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 #
1R01CA075014-01
Application #
2372231
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1997-09-01
Project End
1997-12-31
Budget Start
1997-09-01
Budget End
1997-12-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Russell, Heidi V; Strother, Douglas; Mei, Zhuyong et al. (2008) A phase 1/2 study of autologous neuroblastoma tumor cells genetically modified to secrete IL-2 in patients with high-risk neuroblastoma. J Immunother 31:812-9
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
Rousseau, Raphael F; Haight, Ann E; Hirschmann-Jax, Charlotte et al. (2003) Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 101:1718-26
Dotti, Gianpietro; Savoldo, Barbara; Yotnda, Patricia et al. (2002) Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40(+) and CD40(-) plasmacytoma cells. Blood 100:200-7
Rossig, C; Bollard, C M; Nuchtern, J G et al. (2001) Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes. Int J Cancer 94:228-36
Takahashi, S; Rousseau, R F; Yotnda, P et al. (2001) Autologous antileukemic immune response induced by chronic lymphocytic leukemia B cells expressing the CD40 ligand and interleukin 2 transgenes. Hum Gene Ther 12:659-70
Takahashi, S; Yotnda, P; Rousseau, R F et al. (2001) Transgenic expression of CD40L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin's lymphoma. Cancer Gene Ther 8:378-87
Dotti, G; Savoldo, B; Takahashi, S et al. (2001) Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy. Exp Hematol 29:952-61
Roskrow, M A; Dilloo, D; Suzuki, N et al. (1999) Autoimmune disease induced by dendritic cell immunization against leukemia. Leuk Res 23:549-57