CRISPR/Cas9-mediated inactivation of CD33 in hematopoietic stem cells (HSC) may broaden the therapeutic index of CD33-directed immunotherapy for patients with AML by rendering healthy hematopoietic stem and progenitor cells (HSPC) resistant to escalating doses and/or shorter dosing intervals of the CD33-specific antibody-drug conjugate (ADC) Gemtuzumab-ozogamicin (GO).~In this proof of concept trial, we will develop a platform for genome editing of CD34+ HSC and demonstrate the feasibility, safety and efficacy of this approach for targeted therapy of AML.~Upon implementation, the platform shall be used for innovative clinical trials in diverse types of cancer. Outside of leukemias, autologous HSC could be used to ease the procedure.~Patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.~Upon HSC engraftment, patients will be treated with escalating doses of the anti-CD33 antibodydrug conjugate Gemtuzumab-Ozogamicin (GO). A conditioning regimen containing GO (d-14, d-11, d-8),Fludarabine 30 mg/m2 (d-6 to d-3) and Melphalan 140mg/m2 (d-2) is used prior to transplantation.~The clinical trial will be conducted at two trial sites in the University Hospitals in Heidelberg and Dresden.~25 patients will be assessed for eligibility and 12 patients will be allocated into the trial.
The study GALAXY33 is an open-label, prospective, nonrandomized, one arm phase I clinical trial in which patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.