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 #
5R01CA134844-02
Application #
7937057
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2009-09-23
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$321,841
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Reap, Elizabeth A; Suryadevara, Carter M; Batich, Kristen A et al. (2018) Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma. Cancer Res 78:256-264
Batich, Kristen A; Reap, Elizabeth A; Archer, Gary E et al. (2017) Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination. Clin Cancer Res 23:1898-1909
Saraswathula, Anirudh; Reap, Elizabeth A; Choi, Bryan D et al. (2016) Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy. Cancer Immunol Immunother 65:205-11
Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D et al. (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:366-9
Mitchell, Duane A; Sayour, Elias J; Reap, Elizabeth et al. (2015) Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide. Cancer Immunol Res 3:320-5
Sayour, Elias J; McLendon, Pat; McLendon, Roger et al. (2015) Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. Cancer Immunol Immunother 64:419-27
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
Lenarcic, Erik M; Ziehr, Ben; De Leon, Gabe et al. (2014) Differential role for host translation factors in host and viral protein synthesis during human cytomegalovirus infection. J Virol 88:1473-83
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
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