Immunotherapy has the potential to become the new paradigm of cancer treatment. While anatomic imaging has been the gold standard to monitor treatment efficacy based upon decreases in tumor size, patients treated with immunotherapies often present with a period of apparent tumor growth before prolonged regression. Due to the high cost and delayed response time, there exists a compelling need to accurately predict which patients are most likely to benefit from immune based treatment strategies. Aaron hopes to develop a molecular imaging toolkit including novel software, hardware, and biological wetware to improve monitoring of cancer immunotherapies in the clinic. He is advised on this project by Dr. Sam Gambhir. Aaron brings with him experience in multi-modality molecular imaging of cancer from his time spent under the mentorship of Dr. Efstathios Karathanasis and Dr. Mark Griswold at the Case Center for Imaging Research in Cleveland, Ohio. After graduating from CWRU, Aaron spent a year in Switzerland as a Fulbright Fellow at the Ecole Polytechnique Federale de Lausanne (EPFL) where, with the guidance of Dr. Melody Swartz and Dr. Jeffrey Hubbell, he utilized imaging tools to better understand the mechanisms of therapeutic cancer vaccines.
Honors & Awards
Fulbright Fellow, US Fulbright Comittee
Tbi2 Fellow, Stanford University
BioX Fellow, Stanford University
NSF GRFP, National Science Foundation
Education & Certifications
Master of Science, Stanford University, BIOE-MS (2016)
Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.
Proceedings of the National Academy of Sciences of the United States of America
2015; 112 (47): E6506-14
Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm(3)) and large tumors (150 mm(3)), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics.
View details for DOI 10.1073/pnas.1519623112
View details for PubMedID 26604307
View details for PubMedCentralID PMC4664306
- Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2015; 112 (47): E6506-E6514
Novel Radiotracer for ImmunoPET Imaging of PD-1 Checkpoint Expression on Tumor Infiltrating Lymphocytes.
2015; 26 (10): 2062-2069
Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) significantly dampens anti-tumor immune responses. Cancer patients treated with checkpoint inhibitors that block this suppressive signaling have exhibited objective response rates of 20-40% for advanced solid tumors, lymphomas, and malignant melanomas. This represents a tremendous advance in cancer treatment. Unfortunately, all patients do not respond to immune checkpoint blockade. Recent findings suggest that patients with tumor infiltrating lymphocytes (TILs) expressing PD-1 may be most likely to respond to αPD-1/PD-L1 checkpoint inhibitors. There is a compelling need for diagnostic and prognostic imaging tools to assess the PD-1 status of TILs in vivo. Here we have developed a novel immunoPET tracer to image PD-1 expressing TILs in a transgenic mouse model bearing melanoma. A (64)Cu labeled anti-mouse antibody (IgG) PD-1 immuno positron emission tomography (PET) tracer was developed to detect PD-1 expressing murine TILs. Quality control of the tracer showed >95% purity by HPLC and >70% immunoreactivity in an in vitro cell binding assay. ImmunoPET scans were performed over 1-48 h on Foxp3+.LuciDTR4 mice bearing B16-F10 melanoma tumors. Mice receiving anti-PD-1 tracer (200 ± 10 μCi/10-12 μg/200 μL) revealed high tracer uptake in lymphoid organs and tumors. BLI images of FoxP3(+) CD4(+) Tregs known to express PD-1 confirmed lymphocyte infiltration of tumors at the time of PET imaging. Biodistribution measurements performed at 48 h revealed a high (11×) tumor to muscle uptake ratio of the PET tracer (p < 0.05). PD-1 tumors exhibited 7.4 ± 0.7%ID/g tracer uptake and showed a 2× fold signal decrease when binding was blocked by unlabeled antibody. To the best of our knowledge this data is the first report to image PD-1 expression in living subjects with PET. This radiotracer has the potential to assess the prognostic value of PD-1 in preclinical models of immunotherapy and may ultimately aid in predicting response to therapies targeting immune checkpoints.
View details for DOI 10.1021/acs.bioconjchem.5b00318
View details for PubMedID 26307602
On-Command Drug Release from Nanochains Inhibits Growth of Breast Tumors
2014; 31 (6): 1460-1468
To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor.A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-LUC-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-LUC-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI).Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n=5 animals per group).These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.
View details for DOI 10.1007/s11095-013-1102-8
View details for Web of Science ID 000336745800010
View details for PubMedID 23934254
View details for PubMedCentralID PMC3875625
Treatment of cancer micrometastasis using a multicomponent chain-like nanoparticle
JOURNAL OF CONTROLLED RELEASE
2014; 173: 51-58
While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug.
View details for DOI 10.1016/j.jconrel.2013.10.031
View details for Web of Science ID 000329157100007
View details for PubMedID 24188960
View details for PubMedCentralID PMC3873646
Imaging Metastasis Using an Integrin-Targeting Chain-Shaped Nanoparticle
2012; 6 (10): 8783-8795
While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an α(v)β(3) integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced "sensing" of the tumor-associated remodeling of the vascular bed, offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of α(v)β(3) integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (fluorescence molecular tomography and magnetic resonance imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice.
View details for DOI 10.1021/nn303833p
View details for Web of Science ID 000310096100037
View details for PubMedID 23005348
View details for PubMedCentralID PMC3487383
Enhanced Delivery of Chemotherapy to Tumors Using a Multicomponent Nanochain with Radio-Frequency-Tunable Drug Release
2012; 6 (5): 4157-4168
While nanoparticles maximize the amount of chemotherapeutic drug in tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs in their molecular or nanoparticle form, we developed a nanoparticle based on multicomponent nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled in a 100 nm long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models in rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radio frequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results in a widespread anticancer effect.
View details for DOI 10.1021/nn300652p
View details for Web of Science ID 000304231700056
View details for PubMedID 22486623
View details for PubMedCentralID PMC3358486