Adenoviral Vectors in Hematology: Purging, Stem Cell Gene Transfer, or Both

To the Editor:

In a recent report, Watanabe et al1 reported that adenoviral vectors can mediate gene transfer to CD34⁺ hematopoietic stem cells. A subsequent letter to the editor suggested alternate interpretations for some of the data.2 These communications reflect a broader debate regarding how best to apply adenoviral vector technology to hematology. There is much at stake in this debate.

On the one hand, data support the potential efficacy of adenoviral vectors for purging of contaminating malignant cells from hematopoietic autographs.3-5 On the other hand, data suggest that, under some conditions, hematopoietic stem cells can be transduced using adenoviral vectors.1 6 To understand the current state of this area, it is important to realize that no two groups have used identical experimental approaches, accounting in part for the different conclusions.

Important experimental variables include multiplicity of infection (moi), length of time of viral incubation, medium used for viral incubation, the viral construct (including promotor and gene), and the source of hematopoietic stem cells. In our review of the conditions used by different groups (Table 1), we were struck by the variability in experimental protocols being used by different groups. However, one clear observation was the correlation between stem cell gene transfer and long periods of incubation with virus. Apparently, purging can be achieved with short incubation times that may limit gene transfer to stem cells.

In an effort to maximize the therapeutic index in purging, vectors can be designed with tissue-specific and tumor-specific promotors that are nonfunctional in normal hematopoietic cells or fiber proteins that allow more selective binding to cancer cells. To improve vectors for stem cell gene transfer, recent vectors have been developed that have a deletion of the majority of the adenoviral genome. These and other developments will undoubtedly improve the utility of adenoviral vectors.

Thus, it is our thesis that the data support the use of adenoviral vectors for both purging and stem cell gene transfer, and either goal will be achievable by selecting appropriate vectors and experimental conditions.