Based on the promising preclinical studies over many years of investigation, this methodology utilizing an engineered Notch ligand for the ex vivo generation of increased numbers of CD34+ cells is under clinical investigation in several completed and currently enrolling trials.
The first clinical trial using Notch-mediated ex vivo expanded cord blood HSPC was opened by Dr. Delaney in 2006 in the myeloablative double cord blood transplant setting. Although this trial was initiated as a first in human safety trial, the clinically relevantance of using Notch ligand for ex vivo generation of increased numbers of human stem and progenitor cells was established. Furthermore, this trial was the first trial conducted demonstrating that infusion of ex vivo expanded cord blood progenitor cells, without co-infusion of T cells from the same donor, could result in a significant decrease in the time to hematopoietic recovery of both neutrophils and platelets.
Thus, with established proof of concept, the goal was further development of this T cell deplete cellular therapy as an economically and clinically feasible product with ready patient access, specifically as a pre-expanded, cryopreserved universal donor cell product. Without the need for HLA matching, qualified fresh CB units that are collected at birth, undergo immediate CD34 cell selection and ex vivo expansion and the final product cryopreserved for future on demand use. In contrast to our initial trial using at least partially HLA-matched CB units for ex vivo expansion followed by immediate infusion, patient access to this product would be dramatically enhanced as all of the expanded products banked would be potentially available for any given patient, regardless of HLA typing, race/ethnicity or location of the patient. Moreover, the ability to create an off-the-shelf universal donor expanded cell therapy is relevant for much broader applications to enhance hematopoietic recovery outside of the setting of cord blood transplant. This product could be used as a way of providing temporary myeloid engraftment, for example, in the treatment of chemotherapy-induced severe neutropenia, sepsis, or accidental radiation exposure.
Two clinical trials have been completed in adults using this cryopreserved universal donor product in the context of cord blood transplant and high dose chemotherapy, showing that it is safe and effective at reducing treatment side effects and time to engraftment. Other trials are ongoing, including a multicenter randomized trial comparing cord blood transplant with and without use of the expanded cell product and a pediatric trial using the product in the setting of intensive chemotherapy.
Advantages of the product
The cryopreserved universal donor expanded CB progenitor product has many advantages:
- It is devoid of T-cells and can thus be administered without need for HLA matching, making it a true universal donor product
- It is a “pre-expanded” cryopreserved product and can be distributed and stored for immediate on demand use
- It has potential uses in a broad variety of indications requiring temporary myeloid engraftment (for example chemotherapy-induced severe neutropenia, sepsis, or accidental radiation exposure)
Advantage of the platform
The true advantage of this ex vivo expansion platform is the ability to manipulate the Notch signaling pathway with tight regulation, thereby optimizing this methodology to direct stem and progenitor cell fate in vitro for the ex vivo generation of other cell types: NK cells, pre-T cells, platelets and red cells.
One Product: Multiple Indications
One Platform: Multiple Products