Update on retroviral
vector-mediated tumorigenesis
in gene transfer clinical trials
ERRATUM (modifications shown
in bold, italic)
Appendix 4.
Table 1. Comparison of X-SCID Retroviral
Vector-Mediated Gene Transfer
|
Characteristic |
Fischer [1] |
Thrasher [2] |
Weinberg* |
Malech* |
|
Cell Source |
Bone Marrow |
Bone Marrow |
Bone Marrow |
G-CSF mobilized CD34+
PBSC |
|
CD34+ Selection |
Miltenyi Biotec |
CliniMACS |
Isolex 300 I |
Isolex 300I |
|
Media |
X-Vivo-10 |
X-Vivo-10 |
X-vivo-15 |
X-Vivo 10 |
|
Serum/Other |
4% FCS |
1% HSA |
None |
1% HSA |
|
Cytokines (Source): 1. Flt-3 ligand 2. IL-3 3. TPO 4. MGDF 5. SCF 6. IL-6 |
300 ng/ml (Immunex) 60 ng/ml (Novartis) ----------- 100 ng/ml (Amgen) 300 ng/ml (Amgen) ------------ |
300 ng/ml (R&D) 20 ng/ml (R&D) 100 ng/ml (R&D) ------------ 300 ng/ml (R&D) ------------
|
300 ng/ml (Immunex) ------------ 50 ng/ml (R&D) -----------
50 ng/ml (R&D) ------------ |
50 ng/ml (R&D) 5 ng/ml (R&D) 50 ng/ml (R&D) -------------- 50 ng/ml (R&D) 25 ng/ml (R&D) |
|
Hrs Prestim. |
24 |
40 |
40 |
18 |
|
Transduction 1. Fibronectin 2. Exposures 3. Time |
Yes Three 72 hours |
Yes Three 56 hours |
Yes Three 72 hours |
Yes Four 78 hours |
|
Vector Backbone (LTR) |
MFG (MoMLV LTR) |
MFG (MoMLV LTR) |
MND (MPSV LTR) |
MFG (MoMLV LTR) |
|
Vector Envelope (Packaging Line) |
A-MuLV (Psi-CRIP) |
GaLV (PG-13) |
GaLV (PG-13) |
GaLV (PG13) |
1. Hacein-Bey-Abina, S., et al., Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine, 2002. 346(16): p. 1185-1193.
2. Gaspar, H.B., et al., Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet, 2004. 364(9452): p. 2181-7.
* Details provided with kind permission from Drs. Weinberg and Podsakoff of The Saban Research Institute of Childrens Hospital Los Angeles, and Dr. Malech of NIH/NIAID.
Table 4. Clinical Summary of ADA-SCID Trials
|
Investigator |
Previous BMT/ Conditioning |
Previous infectious or other complications |
Max Dose
transplantedADA+ cells/kg |
Longest time from
treatment |
|
Bordignon[3] |
1 of 2 subjects Busulfan conditioning |
Yes |
2.15 x 106 |
Approx 3.5 years |
|
Kohn* |
No Previous BMT No conditioning |
No |
6.67 x 106 |
3.5 years |
3. Aiuti, A., et al., Gene therapy for adenosine deaminase deficiency. Curr Opin Allergy Clin Immunol, 2003. 3(6): p. 461-6.
*Details provided with kind permission from Drs. Kohn and Podsakoff of The Saban Research Institute of Children’s Hospital Los Angeles. Conditions reflect methods used since 2001, not previously.