Glioblastoma (GBM) is universally fatal, and effective therapy is limited by collateral damage to normal tissue. Immunotherapy directed against tumor-specific antigens holds the potential to precisely target infiltrative brain tumors with limited damage to surrounding eloquent brain. The recent finding and confirmation by four independent laboratories, including ours, that human cytomegalovirus (CMV) propagates within a high proportion of GBMs, without infecting surrounding normal brain, provides an unparalleled opportunity to direct brain tumor immunotherapy against well-characterized and highly immunogenic viral targets. We have recently completed enrollment on a clinical trial evaluating CMV pp65 RNA-loaded dendritic cell (DC) vaccines in patients with newly diagnosed GBM that has shown promising immunologic and clinical responses. While DC vaccination increased CMV-specific cellular responses, the magnitude of these responses did not approach that typically induced during acute viral infections, and did not reflect the polyfunctional effector phenotype that has been associated with protective immunity against chronic viruses. We have shown that expansion of CMV- specific T cells in vitro however, using RNA pulsed DCs produced marked polyfunctional CMV- specific T cells responses from patients with GBM, highlighting adoptive cellular therapy as a potential strategy to restore effective polyfunctional CMV immunity in these patients and potentially eradicate CMV-associated astrocytomas. In this proposal, we aim to evaluate the safety and estimate the efficacy of adoptive cellular therapy targeting CMV pp65 during hematopoietic recovery from TMZ-induced lymphopenia in patients with newly-diagnosed GBM. The capacity to prolong the in vivo persistence and expansion of adoptively transferred T cells with concurrent pp65 RNA-pulsed DC vaccines will be explored in the context of a Phase I/II clinical trial. This research has the potential to significantly improve currently available treatments for patients with GBM, as well as provide a platform strategy for adoptive cellular therapy that may be applicable to the immunologic treatment of other malignancies.

Public Health Relevance

The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134844-04
Application #
8304369
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2009-09-23
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$312,186
Indirect Cost
$110,911
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Nair, Smita K; De Leon, Gabriel; Boczkowski, David et al. (2014) Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin Cancer Res 20:2684-94
Choi, Bryan D; Suryadevara, Carter M; Gedeon, Patrick C et al. (2014) Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma. J Clin Neurosci 21:189-90
Sanchez-Perez, Luis A; Choi, Bryan D; Archer, Gary E et al. (2013) Myeloablative temozolomide enhances CD8? T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One 8:e59082