Introduction 

Induced pluripotent stem cell (iPSC)-derived allogeneic cell therapies hold significant promise for treating a wide range of diseases by providing a renewable and scalable source of cells. These cells, derived from iPSCs, can be differentiated into various specialized cell types. However, a major challenge in allogeneic therapies is the risk of immune rejection. Since the cells are not from the patient's own body, the immune system can recognize them as foreign, leading to an immune response that can compromise the efficacy and safety of the therapy. To mitigate this, strategies such as "cloaking" have been developed to help allogeneic cells evade immune detection.

 
What is cloaking?

Cellistic image_Cloaking In this context, cloaking refers to the genetic modifications of cells to render them less visible or non-immunogenic to the host's immune system. By reducing the immunogenicity of iPSC-derived cells, cloaking can prevent the immune system from recognizing and attacking the transplanted cells, allowing for long-term survival and function of the therapeutic cells.

 

Why is cloaking necessary?

In the absence of cloaking, allogeneic iPSC-derived cell therapies would require long-term immunosuppressive therapy to prevent rejection. Immunosuppression, however, carries risks such as increased susceptibility to infections, cancers, and other complications, reducing the appeal of allogeneic therapies. By cloaking, the need for immunosuppressants can be eliminated or minimized, thus enhancing the safety and feasibility of these therapies. Clinical studies have demonstrated the importance of cloaking. For instance, trials using unmodified allogeneic stem cells have shown rapid rejection due to immune response, limiting the durability of the therapeutic effect. Early-stage studies involving cloaking strategies such as the generation of Human Leukocyte Antigen (HLA) Class-I and -II null cells or overexpression of immune-modulatory proteins have shown promising results in preventing rejection without the need for aggressive immunosuppression.

How are cloaking strategies applied?

CRISPR gene editing, relying on the proprietary STAR-CRISPRTM technology of Cellistic, is an effective tool for generating cloaked iPSC-derived allogeneic cell therapies by modifying the immune recognition pathways in donor cells. CRISPR can be used to disrupt genes responsible for HLA class I and II function, effectively generating HLA class I- and II-null cells and reducing the risk of rejection. By applying this approach, we used our PluseTM platform to create the Cellistic's Allo Chassis® cell lines. Through advanced CRISPR gene editing, NK inhibitory ligands can be incorporated to prevent the patient's own NK cells from eliminating the cell therapy. This precise modification improves the longevity and acceptance of transplanted cells, eliminating the need for prolonged immunosuppression. 

Conclusion

Cloaking is a vital strategy for overcoming immune rejection in iPSC-derived allogeneic cell therapies. By reducing immunogenicity through genetic modifications, cloaked cells can evade immune detection and persist in the host, offering long-term therapeutic benefits without the need for extensive immunosuppression. As cloaking technologies continue to evolve, they will play a crucial role in the clinical translation of iPSC-based therapies for a wide range of diseases.

 

Author: Suzanne Snellenberg, PhD