Dissection of immunomodulatory mechanisms affecting adoptive transfer of peripheral blood derived-tumor reactive T cells in combination with low-dose IFN-alpha as treatment for advanced melanoma. (LSBR 1207)
Project leader: Dr. ir. Els M.E. Verdegaal, Dept. of Clinical Oncology, LUMC, Leiden, Prof. Dr. Sjoerd. H. van der Burg (co-applicant), Dept. of Clinical Oncology, LUMC, Leiden, Prof. Dr. John B.A.G. Haanen (co-applicant), Dept. of Medical Oncology, Netherlands Cancer Institute, Amsterdam
Post-doc investigator: Dr. Sara Melief (Apr. 2013 – Jul. 2016)
Research technician: Marten Visser (Jan. 2014 – Jan. 2016
In our ongoing clinical trial we treat patients that suffer from metastatic melanoma with T cells that recognize and attack the tumor. These tumor-reactive T cells are derived from peripheral blood cells that were stimulated with the patient’s’ own tumor cells to expand outside the body. When a large number of tumor-reactive T cells were obtained they were infused back into the patients. Five out of 10 patients treated with these T cells showed a long-lasting clinical benefit (responder patients). We observed that the T cells that were given to responder patients expanded better than the T cells that were given to the non-responder patients. We hypothesize that in the cultures with slowly expanding T cells, the tumor cells that are present exert a suppressive activity that affects the expansion capacity of the T cells. The aim of our study was to identify these suppressive mechanisms and to identify means to neutralize the responsible inhibitory factors thereby improving expansion.
Several inhibitory factors were identified, including the accumulation of regulatory T cells that are known to suppress the expansion of tumor-reactive T cells. Furthermore, we identified the production of the suppressive factors indoleamine-2-3-dioxygenase (IDO) and galectin-3 by the tumor cells. We were successful in neutralizing the suppression induced by these factors in the cultures leading to better expansion of tumor-reactive T cells. These strategies are considered for implementation in clinical protocols leading to generation of clinically more effective T cells.