Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma.
BACKGROUND
Interferon-beta (IFN-beta) has potent antitumor activity; however, systemic toxicity has limited its clinical use. We investigated the potential of targeted delivery using tumor-tropic neural progenitor cells (NPCs) transduced to express human IFN-beta (hIFN-beta).


METHODS
Disseminated neuroblastoma was established in SCID mice by tail vein injection of tumor cells. Fourteen days after tumor cell inoculation, systemic disease was confirmed with bioluminescence imaging (BLI). Mice were then treated by intravenous injection of human F3.C1 NPCs that had been transduced with a replication deficient adenovirus to overexpress hIFN-beta (F3-IFN-beta). Two injections were given: the first at 14 days and the second at 28 days following tumor cell injection. Control mice received NPCs transduced with empty vector adenovirus at the same time points. Progression of disease was monitored using BLI. At sacrifice, organ weights and histology further evaluated tumor burden.


RESULTS
After initiation of therapy, BLI demonstrated a significant decrease in the rate of disease progression in mice receiving F3-IFN-beta. At necropsy, control mice had bulky tumor replacing the liver and kidneys, as well as extensive retroperitoneal and mediastinal adenopathy. Impressively, these sites within mice receiving F3-IFN-beta therapy appeared grossly normal with the exception of small nodules within the kidneys of some of the F3-IFN-beta-treated mice. The accumulation of F3.C1 cells within sites of tumor growth was confirmed by fluorescence imaging. Importantly, systemic levels of hIFN-beta in the treated mice remained below detectable levels.


CONCLUSIONS
These data indicate that in this model of disseminated neuroblastoma, the tumor-tropic property of F3.C1 NPCs was exploited to target delivery of IFN-beta to disseminated tissue foci, resulting in significant tumor growth delay. The described novel approach for effective IFN-beta therapy may circumvent limitations associated with the systemic toxicity of IFN-beta.
Dickson
Paxton V
PV
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hamner
John B
JB
Burger
Rebecca A
RA
Garcia
Elizabeth
E
Ouma
Annastasia A
AA
Kim
Seung U
SU
Ng
Catherine Y C
CY
Gray
John T
JT
Aboody
Karen S
KS
Danks
Mary K
MK
Davidoff
Andrew M
AM
D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D018450:Disease Progression; D016503:Drug Delivery Systems / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007275:Injections, Intravenous; D016899:Interferon-beta / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma; D013234:Stem Cells / Q000502:physiology*; D014161:Transduction, Genetic; D047368:Tumor Burden
D000970:Antineoplastic Agents; D016899:Interferon-beta