Peptide Vaccination Associated With Tumoral Immunomodulation in Patients With Advanced Metastatic Melanoma
Status:
Terminated
Trial end date:
2012-08-01
Target enrollment:
Participant gender:
Summary
Human cancers express tumor antigens that can be targeted by cytolytic T lymphocytes (CTL).
These antigens consist of a small peptide, derived from endogenous proteins, that is
presented at the cancer cell's surface by an HLA class I molecule. Such antigenic peptides,
including MAGE-3.A1 and NA17.A2, have been tested in experimental therapeutic vaccines to
elicit CTL responses in cancer patients, mainly with metastatic melanoma. Up to now, only
rare tumor responses have been observed.
Tumor resistance to CTL killing is the most likely explanation for the poor effectiveness of
cancer vaccines. This resistance is probably acquired by the tumor during its development and
selected by its repetitive challenge with spontaneous anti-tumoral immune responses. The
precise molecular mechanisms of tumor resistance remain unknown. The observation that
tumor-infiltrating lymphocytes (TIL) purified from melanoma metastases can recognize and kill
autologous tumor cells in vitro, whilst they seem unable to control tumor growth in vivo,
suggests that this resistance is hosted by the tumor environment, rather than being the
result of a generalized immune suppression.
The investigators have developed a murine model of cutaneous graft rejection that mimics the
situation in melanoma. Female CBA mice do not reject syngeneic male skin grafts, even though
they mount a spontaneous CTL response against H-Y, a male specific minor histocompatibility
antigen, following grafting. The investigators have tested various experimental procedures
aimed at inducing effective graft rejection in these mice. This was obtained with a
combination of IFN-α, IL-2, GM-CSF, each administered separately under the skin graft,
associated with topical applications of imiquimod. All these agents are available as
registered drugs. Based on this murine model of cutaneous allograft rejection, the
investigators postulate that local immunomodulation with this combination can trigger an
effective tumor rejection process, and induce a more efficient and long-lasting anti-tumoral
immune response following peptide vaccination.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Cliniques universitaires Saint-Luc- Université Catholique de Louvain