Multiplexed Immunomarker Screening to Enable Patient-Tailored Immunotherapies
Abstract
Melanoma is a highly aggressive disease with rapid metastasis in distant organs. Metastatic melanoma has been associated with poor prognosis with a median survival of <1 year. Blockade of immunomarker programmed death ligand 1 (PD-L1) overexpressed in melanoma has recently shown promise in activating the patient’s own immune system to improve antitumor immunity, eradicate cancer cells, and prevent relapse. However, ~75% of melanoma patients do not respond to this immunotherapy in part due to poor assessment of PD-L1 in tumors. Current predictive measures in clinic relies on immunohistochemistry (IHC) of biopsies to determine PD-L1 status, but IHC is prone to uncertainties, often provide inaccurate diagnosis, and requires multiple invasive biopsies. Inaccurate diagnosis results in high cost of unsuccessful therapies and fatal toxicities in patients due to prolonged antibody treatment. Therefore, there is an unmet clinical need for noninvasive diagnostic tools that will provide rapid, reliable, and accurate prognosis if a patient will respond to immunotherapies and spare those with pre-identified unresponsive tumors from toxic side effects. This proposal will address this urgent need by developing an innovative, noninvasive imaging platform that will not only diagnose PD-L1 accurately but also identify other immunomarkers of melanoma enabling patient selection for immunotherapies. Our proposed ImmunoPET-Raman synergistically combines positron emission tomography (PET) with surface-enhanced Raman imaging using immunoactive gold nanostructures (IGNs) that are coated with antibodies, Raman labels, and radiotracers. IGNs are biocompatible, safe, and are rapidly cleared with no in vivo toxicity. ImmunoPET-Raman seamlessly integrates the depth-resolved whole body imaging of PET with the high spatiotemporal resolution and multiplexing of Raman, allowing one to locate the macroscopic distribution of the tumors deep within organs followed by rapid molecular identification of multiple immunomarkers in real time. We anticipate ImmunoPET-Raman will improve outcomes in melanoma patients guiding clinical decisions to an optimal, personalized immunotherapy within hours, before treatment begins. This award will propel my long-term goal to be a leader in melanoma research through “immunonanomedicine” utilizing nanostructures to simultaneously detect predictive immunomarkers of cancer and enable therapies for prolonged tumor regression. This award will also promote my near-term goal to expand my current expertise in Raman imaging and preclinical mouse models and become proficient in clinically relevant humanized mice implanted with melanoma patient tumors. These studies will ultimately promote the clinical translation of this work from small animals to patients. My career goals will be achieved through a mentored pathway with my designated mentor, Dr. Richmond, and the outstanding mentoring committee I have assembled including Dr. Manning, Dr. Johnson, and Dr. Mahadevan-Jansen with expertise in areas relevant to this work. Vanderbilt also has a strong melanoma research program and several initiatives focused on immunotherapies and early detection that will be leveraged for successful achievement of the project goals. The proposed work will have significant impact on both patients with localized disease and metastatic melanoma guiding clinical decision to an optimal immunotherapy plan. Whereas hybrid imaging combining PET/CT and PET/MRI are already established in clinic, they are limited in resolving the presence of micrometastasis and cannot identify multiple markers simultaneously. These limitations often result in poor prognosis of patients who may likely benefit from combinatorial treatment. ImmunoPET-Raman imaging with IGNs can address these limitations in current modalities and has tremendous translational potential because gold nanoparticles are already in clinical trials (Aurimune, AuroLase); PET has successfully
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810139
Entities
People
- Rizia Bardhan
Organizations
- United States Army
- Vanderbilt University