Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T-cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. Chimeric antigen T-cell receptors (CARs) combine the variable region of an antibody with T-cell signaling moieties to confer T-cell activation with the targeting specificiy of an antibody and are not MHC-restricted. Additionally, co-stimulatory molecules, such as CD28 and 4-1BB, can be added to these constructs to improve T-cell expansion, survival, cytokine secretion, and tumor lysis. Clinical trials utilizing CARs have demonstrated their remarkable potential. However, severe adverse events and even patient deaths have occurred when these CARs have been directed against antigens shared by normal tissues. EGFRvIII is a tumor-specific mutation of the epidermal growth factor receptor that is expressed in GBMs and several other neoplasms. We have previously shown that EGFRvIII can be recognized by highly avid antibodies, so have developed human and murine CAR vectors that specifically recognize EGFRvIII inducing cytokine secretion and in vitro and in vivo tumor lysis. We have also demonstrated that an EGFRvIII-specific peptide (PEPvIII) contains the conformational epitope for EGFRvIII-specific antibodies used in these CARs. Using this peptide, we have shown that these cognate peptides are sufficient antidotes for CARs, suggesting a novel paradigm for reducing the target-specific toxicity of less tumor-specific CARs. Despite their potency, however, CARs still require host conditioning with lymphodepletion for efficacy and are still limited by being susceptible to inhibition by host immunosuppressive factors of which regulatory T-cells (TRegs) have been most frequently implicated. Similarly, while total body irradiation or non-therapeutic chemotherapy has been applied to optimize CAR therapy, it adds additional toxicity without direct anti-tumor efficacy. Our prior experience with TMZ demonstrates that, in addition to having direct clinical benefit in GBM, TMZ can potentiate anti-tumor immune responses directly related to the rebound homeostatic proliferation it induces. To address these issues, in this proposal, we will 1) Evaluate the risk of toxicity, utility of TMZ, and the requirements for efficacy of a tumor-specific, EGFRvIII-targeted CAR in a syngeneic, immunocompetent, orthotopic murine GBM model; 2) Determine if CD3-CD28-4-1BB CAR vectors naturally transfect and activate TRegs and dissect the role of CAR-secreted IL-2 in supporting the growth of intratumoral TRegs and effector T-cells; and 3) Conduct a Phase I clinical trial in TMZ-treated patients with EGFRvIII-expressing GBM to assess CAR safety, kinetics and function.

Public Health Relevance

Glioblastoma (GBM) is uniformly lethal; it is also the most common malignant primary brain tumor, and these tumors now represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Current therapy is incapacitating and produces a median overall survival (OS) of <15 months because of limits defined by non-specific toxicity. We have developed a method to specifically target patient GBM using gene-engineered, tumor-specific receptors that redirect patients' own immune T-cells to recognize and destroy tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA177476-04
Application #
9040110
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Timmer, William C
Project Start
2013-04-05
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Suryadevara, Carter M; Desai, Rupen; Abel, Melissa L et al. (2018) Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology 7:e1434464
Gedeon, Patrick C; Schaller, Teilo H; Chitneni, Satish K et al. (2018) A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res 24:3611-3631
Swartz, Adam M; Reap, Elizabeth; Norberg, Pamela et al. (2018) A simple and enzyme-free method for processing infiltrating lymphocytes from small mouse tumors for ELISpot analysis. J Immunol Methods 459:90-93
Cornetta, Kenneth; Duffy, Lisa; Feldman, Steven A et al. (2018) Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience. Mol Ther Methods Clin Dev 10:371-378
Atik, Ahmet F; Suryadevara, Carter M; Schweller, Ryan M et al. (2018) Hyaluronic acid based low viscosity hydrogel as a novel carrier for Convection Enhanced Delivery of CAR T cells. J Clin Neurosci 56:163-168
Farber, S Harrison; Elsamadicy, Aladine A; Atik, Ahmet Fatih et al. (2017) The Safety of available immunotherapy for the treatment of glioblastoma. Expert Opin Drug Saf 16:277-287
Khatri, Kshitij; Klein, Joshua A; Zaia, Joseph (2017) Use of an informed search space maximizes confidence of site-specific assignment of glycoprotein glycosylation. Anal Bioanal Chem 409:607-618
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
Schaller, Teilo H; Sampson, John H (2017) Advances and challenges: dendritic cell vaccination strategies for glioblastoma. Expert Rev Vaccines 16:27-36
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

Showing the most recent 10 out of 23 publications