Improved safety of induced pluripotent stem cell-derived antigen-presenting cell-based cancer immunotherapy

Abstract

The tumorigenicity and toxicity of induced pluripotent stem cells (iPSCs) and their derivatives are major safety concerns in their clinical application. Recently, we developed granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing proliferating myeloid cells (GM-pMCs) from mouse iPSCs as a source of unlimited antigen-presenting cells for use in cancer immunotherapy. As GM-pMCs are generated by introducing c-Myc and Csf2 into iPSC-derived MCs and are dependent on self-produced GM-CSF for proliferation, methods to control their proliferation after administration should be introduced to improve safety. In this study, we compared the efficacy of two promising suicide gene systems, herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) and inducible caspase-9 (iCasp9)/AP1903, for safeguarding GM-pMCs in cancer immunotherapy. The expression of HSV-TK or iCasp9 did not impair the fundamental properties of GM-pMCs. Both of these suicide gene-expressing cells selectively underwent apoptosis after treatment with the corresponding apoptosis-inducing drug, and they were promptly eliminated in vivo . iCasp9/AP1903 induced apoptosis more efficiently than HSV-TK/GCV. Furthermore, high concentrations of GCV were toxic to cells not expressing HSV-TK, whereas AP1903 was bioinert. These results suggest that iCasp9/AP1903 is superior to HSV-TK/GCV in terms of both safety and efficacy when controlling the fate of GM-pMCs after priming antitumor immunity.

Future prospects for cancer immunotherapy using induced pluripotent stem cell‐derived dendritic cells or macrophages

“…In the HSV‐TK/ganciclovir method, the iPSC‐pMCs are transfected with a gene that makes it susceptible to ganciclovir, and ganciclovir can be administered to remove the iPSC‐pMCs from the body when needed. Also, the method of introducing the iCASP9 gene and then administering AP1903 when necessary is safer and has superior removal ability 45 . We believe that iPS‐MPs and iPS‐DCs could be clinically applicable if equipped with such a safety system and using allo‐iPSCs from healthy donors.…”

“…Also, the method of introducing the iCASP9 gene and then administering AP1903 when necessary is safer and has superior removal ability. 45 We believe that iPS-MPs and iPS-DCs could be clinically applicable if equipped with such a safety system and using allo-iPSCs from healthy donors.…”

“…Mashima et al 45 investigated the use of HSV-TK/ganciclovir and iCASP9/AP1903 as safeguard systems in a mouse model. 45 In the HSV-TK/ganciclovir method, the iPSC-pMCs are transfected with a gene that makes it susceptible to ganciclovir, and ganciclovir can be administered to remove the iPSC-pMCs from the body when needed. Also, the method of introducing the iCASP9 gene and then administering AP1903 when necessary is safer and has superior removal ability.…”

“…However, we believe that more stringent safeguards need to be implemented when administering iPS‐MPs or iPS‐DCs to humans. Mashima et al 45 investigated the use of HSV‐TK/ganciclovir and iCASP9 /AP1903 as safeguard systems in a mouse model 45 . In the HSV‐TK/ganciclovir method, the iPSC‐pMCs are transfected with a gene that makes it susceptible to ganciclovir, and ganciclovir can be administered to remove the iPSC‐pMCs from the body when needed.…”

Cancer cells as a new source of induced pluripotent stem cells

“…They used these cells in cancer immunotherapy. Therefore, cell reprogramming in cancer cells equipped with suicide genes as a safety switch introduced a less dangerous cell source of cancer cells for transplantation [ 50 ].…”