Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

such mice could specifically lyse LLC-CEA-KSA tumor target cells in vitro in an
MHC class I antigen-restricted manner. Furthermore, this effect proved to be specific
since splenocytes isolated from mice in all control groups failed to lyse these tumor
target cells. It was quite evident from these results that the boost of IL-2 targeted to
the tumor microenvironment by the IL-2 immunocytokine was highly effective in
up-regulating several receptor ligand pairs critically important for activation of T
cells and their interaction with APCs. Importantly, the up-regulation of these activation
markers correlated completely with the increase in tumor-protective immunity
induced by the CEA-based DNA vaccine.
Taken together, these results demonstrated that breaking of peripheral T cell tolerance
toward the human CEA self-antigen by a CEA-based DNA vaccine was also
achieved in an aggressive model of Lewis lung carcinoma which lead to eradication
of s.c. tumor growth and prevented dissemination of pulmonary metastases in CEAtransgenic
mice. In this prophylactic setting, tumor-protective immunity was induced
by MHC class I antigen-restricted CTLs, a finding which correlated with the
up-regulated expression of receptor/ligand pairs critical for the activation of T lymphocytes
and DCs. Importantly, boosts with small, non-curative doses of an IL-2 immunocytokine
resulted in increased efficacy of this therapy, suggesting that combinations
of DNA vaccines with such immunocytokines may lead to improved treatments
for non-small cell lung cancer.
16.4
Prostate Carcinoma
16.4 Prostate Carcinoma
16.4.1
Suppression of Human Prostate Cancer Metastases by an IL-2 Immunocytokine
Prostate cancer, the most frequent cancer in men in the US, with an estimated
184 500 new cases, is being projected with an annual death rate of 39 000 [54]. One
of the most common immunological therapies applied to treat this malignancy is
the use of local immunotherapy with immunoregulatory cytokines, which is referred
to as cytokine gene therapy. The effectiveness of such an approach for prostate carcinoma
was established in studies involving the challenge of the Copenhagen rat with
syngeneic Dunning rat prostate carcinoma cells modified to secrete xenotypic murine
cytokines, IL-2 [55, 56], IFN-g [56] and GM-CSF [56, 57], indicating an anti-prostate
cancer immune response. The role for IL-2 in the induction of this antitumor
immune response was further supported by the finding that Dunning rat prostate
carcinoma cells, genetically modified ex vivo to express IL-2, produced a local inflammatory
response, resulting in the elimination of the injected tumor cells, even when
mixed with wild-type parental cells [55]. This gene transfer is consistent with the
paracrine nature of IL-2 working physiologically at high concentrations within a few
cell diameters from its cell of origin. We applied an alternative approach for directing
cytokines preferentially to the tumor microenvironment by a simple modus operandi,
which complies with the paracrine nature of most cytokines. This was based on our
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