Immunomodulation and antiangiogenesis in cancer using metronomic chemotherapy. New therapeutic paradigm

O. Graciela Scharovsky

LIX Annual Scientific Meeting of the Argentine Society of Immunology San Miguel de Tucumán, Argentina, 19-10-2011.

The picture of the situation related to cancer treatment and the therapeutic success derived from it has significantly improved in the last half century. While the 5-year survival rate was 40% in the 60’s, in 2007 it has reached 67%. Even though many a death has been avoided, lots of people continue to die because of cancer. Such a reality permanently fuels the search for new treatments which, at present, are asked to be not only therapeutically successful but also to provide the patient a good quality of life. Following this line of thinking, and working experimentally, we began to investigate the effect of a single-low dose of cyclophosphamide (Cy) on metastasis development of a rat B-cell lymphoma. We demonstrated the antimetastatic effect of the treatment as well as its lack of toxicity. The modulation of the host immune response would be responsible for such effect, since the treatment induced a change in the cytokines profile from Th2 to Th1, an increase in lymphocyte proliferation, a decrease in Galectin-1 expression by the tumor, a decrease in circulating Tregs and also a negative regulation of IL-10 production and IL-10 receptor expression in cells with metastatic phenotype. With those results we developed a hypothetical model of the modifications produced during tumor progression and the effect on them caused by a single-low dose of Cy. Then, with the objective of obtaining a therapeutic effect on the primary tumor, we designed treatments in which we repeated the Cy low doses administering them at regular intervals, without extended rest periods. Thus, we entered in the field of metronomic chemotherapy (MCT), a therapeutic philosophy that differs from that presently accepted of the maximum tolerated dose. In the MCT treatment modality the main cell targets are the tumor endothelial cells, the modifications of which would be responsible, at least in part, for the therapeutic effect. We utilized several tumor models as lymphoma, sarcoma, and mammary adenocarcinomas and we could demonstrate the antitumor and antimetastatic effect of MCT with Cy as a monotherapy or, even better, combined with Celecoxib (Cel), a COX-2 inhibitor, increasing the survival of tumor-bearing animals. Generally speaking, this therapeutic modality was devoid of overall cardiac, hematologic, hepatic and renal toxicity. Interestingly, tumor angiogenesis inhibition, along with modulation of the immune response of treated animals, accounted for the observed therapeutic effects. The pre-clinical results obtained, and the incipient clinical experience in MCT protocols with different therapeutic schemes or different types of tumors, carried out by other research groups, led us to design and develop a Phase I/II trial for the treatment of advanced breast cancer patients with MCT with Cy + Cel. The project was approved by the School of Medical Sciences Bioethics Committee and by A.N.M.A.T. (the Argentine Regulatory Agency) and it is now under way, with the first out of two stages, completed. So far, the results obtained are encouraging and have allowed us to proceed with the second stage. Thus, these results, together with those coming from other laboratories, tend to build a stronger case for a paradigm change in the field of cancer therapeutics in which “more is not better” and “less is more if administered chronically”.