Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens. Comparison between IL-12 and IL-2 gene-transduced tumor cell vaccines.
We have compared the therapeutic activity and characterized the antitumor response induced by IL-12 and IL-2 gene-transduced tumor cell vaccines. Mice bearing lung metastases of the BALB/c colon carcinoma C51 were treated with syngenic, histologically related, and antigenically cross-reacting irradiated IL-12 (C26/IL12) or IL-2 (C26/IL2) gene-transduced C26 tumor cells given s.c. Vaccination with C26/IL12 cells cured 40% of mice, while vaccination with C26/IL2 cells reduced the number of metastatic nodules without affecting survival. Despite this difference, similar antitumor CTL activation was shown in mice treated with C26/IL12 or C26/IL2 cells. The lytic pattern of CTL was shown to be directed to tumor-associated Ags (TAA) shared between the colon carcinomas C51, C26, and CC36 as well as with other syngenic tumors. Both treatments induced anti-TAA Abs, but only sera from mice treated with C26/IL12 contained Ab that lysed tumor cells in a C-dependent cytotoxicity assay. Early infiltration of activated T cells was found in the lungs of mice vaccinated with C26/IL12. CD4+ lymphocytes purified from the lymph nodes draining the vaccination site or from the spleen showed a higher production of IFN-gamma in response to anti-CD3 mAb in C26/IL12 vaccinated mice, while a higher production of IL-4 was shown in mice vaccinated with C26/IL2 cells. These results indicate that the better therapeutic efficacy of vaccination with C26/IL12 is associated with the production of C-binding Ab, an early infiltration of the metastatic lungs by activated T lymphocytes and a predominant systemic activation of Th1 more than Th2 cells.
Rodolfo
M
M
Gene Therapy Program, Division of Experimental Oncology D, National Tumor Institute, Milan, Italy.
Zilocchi
C
C
Melani
C
C
Cappetti
B
B
Arioli
I
I
Parmiani
G
G
Colombo
M P
MP
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003110:Colonic Neoplasms / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D005260:Female; D007167:Immunotherapy; D018664:Interleukin-12 / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000556:secondary; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007376:Interleukin-2; D018664:Interleukin-12