Induced pluripotent stem cells (iPSCs) are opening new avenues to expand the number of patients who can benefit from cell therapies. Currently, most advanced cell therapies are autologous. Cells are drawn from a patient, manipulated in some way to create a therapeutic subpopulation of cells, and then returned to the same patient as treatment. All six of the current FDA-approved T cell immunotherapies are autologous (1). Autologous therapies rely on complex logistics that are expensive and time sensitive. Cell therapies that follow an allogeneic strategy using donor-sourced cells may be restricted to cell transplantations from close-matched donors and accompanied by a regime of immunosuppressants to help minimize rejection of the therapeutic cells. Donor matching for allogeneic therapies is difficult, and immunosuppression has myriad side effects.
The use of iPSCs as starting material can help reduce the logistical and immunosuppression challenges facing cell therapies and iPSC lines can be established as off-the-shelf stocks to treat a broad patient population. One method to address immunogenicity is to use precise gene editing techniques to alter iPSCs. Editing either renders cells invisible to a patient’s immune system or ‘personalizes’ them, essentially mimicking recognition traits of host cells. The advantages are that these adapted cells would not have to come from the patient being treated, thereby eliminating at least one arm of the logistics required for autologous therapies, and immunosuppressant therapy possibly could be reduced.
Another approach to expand the matchability of an iPSC line is to build a library of cell lines derived from human leukocyte antigen (HLA)-homozygous donors. The HLA system is a large group of proteins encoded by the major histocompatibility complex in humans. They are relevant for tissue recognition by the immune system and are, therefore, a main contributor to transplant rejection. Given that HLA genes are highly polymorphic, most people have different HLA genes on their paternal and maternal chromosomes. The thousands of HLA variants in the population complicate cell donor-recipient matching and often lead to immune rejection. By contrast, HLA-homozygous (HLAh) donors mitigate the immunogenicity challenges. Carrying a single HLA haplotype, HLAh cell lines genetically match a statistically larger portion of the population. By generating HLAh iPSC lines representing the most frequent HLA haplotypes in a population, one can establish immune compatibility for a large fraction of that population without the need to genetically manipulate cells.
One of Catalent’s programs for addressing the immunogenicity challenge is the creation of iPSC lines from HLAh donors. The CD34+ cells are generated from cord blood and have a low mutation load with intact DNA. The origin of this material helps ensure low genetic mutations when blood cells are used to produce iPSCs. Catalent uses cutting-edge iPSC technology to reprogram clinically approved cord blood collections into iPSC lines resulting in a superior quality HLAh GMP-grade library.
Catalent’s iPSC banks are continually expanding to meet the safety and donor criteria set forth by regulatory agencies. Where necessary, our quality testing and tissue sourcing guidelines are reviewed and revised to stay current with the evolving regulatory landscape for iPSC banking. The donor tissue used carries informed consent for commercial use for therapeutic applications. End-to-end GMP processes are implemented from banking to manufacturing to meet strict quality standards as customer programs move from the preclinical stage into the clinic.
Catalent’s iPSC lines are designed to accelerate the path to clinic, creating a renewable resource for GMP-compliant cell therapies while reducing barriers to entry for companies developing new therapies. The iPSC lines can support both HLAh and gene editing strategies for reducing immunogenicity. Expanding the recipient compatibility of well-characterized cell lines, produced under highly standardized processes and relying less on complex logistical infrastructures results in cost and time savings that can foster reimbursement willingness and bring these life-saving therapies to a much larger population. For more information, visit https://biologics.catalent.com/cell-therapy/ipscs/.
Reference:
(1) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products