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

324 16 Immunocytokines: Versatile Molecules for Biotherapy of Malignant Disease
crease LFA-1's affinity for ICAM-1, and stabilize the association between the antigen-specific
T cell and the APC [35, 36]. Second, the marked increase in expression
of CD28 on T cells as well as the co-stimulatory molecules B7±1 and B7±2 on DCs,
following vaccination and tumor cell challenge is particularly significant since it provides
the two signals required for activation of naive T cells. Third, a clear indication
of T cell activation in secondary lymphoid tissues was provided by marked increases
in expression of CD25, the high-affinity IL-2 receptor a chain, and CD69, an early
T cell activation antigen.
The significant elevation in the production of pro-inflammatory cytokines IFN-g and
IL-12 by T cells induced by our dual-function DNA vaccine suggested that a third signal
may act directly on T cells [40]. This ªdanger signalº, was reported to be required
for Th1 differentiation leading to clonal expansion of T cells [40]. In fact, whenever
T cell help is required to generate an effective CD8 + T cell response against a tumorself
antigen like CEA, triggering of DCs is necessary prior to their encounter with an
antigen-specific CD8 + T cell [41]. This effect is mediated by ligation of CD40 on the
surface of APCs [35] with CD40L expressed on activated CD4 + T cells. CD40LT expressed
by our DNA vaccine likely acted as a surrogate for activated CD4 + T cells,
leading to maturation of DCs as indicated by their decisive up-regulation of B7±1
and B7±2 co-stimulatory molecules [42]. Taken together our results indicated that
the orally administered dual-function DNA vaccine containing genes encoding for
both CEA and CD40LT induced a highly efficient tumor-protective immunity against
CEA self-antigen in all experimental CEA-transgenic mice. It is anticipated that this
strategy may ultimately aid in improving the efficacy of DNA vaccines for colon cancer
therapy.
16.3
Non-small Cell Lung Carcinoma
16.3.1
Boost of a CEA-based DNA Vaccine by the huKS1/4±IL-2 Immunocytokine
We asked whether a CEA-based DNA vaccine also could overcome peripheral Tcell tolerance
toward this human tumor-self antigen when expressed by highly tumorigenic
murine non-small cell lung carcinoma cells. To this end, we used Lewis lung carcinoma
cells, stably transduced with CEA and Ep-CAM/KSA (LLC-CEA-KSA), and injected
them both s.c. and i.v. into CEA-transgenic mice [43]. We were particularly interested
to assess whether this vaccine could induce a T cell-mediated, tumor-protective
immunity which was sufficiently effective to eradicate not only s.c. tumor growth, but
also prevented the dissemination of experimental pulmonary metastases. Since, as
discussed above, boosts of suboptimal doses of IL-2 specifically targeted to the tumor
microenvironment by an IL-2 immunocytokine markedly enhanced the tumor-protective
immunity induced by a DNA vaccine against colon carcinoma, we determined
whether this concept was also applicable in a highly aggressive non-small cell lung
carcinoma model and examined some of its mechanisms of action.