Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice.
There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 x 10(5) per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.
Westwood
J A
JA
Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Murray
W K
WK
Trivett
M
M
Shin
A
A
Neeson
P
P
MacGregor
D P
DP
Haynes
N M
NM
Trapani
J A
JA
Mayura-Guru
P
P
Fox
S
S
Peinert
S
S
Honemann
D
D
Prince
H M
HM
Ritchie
D
D
Scott
A M
AM
Smyth
F E
FE
Smyth
M J
MJ
Darcy
P K
PK
Kershaw
M H
MH
D019264:Adoptive Transfer; D000818:Animals; D002472:Cell Transformation, Viral; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007938:Leukemia / Q000821:virology; D008223:Lymphoma / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000637:transplantation / Q000821:virology*; D013995:Time; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes