Malignant brain tumors are the second most common cause of cancer-related deaths in children. Furthermore, due to the sensitive nature of the developing central nervous system, standard treatments for pediatric brain tumors almost invariably leave surviving children with profound and lifelong neurologic deficits. The development of highly effective and specific therapies that can increase the efficacy of current treatment modalities without additional toxicity is an extraordinarily high priority for the future management of invasive pediatric brain tumors. Adoptive cellular therapy, involving the ex vivo expansion of tumor-specific lymphocytes and re-infusion into patients following non-myeloablative (NMA) and myeloablative (MA) conditioning regimens has emerged as a remarkably effective treatment modality for refractory metastatic melanoma. This specialized cellular treatment strategy has achieved objective clinical responses in approximately 50% of patients receiving NMA conditioning and up to 75% of patients receiving MA treatment prior to adoptive cellular therapy. These responses have also included a greater than 40% durable and complete response rate of metastatic lesions within the CNS, demonstrating that the brain is not refractory to effective treatment by cellular immunotherapy. In contrast to recently developed and FDA-approved treatment strategies employing pathway inhibitors, adoptive cellular therapy has significant curative potential in patients with advanced cancer. This proposal advances a platform approach to adoptive cellular therapy for pediatric gliomas that overcomes many of the challenges that, to date, have largely limited the application of adoptive cellular therapy to the melanoma experience. The use of amplified tumor RNA-loaded dendritic cells in immunotherapeutic treatment of cancers provides a renewable resource of tumor antigen from limited surgical biopsy specimens or even cerebral spinal fluid cytospins. We have adapted RNA-loaded dendritic cells as a presentation platform for expanding tumor-specific T cells from the peripheral blood, furthermore negating the need to isolate and expand sufficient tumor-infiltrating lymphocytes from limited tumor specimens. Additionally, we have shown in an orthotopic, radiation-resistant, and temozolomide-resistant, malignant glioma model that hematopoietic stem cells (HSCs) under both MA and NMA conditioning play a novel role in greatly facilitating the intratumoral trafficking of adoptively transferred lymphocytes and mediating the immunologic rejection and cure of established and highly-invasive tumors. This proposal will advance our mechanistic understanding of the novel role for HSCs in the immunologic rejection of infiltrative malignant gliomas and apply that knowledge to advance adoptive cellular therapy for children with malignant gliomas in the context of a phase I/II clinicl trial.
of this proposal is that it will advance a novel therapeutic strategy for the treatment of childhood brain cancers, which remains a significant and unmet clinical need. Furthermore, this research will advance our understanding of the reconstitution of anti-tumor immunity after non-myeloablative and myeloablative treatment regimens, which holds relevance for many pediatric and adult solid and hematologic malignancies. This research therefore has potential to improve therapeutic options for children and adults with malignant brain tumors as well as a variety of other cancers.
| Wildes, Tyler J; Flores, Catherine T; Mitchell, Duane A (2018) Concise Review: Modulating Cancer Immunity with Hematopoietic Stem and Progenitor Cells. Stem Cells : |
| Wildes, Tyler J; Grippin, Adam; Dyson, Kyle A et al. (2018) Cross-talk between T Cells and Hematopoietic Stem Cells during Adoptive Cellular Therapy for Malignant Glioma. Clin Cancer Res 24:3955-3966 |
| Sayour, Elias J; Mitchell, Duane A (2017) Immunotherapy for Pediatric Brain Tumors. Brain Sci 7: |
