Genes that encode diverse types of immunostimulatory molecules can enhance antitumor immunity when introduced into tumor cells, but this strategy rarely leads to rejection of preexisting tumors. Lymphotactin, a recently discovered chemokine, induced T-cell migration in vitro in the absence of any chemotactic effects on monocytes for granulocytes. Thus, combined delivery of lymphotactin and a cytokine such as IL2, to the vicinity of an antigen-expressing tumor cell, could be expected to accelerate and potentiate the antitumor response over that elicited by either agent alone. This prediction has been substantiated in the applicant's laboratory in a murine model (Dilloo et al. Nature Medicine, in press) leading to the current proposal to investigate lymphotactin/IL2 immunomodulation in children with relapsed or refractory neuroblastoma (stage C or D). Preliminary results of a clinical gene transfer protocol at this institution indicate that neuroblastoma cells transduced with an IL2 adenovirus are safe to deliver to children, will elicit both local and systemic antitumor responses, and may induce objective clinical responses. The present application attempts to build on this experience by testing the safety and potential immunogenicity of neuroblastoma cells transduced with lymphotactin, using the same adenoviral vector that was so effective in studies with IL2 (Aim 1). Once the optimal therapeutic concentration of IL2-secreting cells is determined, these neuroblasts will be injected (at a fixed dose) with escalating doses of lymphotactin-secreting cells to patients with drug-resistant disease (aim 2). Comparison of local and systemic antitumor immune responses with those elicited by either agent alone will reveal whether the lymphotactin/IL2 combination has significant immunostimulatory advantages in vivo. The results obtained with neuroblastoma cells should be generally applicable with other human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075014-05
Application #
6173050
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Wu, Roy S
Project Start
1997-09-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
2000
Total Cost
$250,573
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Russell, Heidi V; Strother, Douglas; Mei, Zhuyong et al. (2007) Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J Immunother 30:227-33
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