostimulatory genes, aimed at Cellular Therapy, Omaha, NE.
eliciting a broad-based, robust immune response. NetCord-FACT International Standards for Cord Blood Collection, Process-
From the manufacturing perspective, the autologous product is ing, and Release for Administration, Omaha, NE.
much more of a challenge because a stable tumor cell line must be
isolated from each patient. This can be an extremely difficult process.
Many isolated lines do not expand well in culture, or they change FDA REGULATIONS: CGMP AND CGTP
phenotype over time. In some patients, the line cannot be generated;
other patients progress clinically before the vaccine is available and cGMP in Manufacturing, Processing, Packing, or Holding of Drugs and
are excluded from the study. As a result, the autologous approach Finished Pharmaceuticals. Code of Federal Regulations Title 21, Parts
has a relatively high “failure rate”. The allogeneic cell line approach 210 and 211.
is technically easier because a line is selected before the study and Human Cells, Tissues, and Cellular and Tissue Based Products. Code of
can be used as the generic immunogen. This line must be tested Federal Regulations Title 21, Part 1271.
extensively for infectious agents and should pass the FDA testing
criteria for Master and Working Cell Banks. Currently, testing of
this type costs $100,000–200,000 for each line. Scientifically, the FDA GUIDANCES ON CELLULAR AND GENE THERAPY
drawback is that the selected line may not adequately express the
antigen or range of antigens present on each patient’s tumor. In addi- Guidance for FDA Reviewers and Sponsors: Content and Review of Chem-
tion, the choice of immunostimulatory molecules that are expressed istry, Manufacturing, and Control (CMC) Information for Human
or enhanced by transduction of the cell line may not be those that Somatic Cell Therapy Investigational New Drug Applications (INDs).
would most effectively evoke an immune response. These products U.S. Department of Health and Human Services, Food and Drug Admin-
are relatively expensive to produce, involving not only the costs of istration, Center for Biologics Evaluation and Research, April 2008.
testing the tumor cell line, but also the expense of manufacturing Guidance for Industry: CGMP for Phase 1 Investigational Drugs. U.S.
and testing the vectors used for transduction. However, these are Department of Health and Human Services, Food and Drug Administra-
one-time costs because the same vaccine is used for all patients in the tion, Center for Biologics Evaluation and Research, July 2008.
study. Guidance for Industry: Considerations for the Design of Early-Phase Clini-
Release testing involves testing for sterility, endotoxin, and myco- cal Trials of Cellular and Gene Therapy Products. U.S. Department of
plasma, with immunophenotyping of the cells and some form of test Health and Human Services, Food and Drug Administration, Center for
demonstrating that the line has been effectively transduced (e.g., flow Biologics Evaluation and Research, June 2015.
cytometry for CD40 ligand and IL-2 production in the examples
described earlier). Because the product will be stored cryopreserved
over the course of the study and thawed for administration to each GMP FACILITIES AND PRODUCT MANUFACTURING
patient, the requirement for an ongoing stability study should be
anticipated. Cell therapy – cGMP facilities and manufacturing. Gee AP, editor: New York,
NY, 2009, Springer.
Cellular therapy: principles, methods, and regulations. Areman E, editor:
FUTURE DIRECTIONS Bethesda, MD, 2009, AABB.

The science and practice of hematopoietic transplantation has
expanded dramatically over the past 10 years and has stimulated SPECIFIC CELL TYPES: CURRENT REVIEWS
entirely new areas of medicine. New sources of stem cells have been
discovered that have expanded the availability of grafts and provided
new insights into stem cell biology. An improved understanding
of the immunology of transplantation and immune responses to OVERVIEW
malignancies has led to more sophisticated methods to manipulate
the hematopoietic graft and the immune system in the recipient June CH, Riddell SR, Schumacher TN: Adoptive cellular therapy: a race to
to produce more favorable outcomes. The ability to target T cells the finish line. Sci Transl Med 7(280):280ps7, 2015.
to residual disease by genetic modification of the cells to express Kongtim P, Lee DA, Cooper LJ, et al: Haploidentical Hematopoietic Stem
chimeric antigen receptors has produced promising results that Cell Transplantation as a Platform for Post-Transplantation Cellular
have reinvigorated prospects for effective immunotherapy of Therapy. Biol Blood Marrow Transplant 21(10):1714–1720, 2015.
cancer. Melero I, Berman DM, Aznar MA, et al: Evolving synergisitic combinations
In parallel, the regulatory situation has become clearer and we are of targeted immunotherapies to combat cancer. Nat Rev Cancer 15:457,
starting to see widespread development of commercial reagents and 2015.
devices that facilitate easier compliance when manufacturing cell Themeli M, Riviere I, Sadelain M: New cell sources for T cell engineering
products. and adoptive immunotherapy. Cell Stem Cell 16(4):357–3566, 2015.
These advances in knowledge coupled to development in technol-
ogy promise a bright future for engineering specific cell populations
to provide targeted therapies. MESENCHYMAL STROMAL CELLS
Luk F, de Witte SF, Bramer WM, et al: Efficacy of Immunotherapy with
SUGGESTED READINGS mesenchymal stem cells in man: a systematic review. Expert Rev Clin
Immunol 11:617, 2015.

PROFESSIONAL STANDARDS FOR CELLULAR THERAPY DENDRITIC CELLS

AABB Standards for Cellular Therapy Services, AABB, Bethesda, MD. Atta J, Berk E, Cintolo JA, et al: Rationale for a multimodality strategy to
FACT Common Standards for Cellular Therapy. Foundation for Accredita- enhance the efficacy of cell based cancer immunotherapy. Front Immunol
tion of Cellular Therapy, Omaha, NE. 2:271, 2015.