Current Research in Neurosurgery: Amy Heimberger, M.D.
Glioma, immunotherapy, EGFRvIII, microglia
High-grade malignant gliomas are extremely aggressive and are characterized by diffuse infiltration of the brain parenchyma, recurrent growth and an extremely poor prognosis for survival. Current therapeutic interventions are highly ineffective at eradicating intracranial reservoirs. Although the immune system is capable of recognizing these tumors, gliomas continue to infiltrate and grow. Both our clinical and laboratory objective is to modulate the immune system to more effectively eradicate brain tumors.
The epidermal growth factor receptor (EGFR) is often amplified and structurally rearranged in malignant gliomas and other tumors such as breast and lung, with a most common mutation being EGFRvIII. This tumor specific antigen is present on approximately 31% of glioblastoma multiforme tumors. The EGFRvIII has been shown previously to increase brain invasion and we have previously demonstrated that the expression of EGFRvIII is an independent negative prognostic indicator in patients surviving more than one year. Because the EGFRvIII is only expressed on malignant tumors this represents an excellent immunological target while minimizing potentially fatal autoimmune reactions. In a murine syngeneic intracerebral treatment model vaccination with a peptide (PEP-3) spanning the spliced junction of the EGFRvIII, either with granulocyte macrophage – colony stimulating factor (GM-CSF) or dendritic cells resulted in significantly increased survival. This vaccination strategy resulted in cytotoxic and humoral responses. The immunological mechanism of efficacy was found to be in part mediated by antibody dependant cellular cytotoxicity. Our pre clinical data has resulted in several clinical trials for human patients with malignant gliomas. This included a Phase one dendritic cell clinical trial, as well as an ongoing Phase 2 clinical trial in which GBM patients are vaccinated with PEP-3 and GM-CSF.
Although very preliminary data indicates that the Phase 2 clinical trial is promising, immunotherapeutic failures are likely occurring within the tumor microenvironment. Utilizing three-color flow analysis cytometery have found the predominate immune cells within malignant gliomas to be CD4 T-cells and microglia. Microglia have previously been thought to be the antigen presenting cells within the brain. By isolating microglia directly from brain tumor patients, utilizing a series of sequential percoll ingredients that do not alter the phenotype and function of these cells, we have discovered that microglia cannot provide appropriate co-stimulation to the incoming glioma-infiltrating T-cells. This would imply that despite the generation of a successful systemic immune response that upon entry into the malignant glioma these cells are rendered ineffective. Our data indicates that if microglia could be rendered functionally collaborative with the systemic immune response more efficacious immunotherapeutics can be generated. The microglia do possess some immunological capabilities including phagocytosis, direct tumor cytotoxicity, antibody dependent cellular cytotoxicity and the operational machinery for innate immunity (i.e. toll-like receptors). Our laboratory is currently examining ways to exploit the innate immune system through the toll-like receptors to increase the co-stimulation to enhance and generate more efficacious T-cell responses against gliomas.
In addition to our immunotherapeutic research and clinical trials, our laboratory also evaluates novel chemotherapeutics for efficacy and evaluates genetic alterations that may impact progression and prognosis.