My laboratory has been bridging the fields of biomedical imaging with cell/molecular biology, oncology, molecular pharmacology, and chemistry in order to advance molecular imaging of cancer in living subjects. We have developed and validated enzyme and receptor based reporter gene/probe systems for noninvasive multimodality imaging in living subjects, including humans. The potential of cellular immuno-gene therapy for cancer has been demonstrated resulting in progression to clinical trials. The main promise of these approaches is site-specific targeting of the therapeutic immune cell effect. Positron emission tomography (PET) reporter genes (PRG)/probes (PRP) can be used for long-term monitoring of ex-vivo genetically engineered therapeutic cells in small animal disease models and then in human patients. We have recently obtained FDA approval for clinical evaluation of the PRP [18F]FHBG, which can be used for monitoring the trafficking of cells expressing the Herpes Simplex Virus 1 Thymidine Kinase (HSV1-TK or mutant HSV1-sr39TK). [18F]FHBG has been safe and demonstrated excellent imaging characteristics in human volunteers and hepatocarcinoma patients being treated with HSV1-tk gene therapy.
The specific aims are logical extensions of preclinical and phase 1 clinical [18F]FHBG imaging studies to clinical trials in cancer patients who will be treated with genetically engineered cytolytic T cells.
Aim 1. Optimization of [18F]FHBG PET-CT imaging in glioma patients to characterize background [18F]FHBG signal in areas of tumor with a compromised blood-brain-barrier as well as in normal brain.
Aim 2. Optimization of [18F]FHBG PET-CT imaging in glioma patients undergoing cytotoxic T-Cell therapy to image cell based therapies.
Aim 3. Extension of [18F]FHBG PET-CT imaging for patients undergoing cytotoxic T-Cell therapy for various tumor types and improvement of strategy sensitivity. This work would be highly enabling for several reasons. It will lay the groundwork for many cell based therapies yet to come by allowing them to be successful through use of state-of-art molecular imaging. By having the ability to directly image cells we can optimize cell-based therapies in general. There is no more a need to work blindly. We can directly link the survival of the cells to clinical response and eventual outcome. This should markedly improve our ability to make cell based therapies an eventual success and allow for reporter gene imaging in multi-center trials.
Adoptive cellular gene therapy is the process of genetically engineering cells to make them therapeutic agents for a particular disease and then administer them to a patient. In order to achieve a therapeutic effect without having adverse effects, the adoptively transferred therapeutic cells must only traffic to specific tissues of the patient's body. We have developed a reporter gene/probe system that can be used in humans to track trafficking of adoptively transferred cells. Here, we propose non-invasive imaging of therapeutic immune cells that will be infused into patients with glioma brain tumors and have been shown to kill glioma brain tumor cells.
|Ronald, John A; Chuang, Hui-Yen; Dragulescu-Andrasi, Anca et al. (2015) Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker. Proc Natl Acad Sci U S A 112:3068-73|
|Chen, Ian Y; Paulmurugan, Ramasamy; Nielsen, Carsten H et al. (2014) A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor. Mol Imaging Biol 16:224-34|
|Yan, Xinrui; Ray, Pritha; Paulmurugan, Ramasamy et al. (2013) A transgenic tri-modality reporter mouse. PLoS One 8:e73580|
|James, Michelle L; Gambhir, Sanjiv S (2012) A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 92:897-965|
|Yaghoubi, Shahriar S; Jensen, Michael C; Satyamurthy, Nagichettiar et al. (2009) Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat Clin Pract Oncol 6:53-8|