Overview of Cellular Therapy

Donors

Autologous donors provide their own cells. Autologous cells are readily available, do not cause immunologic complications such as graft-versus-host disease (GVHD) or graft rejection and transmission of infectious agents is not relevant. However, autologous cells may contain tumor or other abnormal cells and do not provide tumor-suppressing immunologic effects (graft-versus-tumor effects, GVT).

Syngeneic donor cells are genetically identical to those of the recipient, i.e., from an identical twin, and therefore immunologic complications such as rejection, hemolysis, or GVHD should not occur. However, immunologic effects that help to eradicate malignancy and prevent tumor relapse (GVT) are also absent. Transmission of infectious agents from donor to recipient can occur.

Allogeneic donors, either related or unrelated to the recipient, are genetically distinct from the recipient. Depending on cell type and planned use of cells, it may be necessary for the donor and the recipient to be human leukocyte antigen (HLA) matched to prevent immunologic complications such as GVHD and/or graft rejection. HLA-matched donor availability may be limited. Allogeneic cells may provide immunologic effects such as GVT. Transmission of infectious agents from donor to recipient can occur.

Xenogeneic cells or tissues are obtained from nonhuman animals and are immunologically distinct from human cells; therefore, graft rejection is a major concern. Tissue culture media used to produce cellular therapy products often contain xenogeneic material such as fetal bovine serum. Animal-derived cells and reagents may be contaminated with potentially infectious agents that cannot be detected by currently available assays, for example, prions that cause bovine spongiform encephalopathy.

Donor eligibility must be determined to prevent the spread of communicable diseases. Donors are tested for relevant infectious diseases for which licensed tests are available and outlined in the 21 CFR 1271, including HIV types 0, 1, and 2, hepatitis B and C viruses, human T-cell lymphoproliferative viruses I and II, syphilis, and cytomegalovirus (CMV). Testing for other relevant diseases, which are also licensed, include West Nile virus and Trypanosoma cruzi . Physical examination and review of health history and medical records evaluate risk factors and symptoms of communicable diseases, including those for which no licensed tests are available, such as Zika virus (one platform FDA approved), Babesia microti , and human transmissible spongiform encephalopathy.

Sources of Cells

When selecting a cell type for the development of a cellular therapy, the goals and purpose of the therapy must be considered. The starting cells should be readily available in sufficient quantities to provide the desired effects. Cellular therapies have been developed using either stem cells or adult tissue-specific differentiated cells ( Table 83.1 ). Stem cells are undifferentiated cells that are capable of unlimited self-renewal and under the appropriate conditions can be induced to differentiate into specific cell type(s). Stem cells are most useful for repair or repopulation of damaged tissues and can be derived from embryonic or adult tissues. The dogma surrounding the use of adult stem cells is that adult stem cells have limited differentiation capacity, usually restricted to the tissue from which they are derived. However, this has been blurred by reports of bone marrow (BM) stem cells being used to repair other tissues, such as in cardiac repair. Adult tissue-specific differentiated cells may be used when the function of a specific differentiated cell type is desired. Homologous cells perform the same basic function in the recipient as in the donor (e.g., hematopoietic progenitor cell [HPC] product for BM reconstitution) while a nonhomologous product performs a different function in the recipient than the donor (e.g., HPC product used to enhance cardiac muscle repair). To prevent immune reactions in the recipient and/or graft rejection, the immunogenicity of allogeneic cells must be considered. Large-scale production of “off the shelf” cellular therapies that are available for distribution to patients may require the development of banks of cells with multiple HLA types, or the production of cells that are universally accepted by recipients with varying HLA types.