of the Max - MDC

Molecular Immunotherapy
Antonio Pezzutto
T
he goal of our work is the implementation of basic research into preclinical models and clinical trials. A first
strategy is based on the induction of cancer immune responses by vaccination. A pilot clinical study with a genemodified
tumor cell vaccine for treatment of advanced renal cancer has been concluded, a follow-up study with
simultaneous administration of an antibody against regulatory T-cells is in preparation. A phase I Dendritic cell
vaccination study in chronic myeloid leukemia has also been successfully concluded, leading to a multicenter clinical
trial in patients with persisting minimal residual disease after imatinib treatment, due to start in 2008. These
clinical studies are flanked by preclinical animal models of DNA vaccination whereby vectors coding for cytokines or
the chemokines CCL19 and CCL21 lead to an improved stimulation of antigen presenting cells / T-cells. With the aim
of improving immunity against the adenocarcinoma-associated EpCAM antigen we have generated mutated, heteroclitic
peptides of EpCAM that display a high immunogenicty. These peptides are being evaluated for clinical use. A
further strategy is T-cell receptor gene transfer for adoptive therapy of Lymphomas. Transgenic T-cells that use the
T-cell receptors of EBV-specific CD8 and CD4 T-cell clones are being developed for adoptive immunotherapy of EBV
associated diseases such as Hodgkin’s Disease and Post-Transplant Lymphoproliferative Disorders (PTLDs). Epitopes
of the B-cell antigens CD19 and CD20 are also being evaluated as targets for TCR transgenic T-cells.
Clinical vaccination studies using dendritic cells
or tumor cells for the induction of tumor specific
immune responses
Jörg Westermann and J. Kopp, in cooperation with T.
Blankenstein and W. Uckert.
Having shown that T-cells from chronic myeloid leukemia
(CML) patients specifically recognize the bcr-abl fusion peptide
characteristic of the disease, we have performed a clinical
vaccination study using in vitro-generated, bcr-abl positive
dendritic cells (DC). A reduction in the tumor load has
been seen in 50% of the patients, a follow-up multicenter
national trial is due to start in 2008 in patients who did not
achieved complete remission upon treatment with the tyrosine-kinase
inhibitor imatinib. In renal carcinoma, a genemodified
tumor cell vaccine that expresses co-stimulatory
molecules and secretes Interleukin-7 has been generated in
cooperation with Th. Blankenstein and W. Uckert. After successful
conclusion of a pilot study, a follow-up trial in conjunction
with antibodies that increase T-cell stimulation by
reducing regulatory T-cells is being planned. GMP quality DC
and gene-modified tumor cells are generated in the GMP
laboratory of the Robert Rössle Cancer Clinic.
DNA Vaccination: preclinical models
Jörg Westermann, Tam Nguyeng Hoay in cooperation with
U. Höpken and M. Lipp
DNA vaccination offers several advantages over the use of
peptides as vaccines (DNA covers several MHC-I and MHC-II
epitopes, directly targets the endogenous presentation
pathway and contains immunostimulatory CpG sequences).
In cooperation with the group of M. Lipp (Molecular Tumor
Genetics) we have explored the possibility of recruiting
immune cells at the vaccine site by inserting DNA sequences
coding for the chemokines CCL19 and CCL21 as possible
adjuvants. Using beta-galactosidase as a surrogate tumor
antigen we have found that coexpression of CCL19 with
beta-gal resulted in enhancement of a Th1-polarized
immune response with substantial improvement of the protective
effect of the vaccine. Immunohistochemistry
revealed an increased CD8+ T-cell infiltration in the tumor
tissue. These encouraging results have been extended to a
preclinical model using the human breast-cancer associated
antigen Her-2 as a target antigen, with the aim of developing
a vaccine for breast cancer patients.
Immunity against EpCam (Epithelial Cell
adhesion molecule)
Oliver Schmetzer in cooperation with P. Schlag
The Epithelial Adhesion Molecule, EpCam, is overexpressed
in human adenocarcinomas. Some patients with colorectal
cancer have circulating CD4 positive T-cells that recognize
MHC-II binding EpCam peptides. Heteroclitic peptides with
minor aminoacid substitutions appear able to induce a much
stronger T-cell stimulation by upregulating the TCR. A splice
variant of CD3 delta coding for a 45-mer polypeptide
appears to mediate the increase of the T-cell receptor densi-
Cancer Research 133