Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12.
Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials.
The Scripps Research Institute, Department of Immunology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
H N
HN
Lode
R
R
Xiang
S R
SR
Duncan
A N
AN
Theofilopoulos
S D
SD
Gillies
R A
RA
Reisfeld
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D004195:Disease Models, Animal; D005732:Gangliosides / Q000276:immunology; D015316:Genetic Therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014611:Vaccination
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D005732:Gangliosides; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; C019403:ganglioside, GD2