Abstract B80: NK therapy for pediatric brain tumors of the posterior fossa
Authors: William Benjamin Brugmann, Alvaro Laureano, Cecele Denman, Harjeet Singh, Helen Huls, Zaky Wafik, David Sandberg, Soumen Khatua, Dean Lee, Laurence Cooper, Vidya Gopalakrishnan
Journal: Cancer Research (2014)

Abstract Brain tumors are the second most common childhood malignancies and the leading cause of childhood cancer mortality. Medulloblastomas (MBs) account for approximately 20% of pediatric brain tumors. They develop in the cerebellum and frequently metastasize. Current treatment has increased overall survival to 70-80%, however the prognosis for patients with recurrent disease, metastases or diagnosis at &amp;lt;3 years old is still poor. Atypical teratoid/rhabdoid tumors (ATRTs) represent yet another pediatric brain malignancy with poor prognosis. ATRTs generally occur in children &amp;lt;3 years old and the overall survival rate for children &amp;lt;3 is only 17%. In addition, therapy related toxicities including impaired neurological development and function are a critical problem associated with the treatment of both diseases. Thus, there is an urgent need to discover new therapies for these tumors. Immunotherapy is an alternative to traditional therapies that may circumvent the potential toxicities associated with chemotherapy and radiation. Many therapeutics that harness the power of the immune system to combat cancer rely on the presence of tumor associated antigens (TAAs) and/or antigen processing and class I human leukocyte antigen (HLA I) expression. However, the identification of well-defined TAAs for MB or ATRT has remained elusive and neuronal tissues have very low HLA I expression. Therefore an agent that does not require the presence of TAAs, such as natural killer (NK) cells, might be useful for the treatment of these diseases. The current barriers to clinical application of NK therapy for brain tumors are both quantitative and qualitative. We have overcome the former problem by developing a platform technology wherein large numbers of NK cells can be generated ex vivo through co-culture of peripheral blood mononuclear cells with artificial antigen presenting cells expressing membrane-bound IL-21 (mbIL21). This method results in an average 48,000-fold expansion of donor NK cells from a small volume of blood. The qualitative barriers of NK lifespan, persistence and cytolytic activity have also been addressed by our approach. We demonstrate significantly increased life-span characterized by continued ex vivo proliferation for at least 6 weeks using mbIL21 as compared to only 3 weeks of ex vivo proliferation with IL-15. Furthermore, these NK cells have the ability to persist for up to 3 weeks post-infusion in the murine brain as determined by fluorescence imaging. These cells also express high levels of immune stimulatory and anti-tumor cytokines Ifnγ and TNFα following activation. Finally we demonstrate NK cytolytic activity in vitro against a panel of primary and established ATRT and MB cells and in vivo following locoregional delivery in a mouse orthotopic model of MB. Successful tumor infiltration of mbIL21 expanded NK cells was demonstrated by immunohistochemistry. Our data provide the first pre-clinical evidence supporting the use of mbIL21 expanded NK cells to target pediatric brain tumors. Based on this data our group has begun the first pediatric phase I clinical trial to assess the safety and efficacy of locoregional delivery of mbIL21 expanded NK cells for the treatment of posterior fossa brain tumors. Citation Format: William Benjamin Brugmann, Alvaro Laureano, Cecele Denman, Harjeet Singh, Helen Huls, Zaky Wafik, David Sandberg, Soumen Khatua, Dean Lee, Laurence Cooper, Vidya Gopalakrishnan. NK therapy for pediatric brain tumors of the posterior fossa. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B80.