T cells play a critical role in preventing the growth of precancerous lesions by recognizing changes in cellular behavior and killing those cells before they can divide. In a similar manner, T cells can be “re-educated” to recognize and kill established tumors that have evaded immune control. The Bahjat Laboratory, led by Keith S. Bahjat, Ph.D., is interested in understanding the signals that regulate the expansion and function of CD8+ T cells, and why seemingly healthy, normal T cells would be rendered incapable of killing their intended target. The laboratory primarily utilizes models of microbial infection to elicit a robust, well-characterized T cell response. Within the context of this anti-microbial T cell response we can investigate the precise components and interactions necessary for enabling optimal T cell function. Our goal is to define novel pathways that can be manipulated either alone, or in combination with vaccination, to enhance the T cell response in patients with cancer and chronic viral infection.
L. monocytogenes infected human dendritic cells
Immunotherapy for the treatment of high-grade gliomas: Approximately 40% of GBMs (glioblastoma multiforme) overexpress epidermal growth factor receptor (EGFR). Of cases that overexpress EGFR, approximately 70% also express a mutated form of the EGFR. The most common of these mutations is EGFRvIII, a tumor-specific deletion of exons 2-7 of the EGFR gene. The presence of EGFRvIII leads to constitutive low level, ligand-independent signaling through the EGFR pathway. In addition to promoting proliferation, EGFRvIII up-regulates the anti-apoptotic molecule Bcl-XL and has been shown to mediate resistance to paclitaxel and cisplatin. Those findings are supported by clinical data demonstrating that EGFRvIII expression in the presence of EGFR amplification is the strongest indicator of a poor survival prognosis in GBM. EGFRvIII may also enhance the progression of GBM by promoting cancer stem cell self-renewal. Therefore, cells expressing EGFRvIII have a selective growth advantage over those expressing only EGFR, irrespective of treatment with EGFR-specific inhibitors.
The overall goal of this project is to develop a therapeutic vaccine based on a live-attenuated Listeria monocytogenes vector expressing an immunogenic fragment of the tumor-specific neo-antigen EGFRvIII. We have engineered the vector to secrete exceptionally high levels of the tumor-specific neo-antigen EGFRvIII. Combining the vector-elicited inflammatory response with large numbers of tumor-specific MHC-peptide complexes is an ideal strategy for promoting a potent EGFRvIII-specific T cell response.
We have worked with L. monocytogenes-based vaccines since 2003. We’ve demonstrated safety and potency, established manufacturing processes, and compiled important human safety data. Importantly, we’ve learned how to maximize the quantity of antigen produced by the vaccine, as well as improving the efficiency with which it can be processed and recognized by the adaptive immune system.
We now recognize that this combination of vaccine vector and neo-antigen has numerous positive attributes warranting evaluation in a clinical study, including:
- A tumor-specific neo-antigen known to promote tumor survival and resistance to traditional therapeutics
- An immunotherapeutic target with clinical activity in patients with GBM
- A vaccine vector ( ΔactAΔinlB L. monocytogenes) with proven clinical safety (2 completed phase I trials) in cancer patients
- A vaccine vector that promotes antigen presentation in the appropriate context to maximize the tumor-specific T cell response
- A vaccine vector with established production and qualification methods that can be easily produced on a medium-large scale for less than 1/10th the cost of other biologics (i.e. viral vaccine vectors or monoclonal antibodies)
Role of innate inflammation on secondary T cell function: Following a bacterial or viral infection, T cells specific for the infectious organism are maintained as a long-lived memory T cell population. Upon re-exposure to the same organism, these memory T cells respond faster and more vigorously than those during the primary encounter. What remains unclear is the role of the innate immune system in determining the quality of this recall response. Using microbes such as Listeria monocytogenes, vaccinia virus and adenovirus, we can follow the pathogen-specific CD8+ T cells during secondary infection and determine the number, anatomic location and function of these cells. Using mutants of these model pathogens, we can engage specific receptors of the innate immune system and ask what impact they have on the CD8+ T cell recall response.
Live attenuated microbial-based vaccines for cancer and infectious disease: Live attenuated bacteria and viruses can elicit a robust antigen-specific T cell response while minimizing the risk of harm to the patient. While other projects in the lab intend to identify novel regulatory pathways that might inhibit the T cell response, this project utilizes that knowledge for the rational design of next-generation vaccine vectors intended to maximize the potency of the antigen-specific T cell response. By selecting target antigens abhorrently expressed in specific cancers, we can engineer microbes to express those proteins and display them in an immunogenic manner in vivo. Following vaccination, the combination of inflammation and antigen-presentation can activate and expand tumor specific T cells and promote tumor regression. Our current work utilizes several different live-attenuated vector platforms, including lentivirus, vaccinia virus, adenovirus, and Listeria monocytogenes.
Full List of Publications
PI: Keith S. Bahjat, Ph.D.
Basic Research Lab
Alejandro Alice, Ph.D.
Arthur Jeiranian, Ph.D.
Human Immune Monitoring Lab
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