Abstract 5029: Microglia differentiated from induced pluripotent stem cells treat glioma tumors in mice
Authors: Pandya Hetal , Ichikawa David M. , Shen Michael J. , Sedlock Andrea B. , Johnson Kory R. , Maric Dragan , McGavern Dorian B. , Malech Harry L. , Park John K. 
Published: August 2015

Glioblastoma Multiforme (GBM), a grade IV astrocytoma is the most aggressive primary brain tumor. GBM patients have the worst prognoses with median overall survival of less than 15 months from the time of diagnosis. The standard of care consists of maximal surgical resection followed by chemotherapy, given concomitantly with and following radiotherapy. Despite these measures, disease progression or recurrence is virtually inevitable and occurs at a median time of approximately 7 months. Among the more promising experimental treatments for recurrent GBM is the “vaccination” of patients with dendritic cells to elicit anti-tumor immune responses. The safety of this approach has been well demonstrated, but the clinical response rate of patients has ranged from 8%-30%. To improve upon these responses, we investigated the ability of microglia; the resident immune cells of the CNS, to better activate cytotoxic T lymphocytes within the tumor microenvironment. Using a murine syngeneic intracranial tumor model, we found that combined vaccination with dendritic cells and microglia is more effective than either alone. Combination treated mice had sustained regression of tumors over a four-week imaging period and the median survival of the animals was greater than one year. In contrast, the median survivals of the various control groups were ≤ 52 days. Translation of our findings to the clinical setting requires a source of patient-specific microglia. Here, we report the sequential differentiation of human induced pluripotent stem cells (hiPSC) into hematopoietic progenitor-like cells, and then into cells with a phenotype and gene expression profile resembling that of primary brain-isolated microglia. Similarly, human iPSC-derived microglia (hiPS-MG) exhibit phagocytic activity; produce inflammatory cytokines and reactive oxygen species. We have also differentiated mouse induced pluripotent stem cells into microglia (miPS-MG) with gene expression profile and phenotype similar to primary neonatal microglia. Mice treated with a combination therapy of tumor lysate-pulsed miPS-MG and dendritic cells show median survival greater than one year, whereas the survival for the control group was less than 50 days. For direct clinical translation of our findings, the ability to readily differentiate hiPSC into microglia in vitro will allow for the generation of patient-specific cells for use in a GBM immunotherapy protocol. hiPSC-derived microglia may also be useful as modulatory cells for a variety of CNS diseases and serve as gene and protein delivery vehicles to the CNS.

Acknowledgement: This research was supported by the Intramural Research Program of the NIH [NINDS].

Citation Format: Hetal Pandya, David M. Ichikawa, Michael J. Shen, Andrea B. Sedlock, Kory R. Johnson, Dragan Maric, Dorian B. McGavern, Harry L. Malech, John K. Park. Microglia differentiated from induced pluripotent stem cells treat glioma tumors in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5029. doi:10.1158/1538-7445.AM2015-5029