Faculty of Engineering and Natural Sciences
Natural Killer Cell Therapy in Multiple Myeloma: Towards a Phase I/II Clinical Trial
Tolga Sutlu, Karolinska Institute, Sweden
Despite the advances in autologous stem cell transplantation and chemotherapy, multiple myeloma (MM) remains an incurable disease. The most promising therapeutic options currently available are combinations of transplantation, targeted pharmacotherapy and immunotherapy. Cell-based immunotherapy after hematopoietic stem cell transplantation has been attempted but, with limited efficacy. Natural killer (NK) cells are interesting candidates for new means of immunotherapy; however, their potential clinical use in MM has not been extensively studied.
We have primarily attempted to determine if NK cells provide anti-MM activity following interleukin-2 (IL-2) administration, and if ex vivo activated and intravenously (i.v.) administered NK cells prolong survival in MM bearing C57BL/KaLwRij mice. IL-2 administration into MM bearing mice significantly prolonged their survival. The effects of IL-2 were diminished by in vivo depletion of NK cells but not CD8+ T cells. Moreover, adoptively transferred IL-2 activated syngeneic NK cells in conjunction with IL-2 treatment showed a significant anti-MM effect in vivo.
To further investigate the positive results from in vivo experiments in the mouse model, we explored the possibility of expanding NK cells from the peripheral blood of seven newly diagnosed, untreated MM patients. After 20 days of culture, the number of NK cells from these patients had expanded on average 1,600-fold. Moreover, expanded NK cells showed significant cytotoxicity against primary autologous MM cells, yet retained their tolerance against non-malignant cells. Based on these findings, we have proposed that autologous NK cells expanded ex vivo deserve further attention as a possible new treatment modality for MM.
In order to facilitate an optimal clinical trial, we have attempted to optimize ex vivo expansion and activation of NK cells under good manufacturing practice (GMP) compatible closed systems.
Expansion was successful in all systems and no significant difference was observed in terms of phenotype or cytotoxic capacity of final products. Our results demonstrate that large amounts of activated NK cells can now be produced using GMP compliant procedures and warrant the initiation of a phase I/II clinical trial to investigate the potential use of NK cells for MM immunotherapy.
December 24 (Wednesday), 2008, 13:30, FENS L048