Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity.

Immunotherapy of acute myeloid leukemia (AML) has been challenging because the lack of tumor-specific antigens results in "on-target, off-tumor" toxicity. To unlock the full potential of AML therapies, we used CRISPR-Cas9 to genetically ablate the myeloid protein CD33 from healthy donor hematopoietic stem and progenitor cells (HSPCs), creating tremtelectogene empogeditemcel (trem-cel). Trem-cel is a HSPC transplant product designed to provide a reconstituted hematopoietic compartment that is resistant to anti-CD33 drug cytotoxicity. Here, we describe preclinical studies and process development of clinical-scale manufacturing of trem-cel. Preclinical data showed proof-of-concept with loss of CD33 surface protein and no impact on myeloid cell differentiation or function. At clinical scale, trem-cel could be manufactured reproducibly, routinely achieving >70% CD33 editing with no effect on cell viability, differentiation, and function. Trem-cel pharmacology studies using mouse xenograft models showed long-term engraftment, multilineage differentiation, and persistence of gene editing. Toxicology assessment revealed no adverse findings, and no significant or reproducible off-target editing events. Importantly, CD33-knockout myeloid cells were resistant to the CD33-targeted agent gemtuzumab ozogamicin in vitro and in viv o. These studies supported the initiation of the first-in-human, multicenter clinical trial evaluating the safety and efficacy of trem-cel in patients with AML (NCT04849910).
Competing Interests: J.R.L., M.I.L., H.G.G., A.H., S.W., M.B.J., J.E., G.A., J.X.F., J.L., K.S., Y.K., H.M., J.S., J.H., and T.C. are salaried employees of Vor Biopharma Inc. and hold equity interests in the company. J.R.L., M.L., M.B.J., J.E., J.L., J.S., and T.C. are inventors on patent applications assigned to Vor Biopharma Inc. S.M. is a coinventor on patent applications related to this work, which were filed by Columbia University and are licensed to Vor Biopharma Inc. S.M. has equity ownership and is on the Scientific Advisory Board of Vor Biopharma Inc.
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