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Dendritophages<br />
Therapeutic cancer vaccines<br />
Summary<br />
The patient’s blood monocytes are transformed into eff ector<br />
monocyte-derived dendritic cells (DC) (dendritophages),<br />
which fi ght the patient’s own disease. The therapeutic cell<br />
drug comprises dendritic cells, which are loaded with cancer-specifi<br />
c antigens to activate the patient’s immune<br />
system after re-injection.<br />
This project aims to demonstrate the immune and clinical<br />
effi cacy, reproducibility and feasibility of anticancer cell vaccine<br />
by choosing the best dendritic cell vaccination strategy<br />
via adequate pre-clinical studies (DC diff erentiation and<br />
maturation, tumour antigens selection and loading, dose<br />
delivered, site and vaccination schedule). It will monitor the<br />
immune response in correlation to the clinical response after<br />
defi ning the most relevant immuno-monitoring techniques,<br />
and will demonstrate the immunological effi cacy of DC<br />
immunotherapy in prostate cancer, which will be performed<br />
after loading ex vivo dendritic cells with proteic antigen.<br />
This will require the setting up of quality control criteria and<br />
data base design for the production of the cellular product,<br />
and optimising a GMP process. We will start a clinical trial to<br />
evaluate the cell drug on progressing prostate cancer<br />
patients.<br />
Problem<br />
• Select the most eff ective DC preparation.<br />
• Develop GMP process.<br />
• Show immunogenicity and safety in carcinoma patients.<br />
Aim<br />
Keywords | Vaccine dendritic cells |<br />
The fi nal goal of anticancer therapeutic vaccines is to prevent<br />
metastasis development as well as tumour progression and to<br />
provide long-term protection.<br />
Previous and ongoing clinical studies have shown that there<br />
are no side eff ects associated with this type of dendritic autologous<br />
cellular drugs, and that immune and clinical responses<br />
can be achieved in some patients resistant to conventional<br />
therapies. The preclinical data generated on dendritic cells, as<br />
well as pilot clinical trial data, have driven the dendritic cell<br />
immunotherapy technology to reach adequate maturity to<br />
enter real standardisation and demonstration of immune effi -<br />
cacy. A phase I study of anti-tumour immunisation of patients<br />
with melanoma stage III or IV has been initiated during a previous<br />
EU Project coordinated by the same team, with<br />
autologous DCs (BIO-CT97- 2216, CELLULAR VACCINES,<br />
1997). Nine patients had completed the treatment which consisted<br />
of four series of injections of dendritic cells pulsed with<br />
tumour cell lysate and dendritic cells pulsed with HbsAg and<br />
TetanusT.<br />
Expected results<br />
Results showed excellent safety and the presence of<br />
immune responses after vaccination, as well as signs of clinical<br />
responses in some of the patients. It is to be noted that<br />
one patient showed complete regression of metastases<br />
four months after the last vaccination, and another one<br />
showed stabilisation of the disease.<br />
We have compared several technologies for obtaining DCs<br />
and selected the most appropriate for GMP development.<br />
The initial clinical results have been confi rmed on a randomised<br />
clinical study conducted in malignant melanoma<br />
stage IV patients immunised with dendritic cells pulsed ex<br />
vivo with three melanoma cell lines lysates. The results of<br />
this study are based on 49 treated patients, with 15 patients<br />
having completed the cycle of six DC vaccinations, the others<br />
progressing due to late stage disease. No severe adverse<br />
event has been related to the therapeutic protocol nor to<br />
the DC product; the most frequent minor side eff ects were<br />
injection site reactions. Fourteen patients out of 49 initiated<br />
T-cell immune response against the antigens presented and<br />
ten patients had disease stabilisation; most of these immune<br />
responses and stabilisations were in the group of patients<br />
having received six vaccinations.<br />
Studies are ongoing in colorectal and prostate cancer.<br />
Potential applications<br />
Vaccine therapy of metastatic carcinoma.<br />
186 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME