by Estelle LeCointe, Director of Association Française des Patients du GIST

A French phase I clinical trial, combining Gleevec + interleukin 2 (IL-2) should open in April 2007 at the Institute Gustave Roussy in Villejuif, France. The aim of this study, organized by a team of Professor Laurence Zitvogel’s, is to evaluate the efficacy as well as the toxicity of this medicinal combination in the treatment of various cancers, including GIST, but also to identify the presence and the action of Interferon Killer Dendritic Cells (IKDCs) in humans.

IKDC: Killer cells

Interferon Killer Dendritic Cells are cells of the immune system which are naturally produced by mice bodies and are located in the bone marrow, liver, spleen and ganglions. Their peculiarity lies in their capacity to kill cancer cells.

Several studies conducted on mice allowed Professor Zitvogel’s team to highlight that when IKDCs are numerous and stimulated, they spontaneously move to tumor cells and reduce them to nothingness in a few hours, thanks to the large amount of interferon gamma (IFN- γ) and complex lyse systems (perforine/ granzyme, TRAIL) they naturally secrete or secrete after stimulation.

Indeed, the studies conducted on animals have tended to demonstrate that this natural secretion of IFN-γ plays a key role in the efficacy of IKDCs. It helps other cells of the immune system called “T lymphocytes” to identify and reach tumor cells. IFN-γ also has an effect on tumor angiogenesis and therefore facilitates killing cancer cells.

A necessary stimulation

Unfortunately, IKDCs are very rare and therefore have an extremely limited natural effect on tumors. From this, Professor Zitvogel’s work involves stimulating the production of IKDCs in order to increase the secretion of IFN-γ and to boost the efficacy of the immune system.

Why combine Gleevec and IL-2?

Experiments on animals led to the hypothesis that the Gleevec + IL-2 combination would not only contribute fourfold to the production of IKDCs but would also boost their activity in the body. IL-2, which is a growth factor commonly used in immunotherapy, would facilitate the migration of IKDCs to the tumor sites, while Gleevec would stimulate the communication between dendritic cells and some lymphocytes called “NK cells” or “Natural Killer cells,” making them capable of killing cancer cells.

NK cells are naturally triggered by dendritic cells which stimulate the immune system. The activation of NK entails the secretion of IFN-γ and therefore facilitates the decline of the tumor.

In 2004, scientists observed in GIST patients that NK cell activation during Gleevec treatment was a predictive factor for an objective tumor response to Gleevec and was often correlated to a longer time to progression. About 60 percent of the Gleevec-treated GIST patients, with various exon mutation profiles, had an enhanced activation of NK cells.Immunotherapy

In vitro studies allowed Professor Zitvogel’s team to prove that Gleevec was acting on murine (mouse) or human dendritic cells and facilitated their capacity to activate NK lymphocytes. Thus:

  • Without Gleevec: 1 dendritic cell does not activate any NK cells.
  • With Gleevec: 1 dendritic cell activates 10 NK cells.

Regulating the production of Treg cells

Forty percent of the Gleevec-treated GIST patients do not have NK cell activation. This could be assigned to an unexplained overproduction of “Treg” lymphocytes (regulatory T cells) which significantly inhibits NK cell functions and therefore facilitates the progression of the disease. Treg cells are CD4+CD25+FoxP3+ lymphocytes naturally produced to fight against healthy tissue self-destruction phenomenon (autoimmune diseases).

Treg cells represent less than 5 percent of the T CD4+ circulating lymphocytes but can dramatically increase in the tumor site and its draining ganglions during tumor growth.

Apparently, there is no particular link between the overproduction of Treg cells and the KIT and/or PDGFRa mutational status.

Even though Gleevec can promote the capacity of dendritic cells to stimulate NK cells, it has absolutely no effect on Treg lymphocytes. Therefore, it’s necessary to decrease the number of Treg cells to try and contain tumors. The neutralization of Treg lymphocytes is possible with a low dose pre-treatment of “cyclophosphamide.” The action of cyclophosphamide on angiogenesis and tumor progression has been demonstrated during a non-GIST study in 2006 (Ghiringheili et al. CII, 2007).

The upcoming French “Gleevec+IL-2” clinical trial represents a real hope for many patients. If the existence of IKDCs in humans is confirmed, this would probably lead to a new approach of cancer treatment for thousands of hopeless patients whose diseases could not be controlled for a long time. Immunotherapy may be a step towards a cure.