IM-15 * ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY IS SIGNIFICANTLY INCREASED BY HEMATOPOIETIC STEM CELLS

Abstract

Immunotherapeutic approaches against solid tumors can be curative with a demonstrably high degree of specificity, and adoptive T cell therapies have proven to be efficacious platform against metastatic disease. Superior clinical outcomes in response to adoptive cellular therapies are correlated with anti-tumor function, intratumoral migration and persistence of adoptively transferred tumor-specific T cells at the tumor site. Adoptive cellular therapy after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells to reliably expand CD4+ and CD8+ tumor-reactive T lymphocytes for curative adoptive cellular therapy in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. We have identified the TCR Vb clone largely responsible for immunologic rejection of intracranial murine glioma. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed dendritic cell (DC) vaccines. Hematopoietic stem cells (HSCs), administered for salvage from myeloablative conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during adoptive cellular therapy. In addition, we found that HSCs mediate a significant expansion of tumor-specific T cells under both myeloablative and non-myeloablative host conditioning. The expansion of tumor-specific T cells expressing specific TCR Vβ clones in intracranial tumor bearing mice is associated with tumor rejection. Our data indicate novel roles for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.