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iPSC-Derived Allogeneic Cell Therapies to Be Focus of New Venture From ElevateBio, Boston Children’s

Pre-clinical data showed that EZ-T cells have increased anti-tumor activity compared with traditional iPSC-derived T-cells.

ElevateBio is partnering with George Daley, MD, PhD, and Boston Children’s Hospital with the intention of using a novel platform for developing cell therapies derived from induced pluripotent stem cells (iPSCs).1 The platform circumvents a typical issue with iPSCs generating immature blood cell types by repressing the histone methyltransferase EZH1. A peer-reviewed paper recently published in the journal Cell Stem Cell demonstrated that this repression of EZH1 allows for the production of developmentally mature T-Cells which have potential for application in cell therapy.2

Activated EZ-T cells, the iPSC-T cells derived from the repression of EZH1, enabled the generation of large amounts of memory T-cells, promoting T-cell longevity.1 Additionally, when engineered to express anti-CD19 chimeric antigen receptors (CARs), EZ-T cells were comparable to CAR-T cells derived from adult blood in terms of their cytotoxicity against CD19+ lymphoid tumor cells. Furthermore, in xenograft mouse models injected with CD19+ diffuse large B-cell lymphoma cells, these EZ-T cells were shown to have increased anti-tumor activity compared with traditional iPSC-T cells.

“CAR-T therapies have revolutionized the treatment of certain blood cancers, with complete responses in many patients undergoing this type of treatment. However, current treatment strategies involve manufacturing a customized CAR-T cell product for each individual patient, which is cumbersome and labor-intensive,” Daley, senior author of the newly published Cell Stem Cell paper, said in a statement.1 “Our science offers an approach to circumvent these hurdles by offering an entirely new way of making allogeneic immune cell therapies that could pave the way for powerful treatments for a wide range of cancers.”

However, several important limitations of the pre-clinical study were noted in the paper.2 The investigators pointed out that the EZ-T cells produced by current methods predominantly consist of CD8 cytotoxic T cells, but that a more even ratio of cytotoxic T cells and helper T cells would be preferred, as such a ratio has been associated with better therapeutic responses in previous literature. Additionally, it was noted that clinical applications of EZ-T cells will be hindered by the lack of EZH1-specific inhibitors that do not also repress EZH2 function. They suggested that non-integrating gene knockdown strategies would need to be developed to address this issue.

Despite these limitations, ElevateBio’s chairman and chief executive officer, David Hallal, is hopeful that the research could lead to the development of new therapies for patient use.

“At ElevateBio, we have been rapidly building fully integrated end-to-end cell and gene therapy enabling technologies and capabilities to enable the world’s most prolific scientific innovators and visionaries, such as Dr. Daley, to push the boundaries of the field and deliver powerful new therapeutic modalities for patients,” Hallal added to the statement.1 “This exciting new company is the first from our collaboration with Boston Children’s Hospital and is a prime example of how our integrated ecosystem – our iPSC cell lines and process development capabilities, our gene editing technology, our CAR and TCR constructs, and our scale-up manufacturing capabilities – creates the perfect foundation needed to turn these scientific breakthroughs into transformational medicines.”

REFERENCES
1. ElevateBio announces the formation of a new company with George Daley, MD, PhD, and Boston Children’s Hospital to develop iPSC-derived allogeneic immune therapies. News release. ElevateBio, LLC. August 4, 2022. https://www.elevate.bio/press-releases/elevatebio-announces-the-formation-of-a-new-company-with-george-daley-m-d-ph-d-and-boston-childrens-hospital-to-develop-ipsc-derived-allogeneic-immune-therapies 
2. Jing R, Scarfo I, Najia MA, et al. EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity. Cell Stem Cell. 2022; 29(8):1181-1196.e6. doi:10.1016/j.stem.2022.06.014