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

238 11 Hybrid Cell Vaccination for Cancer Immune Therapy
tion of the tumor, on the other hand, was shown to depend solely on tumor-specific,
self-MHC-restricted CD8 + cytotoxic T cells. Moreover, the initial liver cell carcinoma
study [162] showed that the co-stimulatory molecule B7±1 is required for effective induction
of tumor rejection in vivo. The reported efficiencies in all the animal model
experiments were very similar, and no difference was seen between B cells and DCs
as fusion partners. The inferior APC capacity of B cells might be overcome by the
vigor of the T cell responses against the allogeneic MHC molecules [161]. These initial
observations were extended in the subsequent studies that yielded further evidence
for the need to hybridize the tumor and DC, and the involvement of both
CD4 + and CD8 + T cells in the induction of the antitumor immune response [149].
This work, done with an adenocarcinoma model, also demonstrated that HCV can
prime naive T cells [149]. More recently, the same group has demonstrated antitumor
immunity in MUC1 transgenic mice from vaccination with allogeneic DCs fused
with carcinoma cells [156]. In a lymphoma as well as in a melanoma model where
protective immunity, reduced tumor incidence and prolonged survival was seen in
hybrid cell treated animals, it was demonstrated that hybrids express MHC class I
and II antigens and co-stimulatory molecules, as well as DC-specific and tumor-derived
surface markers. In these experiments it was shown that a fusion rate of 20 %
in the vaccine is sufficient for the vaccination effect and, most interestingly, adoptive
transfer of T cells led to tumor regression in recipient mice. The results of HCV attempts
in brain tumor models [155] which have provided evidence for tumor rejection
without detectable side effects are particularly interesting as patients with brain
tumors or brain metastases are often excluded from clinical studies because of fear
of serious adverse effects such as inflammation and edema which could seriously
harm the vaccinee and which would require immune-suppressive treatment.
In addition to the animal model experiment, the efficacy of tumor/DC hybrids for induction
of tumor-specific CD8 + T cell responses has also been analyzed in in vitro
test systems using human tumor cells and peripheral blood cells as sources for precursor
effector cells [157, 158, 170]. As well as demonstrating the efficacy of hybrid
cells as inducers of primary and recall tumor-specific cytotoxic T cell responses, these
in vitro test systems are also well suited to analyzing and validating hybrid cell vaccines
for new types of tumors, demonstrating the existence of specific TAAs and establishing
tumor-specific T cell lines.
11.4.3
Clinical Experience with HCV
The two initial clinical cancer immune therapy trials to test the HCV strategy were
performed with patients suffering from malignant melanoma [171, 172] or renal cell
carcinoma [151, 173]. The main objective of these initial clinical trials was to test the
toxicity, feasibility and antitumor activity of this treatment. The patients were therefore
mostly stage IV patients. The vaccines were prepared by fusion of autologous tumor
cells with allogeneic activated B cells and given intracutaneously or intradermally.
A tumor response was seen in three out of thirteen patients with renal cell carcinoma.
In patients with metastatic melanoma, two out of 16 patients showed objec-