Immunotherapy of murine hepatocellular carcinoma by alpha-fetoprotein DNA vaccination combined with adenovirus-mediated chemokine and cytokine expression.
Most hepatocellular carcinomas (HCCs) express oncofetal alpha-fetoprotein (AFP). We and others have demonstrated efficient tumor control mediated by cellular immune responses in mice bearing subcutaneous tumors derived from the AFP-expressing murine HCC cell line Hepa 1-6 by DNA vaccination against AFP. In the present study, we examined AFP DNA vaccination in the AFP-expressing primary murine HCC model BW7756. In this model AFP DNA vaccination resulted in only minimal lymphocytic infiltration and failed to control tumor growth. To augment the AFP-specific cellular immune response, intratumoral expression of chemokine IP-10 (interferon-inducible protein-10) and the proinflammatory cytokine interleukin (IL)-12 by adenoviral vectors (AdmIL-12 and AdmIP-10) was analyzed. Intratumoral injection of AdmIL-12 and AdmIP-10 resulted in transient tumor regressions, without prolongation of animal survival. By contrast, AFP DNA vaccination followed by intratumoral injection of AdmIL-12 and AdmIP-10 resulted in tumor regression in all animals and in prolongation of animal survival; in 25% of animals the tumors became undetectable. This study demonstrates for the first time that activation of effector cells against a tumor antigen induced by the combination of DNA vaccination and intratumoral chemokine and cytokine expression is superior to the respective treatment strategies alone. This effect may be mediated by attraction of activated effector cells to the tumor tissue.
Department of Medicine II, University Hospital Freiburg, 79106 Freiburg, Germany.
María Matilde Bartolomé
MM
Rodríguez
Seung-Min
SM
Ryu
Cheng
C
Qian
Michael
M
Geissler
Christian
C
Grimm
Jesús
J
Prieto
Hubert E
HE
Blum
Leonhard
L
Mohr
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D051379:Mice; D016896:Treatment Outcome; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics* / Q000378:metabolism
D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D019444:Vaccines, DNA; D000509:alpha-Fetoproteins; D018664:Interleukin-12