NATURAL KILLER CELL IMMUNOTHERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA

Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal pediatric cancer. Immunotherapy, and specifically Natural Killer (NK) cell therapy has been investigated for glioma and other brain malignancies. Indeed, our group is the first to demonstrate safety of loco-regional infusion of ex vivo expanded and activated NK cells in a Phase-I trial of patients with recurrent/refractory fourth ventricular tumors. But their effectiveness against DIPG has not been assessed. Here, we show that NK cells have cytolytic activity against DIPG cells in vitro. In vivo, DIPG tumors implanted in the forebrain were lysed by intratumoral injections of ex vivo expanded NK cells. In addition, NK cells infused through the fourth ventricle trafficked to and promoted shrinkage of DIPG tumors in their orthotopic location. In work from other investigators, epigenetic modulation of tumors by Histone Deacetylate Inhibitors (HDACIs) is being investigated as a potential therapeutic approach for this disease. However, the effect of HDACIs on immune cell activity has not been examined. We observed that pre-treatment of NK cells with the HDACI, MS-275, enhanced NK cell mediated cytolysis of DIPG cells in vitro. This was associated with significantly enhanced expression of genes controlling motility and cytolysis. The ability of MS-275 primed NK cells to traffic and promote cytolysis of tumors implanted proximal and distal to the site of NK cell introduction will be discussed. In summary, we suggest that the use of epigenetic therapy as an ex vivo primer of NK cells could increase the effectiveness of NK cell therapy against DIPG tumors.