Pw. Chen et al., THERAPEUTIC ANTITUMOR RESPONSE AFTER IMMUNIZATION WITH A RECOMBINANT ADENOVIRUS ENCODING A MODEL TUMOR-ASSOCIATED ANTIGEN, The Journal of immunology, 156(1), 1996, pp. 224-231
Recombinant adenovirus (rAd), deleted of critical genes that enable vi
ral replication and replaced with genes encoding heterologous proteins
, has been shown to be a safe and effective vector in gene therapy stu
dies. To evaluate a potential role for rAd as an immunogen, we used tw
o different replication-defective type 2 rAds encoding the model Ag, b
eta-galactosidase (beta-gal). To determine whether rAd elicited the ki
nd of immune responses therapeutic in an anti-tumor setting, the beta-
gal-expressing adenocarcinoma, CT26.CL25, was used, Splenocytes from B
ALB/c mice immunized with 1 x 10(7) infectious units (iu) of rAd demon
strated anti-beta-gal activity after in vitro culture with the relevan
t L(d) beta-gal peptide. Adoptive transfer of these same splenocytes p
roduced dramatic regression of established pulmonary metastases. Howev
er, when tumor-bearing mice were treated with 1 x 10(7) iu of rAd, no
reduction in established disease was observed even when rAd was given
with exogenous IL-2. To increase the viral dose delivered to each anim
al, we used an E1/E4-deleted rAd that could be grown to much higher ti
ters. Significant reduction occurred when 10-fold more rAd (1 x 10(8)
iu) was administered. Exogenous IL-2 administration with 1 x 10(8) iu
of rAd resulted in augmentation of this anti-tumor effect. These findi
ngs demonstrate that when using a nonreplicating virus, the viral dose
is directly related to the immune response generated. These data cons
titute the first reported use of rAd in the treatment of an establishe
d experimental cancer and may have implications for the treatment of h
uman cancer.