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NCI R01CA209886 – $1,975,000
MRI-guided Dendritic-Cell-based Vaccine Immunotherapy for Pancreatic Cancer
Role: Principle investigator
PI: Zhuoli Zhang
07/01/2016-08/01/2021
Dendritic Cell (DC) is a newly emerging and potent form of cancer immune therapy. However, the efficacy of antigen-loaded DCs (DC vaccines) is strongly influenced by their ability to migrate to peripheral draining lymph nodes (LNs). Therefore, it is critical to monitor the in vivo biodistribution of DC vaccines after vaccination in order to optimize DC therapy for pancreatic cancer. In this study, we propose magnetically labeling DC- vaccines to permit magnetic resonance imaging (MRI) of their migration to LNs. We will use clinically applicable approaches combining FDA-approved drugs (ferumoxytol, heparin, and protamine) for magnetic DC-vaccine labeling, in which magnetic DC vaccines can be visualized with advanced MRI methods. These techniques may offer future insights into the dynamics and kinetics of DC migration in vivo and the related impacts upon therapeutic outcomes in both pre-clinical and clinical research settings. Additional translational studies should ultimately follow to evaluate the efficacy of these approaches for early prediction of longitudinal outcomes during DC therapy in a broad range of tumor etiologies. This project will address the following Specific Aims using the KPC transgenic mouse model of pancreatic cancer. Aim 1: To optimize clinically applicable methods for magnetic labeling of DC-vaccines and determine the quantitative imaging properties of these vaccines with in vitro MRI phantom studies; Aim 2: To assess whether magnetic labeling of the DC-vaccine permits quantitative in vivo MRI of subsequent migration to the draining LNs following DC-based vaccination; and Aim 3: To determine whether that MRI monitored DC-vaccine migration to LNs can predict therapy.
A–C, Representative coronal T2-weighted MR images of bilateral popliteal LN lymph nodes in a mouse model of pancreatic carcinoma after injection of 1 million labeled dendritic cells into the left footpad. Images were obtained, A, prior to dendritic cell administration, B, 6 hours after injection, and, C, 24 hours after injection. White boxes = right popliteal LN lymph nodes, red boxes = left popliteal LN lymph nodes. D, E, Corresponding Prussian blue–stained slices from popliteal LN lymph nodes (collected immediately after 24-hour postinjection MR imaging) in, D, right popliteal LN lymph node, and, E, left popliteal LN lymph node. F, High-magnification image corresponding to the inset (square) in E. Scale bars for D and E = 5 mm; scale bar for F = 50 μm. Radiology, 2015; 274(1): 192–200
NCI R01CA241532 – $1,975,000
Image-guided Interventional Combination Liver Cancer Immunotherapy
Role: Principal investigator
PIs: Zhuoli Zhang and Vahid Yaghmai
03/15/2020-02/28/2025
For clinical application, a critical remaining hurdle for natural killer cell (NK) based adoptive transfer immunotherapy (ATI) is the inadequate homing efficiency of ex vivo-expanded effector NKs to the targeted tumor tissues. Another significant obstacle is the lack of well-established non-invasive tools for monitoring NK cell trafficking to tumor tissues. Currently, NK cell-based ATI (NK-ATI) responders or non-responders are identified by changes in serum biomarkers or tumor size, which may not occur until weeks or months after therapy initiation. Serial monitoring of NK cell migration to tumors during ATI could serve as an essential early biomarker for the timely prediction of longitudinal response, thus affording early adjustments to each patient’s therapeutic regimen. Recently, our studies have demonstrated that sorafenib inhibits tumor cell proliferation and promotes the antitumor activity of NKs. Therefore, concurrent administration of Sorafenib may be critical for sustained NK activation and cytotoxicity. We have developed biodegradable Sorafenib-eluting microsphere (SEM, with a diameter of 492 ± 34 nm; nano-SEM) delivery platforms that significantly increase therapeutic efficacy via image-guided transcatheter IHA delivery. We will develop a new image-guided interventional combination liver cancer immunotherapy approach including a) image-guided transcatheter IHA infusion of NKs directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of nano-SEMs to enhance Sorafenib’s therapeutic efficacy (with minimal side effects) and to strengthen NK antitumor activity.
Figure 1. Quantitative MRI of LNK cell bio-distribution in the targeted tumors. A, representative T2W and T2*W images and R2* maps at pre‐ and post-infusion intervals (24 h and 48 h). T2W images at pre-infusion, post-infusion 24 h, and 48 h are on the top row. T2*W images at pre-infusion, post-infusion is on the middle row. Quantitative R2*maps at pre-infusion, post-infusion 24 h, and 48 h are on the bottom row. B, tumor R2* values at pre‐ and post-infusion intervals (each group N =12) (IHA group: baseline vs. 24 h post-infusion, P =0.039; baseline vs. 48 h post-infusion, P =0.019; 24 h vs. 48 h post-infusion, P =0.754, control group, baseline vs. 24 h post-infusion, P =0.741; baseline vs. 48 h post-infusion, P =0.592; 24 h vs. 48 h post-infusion, P =0.568. IV group, baseline vs. 24 h post-infusion, P =0.803; baseline vs. 48 h post-infusion, P =0.694; 24 h vs. 48 h post-infusion, P =0.907). Tumor R2* value at baseline: control vs. IV, P =0.877; control vs. IHA, P =0.991; IV vs. IHA, P =0.9. Tumor R2* value at 24 h post-infusion, control vs. IV, P =0.676; control vs. IHA, P =0.041; IV vs. IHA, P =0.023. Tumor R2* value at 48 h post-infusion, control vs. IV, P =0.719; control vs. IHA, P =0.006; IV vs. IHA, P =0.006. Circles indicate tumor locations.
NCI R01CA196967 – $1,975,000
MRI-Guided Irreversible Electroporation Ablation for Liver Tumors
Role: Principle investigator
PI: Zhuoli Zhang
07/01/2015-07/01/2019
Irreversible electroporation (IRE) is a powerful new ablation technology that overcomes many of the primary limitations of thermal ablation approaches. However, for accurate, early prediction of treatment response, follow-up imaging methods must permit in vivo discrimination of irreversibly electroporated tissues from adjacent inadequately treated, reversibly electroporated tissues. Our most recent studies have demonstrated that quantitative MRI methods can detect electroporation-induced alterations to the cell membrane in both tumor and normal tissues. We will develop a powerful new MRI-guided IRE approach permitting a) pre-procedural planning to predict IRE ablation volumes, b) intra-procedural monitoring of tissue response, and c) early post-procedural identification of inadequately treated (reversibly electroporated) tissues. Our ultimate goal is to achieve complete treatment of targeted tumors while avoiding excessive damage to adjacent liver tissues. The proposed pre-clinical project will address the following Specific Aims in a well-established rabbit liver tumor model: Specific Aim 1: To develop pre-procedural planning techniques to more accurately predict IRE ablation volumes. Specific Aim 2: To develop intra-procedural imaging methods for immediate functional monitoring of tumor tissue response. Specific Aim 3: To develop post-procedural imaging methods for early identification of inadequately treated, reversibly electroporated tumor tissues.
UCI CFCC Anti-Cancer Challenge – $40,000
Quantification of Irreversible electroporation outcomes based on longitudinal monitoring of hybrid functional/structural variations of HCC microenvironment
09/01/2022 – 08/31/2023
Role: Mentor/Co-investigator
PI: Aydin Eresen
Irreversible electroporation (IRE), a non-thermal tissue ablation technique, facilitates cell death within tumor tissue while preserving the extracellular matrix with minimal inflammation. Unfortunately, translational studies and clinical experience have shown that IRE triggers the up-regulation of many deleterious downstream effects including neo-angiogenesis. The lack of understanding of the pathophysiological effects and tumor microenvironment changes caused by IRE has resulted in a plateau in terms of results and patient outcomes. Although IRE has demonstrated irrevocable results for effectively treating unresectable intermediate HCC, it remains palliative as tumors ultimately recur and progress. Apart from BOLD-MRI, no imaging tool exists that allows real-time in vivo quantification of oxygenation changes throughout the treated tumor tissue. Optical molecular imaging techniques are perfectly suitable to undertake this challenging task. Recently, researchers at IVFOI invented a novel imaging modality termed Pho Magnetic Imaging that can provide in vivo tissue oxygenation through the recovery of oxy- and deoxy-hemoglobin concentrations, which in turn allows monitoring hypoxia and/or ischemia. In this proposed study, we will longitudinally monitor IRE-treated tumors in terms of oxygenation and total hemoglobin concentration and investigate the potential correlation with gold-standard MRI-based findings. If successful, this study will demonstrate the importance of optical molecular imaging in understanding the currently presumed physiological effects of IRE on cellular metabolism and tissue oxygenation. The long-term goal of this project will be using PMI to optimize IRE protocols (number of treatments time points, voltage, probe positioning) that produce optimal ischemia/hypoxia that limits angiogenesis. This study is expected to generate a set of unpresented data that will serve to resubmit our recently reviewed R01 as well as initiate a subproject employing artificial intelligence for automatic quantification of IRE outcome, which will be very soon submitted as an R21.
Figure 1. The representation of irreversibly (IRE) and reversible electroporated (RE) zones following IRE ablation in which complete cell death occurs within IRE region while nanopores in cell wall in RE region are resealable and recoverable (Top row). A rat bearing R3230 AC breast cancer tumor was imaged by PMI (bottom row right) prior to DCE-MRI with Gd-DTPA (bottom row left). The MRI enhancement map reveals the necrotic region since Gd-DTPA cannot diffuse into the necrotic region due to missing vasculature. The absorption coefficient (μa) map correlates well with the DCE-MRI map showing similar enhancement distribution.
SIR Foundation Pilot Grant (PR-0000000012) – $25,000
Combinational DC vaccines and interventional irreversible electroporation for pancreatic ductal adenocarcinoma therapy
06/01/2020 – 11/30/2021
Role: Mentor/Co-investigator
PI: Aydin Eresen
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related mortality in the U.S. Currently, the 5-year survival rate of patients with PDAC is less than 5% due to late diagnosis and early metastases. Surgical resection is the only potentially curative option, but only 10-20% of PDAC patients are eligible for surgery. Even in patients with potentially operable tumors, 5-year overall survival is only about 20-25%.
Dendritic cell (DC) immunotherapy has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers including PDAC. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The limited success of DC therapy is often linked to tumor immunosuppression (barriers to CTLs tumor infiltration) by the tumor microenvironment.
To address these clinical gaps, we need to overcome tumor immunosuppression. Irreversible electroporation (IRE) has been demonstrated to have a potential for the treatment of unresectable PDAC tumors in clinical settings due to cause the destruction of the tumor microenvironment (by the formation of nanopores in tumor cell membranes and reduction of tumor fibrosis) to increase tumor permeability; activated CTLs should more readily gain intra-tumoral access to enhance DC-based immunotherapy. Furthermore, our studies demonstrate that IRE destroys the tumor microenvironment and provides a systemic antitumor immune response.
The proposed project will use a KPC transgenic mouse model of PDAC (technically LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre) to implement the research outlined in Specific Aims below. This model is a well-accepted and excellent animal model for human PDAC, both histologically and genetically.
Specific Aim 1: We advocate using novel intra-procedural MRI to quantitatively monitor the antitumor effect of IRE, and measure the alterations of tumor microenvironment and tumor CTLs (CD8+) infiltration in KPC mouse.
Specific Aim 2: Validate that IRE increases the therapeutic efficacy of DC vaccination for PDAC primary tumors and metastasis.
NCI R01CA209886 – $1,975,000
MRI-monitoring of DC vaccine therapy in prevention of PDAC recurrence after surgical resection
06/15/2023 – 05/31/2028
Role: Principle investigator
PIs: Zhuoli Zhang and Vahid Yaghmai
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer mortality in the US. Surgical resection is the only curative treatment, and due to the high recurrence rate (60%), only 20% survive five years. Chemotherapy and radiotherapy after surgical resection only offer modest improvements in survival. A new approach to prevent tumor recurrence in PDAC patients is urgently needed.
We will compare overall survival (OS) after tumor resection between the combination of dendritic cell (DC) vaccination via an improved intraperitoneal, i.p., route, combined with current therapy (gemcitabine), versus the use of preventive DC vaccination alone or gemcitabine alone (Aim 1).
Given the relationship between migration to lymph nodes (LNs) and anti-tumor immune response, accurate quantification of DC vaccine migration could serve as an early biomarker for predicting longitudinal response (OS) and elucidating the cause of differential response rates between patients. Understanding factors that affect DC vaccine response rates will enable the titration of vaccine doses to optimize outcomes for individual patients. Thus, we will validate magnetic imaging via quantitative susceptibility mapping (QSM) and ultrashort echo time (UTE) R2* techniques for tracking clinically applicable magnetic-labeled DC vaccines to draining abdominal LNs (Aim 2).
We will test whether advanced MRI-tracked DC vaccine homing to LNs can be used as an early imaging biomarker to predict OS of the combination of DC vaccination and gemcitabine treatment post-surgery (Aim 3).
The proposed work will meet the significant demand for a novel DC vaccination strategy of cancer therapy that can rapidly be translated to the clinic to prevent relapse after pancreatic tumor surgery while adding an imaging biomarker as a potentially powerful method to simultaneously predict response to the therapy.
The success of the proposed preventive DC vaccination strategy and prediction of response to treatment could have a broad impact as a clinical extension to other solid organ systems (e.g., stomach, liver, colorectal, renal, or uterine tumors) as novel adjuvant immunotherapy to prevent relapse after surgery.
NCI R01CA181658 – $1,975,000
MRI-Monitored Delivery of Sorafenib-Eluting Microspheres to Liver Tumors
Role: Co-investigator
PI: Andrew Larson
09/01/2015-08/01/2019
Sorafenib is a potent multi-kinase inhibitor for the treatment of patients with unresectable hepatocellular carcinoma (HCC). However, systemic exposures can lead to severe toxicities. Sorafenib dose often must be reduced or administration discontinued altogether. Microsphere drug delivery platforms offer the potential to significantly increase the efficacy of sorafenib therapy for HCC while reducing systemic exposures via targeted image-guided transcatheter delivery. Quantitative approaches for imaging sorafenib-eluting microsphere delivery may be critical to permit early prediction of response thus prompting adjustments to treatment regimens as needed (additional infusions or adoption of alternative therapies). During this pre-clinical project we seek to develop a powerful new approach for image-guided catheter-directed delivery of sorafenib to liver tumors. We will address the following Specific Aims in a well-established VX-2 rabbit model of liver cancer: Aim 1: Characterize the relationship between poly(D,L-lactide-co-glycolide) (PLG) microsphere fabrication methods, sorafenib and contrast agent loading, size distribution, release kinetics, and MRI properties. Aim 2: Optimize methods for in vivo MRI of SPIO-labeled sorafenib-eluting PLG microspheres and validate that these methods permit accurate quantification of transcatheter delivery to liver tumors. Aim 3: Validate that sorafenib-eluting microspheres inhibit angiogenesis and tumor growth, compare outcomes in liver tumors treated with sorafenib-eluting microspheres, bland embolization, and sorafenib chemo- embolization (drug infusion without microsphere encapsulation), and finally compare MRI measurements of transcatheter microsphere delivery to the elicited therapeutic responses.
NIBIB R01EB026207 – $2,300,000
Image-Guided Transcatheter Delivery of Natural Killer Cell Therapy Augmented with IFN-Gamma Eluting Microspheres
Role: Co-investigator
PI: Dong-Hyun Kim
09/01/2018-05/31/2020
Most patients with hepatocellular carcinoma (HCC) are treated with palliative liver-directed therapies; these therapies provide only modest improvements in survival and can be toxic to normal liver tissues. Many patients are not candidates for these therapies due to poor underlying liver function. Natural killer cells (NKs) constitute the first line of defense against invading infectious microbes and neoplastic cells. NKs exert an effector function independent of priming, destroying cancer cells by secreting cytotoxic lymphokines and disrupting the tumor vasculature. Adoptive transfer immunotherapy (ATI) with NK cells is a promising approach for the treatment of both hematopoietic malignancies and solid tumors. However, critical barriers must be overcome to achieve meaningful outcomes in solid tumors. A sufficient number of NK cells must migrate to tumors and infiltrate the tumor tissues to exert potent tumoricidal functions. The limited homing efficiency of NK cells to tumors tissues, following systemic administration, has inhibited clinical efficacy. HCC patients commonly undergo image-guided procedures wherein a catheter is selectively placed to deliver drugs directly into the arterial blood supply of the tumor(s). Targeted infusions afford significant reductions in systemic toxicity and delivery of potent doses of drugs and/or drug-eluting microspheres. We propose radically augmenting the homing efficiency of NK cells to HCC via a) image-guided transcatheter infusion directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of interferon-gamma (IFN-γ) eluting microspheres visible in computed tomography (CT) imaging to strengthen the cytokine gradients that drive NK migration into the tumor tissues. Due to wide variations in effector cell homing efficiency, patient-specific dosimetry and prediction of tumor response can be difficult during these adoptive transfer immunotherapies. Serial in vivo monitoring of NK cell migration to tumors and local delivery of IFN-γ will be critical to permit early prediction of longitudinal response thus affording timely adjustments to each individual patient’s therapeutic regimen (additional NK infusion or adoption of alternative therapies as needed). We propose magnetic labeling of NK cells to permit magnetic resonance imaging (MRI) of transcatheter intra-hepatic delivery and local delivered IFN-γ augmented NK cell migration to liver tumors using CT visible microspheres. Through this collaborative project building upon our strengths in materials science, molecular imaging, cancer immunology, nanomedicine and interventional oncology we seek to develop a powerful new therapeutic approach involving image-guided catheter-directed delivery of both magnetically-labeled NK cells and IFN-γ eluting microspheres to liver tumors.
NIBIB R21EB017986 – $500,000
Magnetic Nanocomposites for Catheter-Directed Drug Delivery to Liver Tumors
Role: Co-investigator
PI: Dong-Hyun Kim
09/01/2013-08/01/2015
6-methoxyethylamino numonafide (MEAN) is an innovative new anti-cancer drug with potent efficacy for the treatment of hepatocellular carcinoma (HCC). However, even though MEAN offers to importantly reduce systemic toxicity compared to prior generation amonafides, systemic administration may still lead to potentially serious adverse events. Previously developed catheter-directed techniques for treatment of HCC include radioembolization with Y-90 microspheres or chemoembolization with drug-eluting beads selectively infused into the tumor vascular beds. For these approaches, local delivery affords significant reductions in systemic toxicity due to selective catheter-directed delivery. We propose the development of MEAN-eluting magnetic nanocomposites (MEAN-MNCs) consisting of embedded porous USPIO nano-clusters in a biodegradable polymer matrix to permit controlled drug release and selective transcatheter delivery to HCC. These nanocomposite drug delivery platforms offer the potential to significantly increase the efficacy of MEAN for the treatment of HCC while reducing systemic exposures via catheter-directed delivery. Through a collaborative project building upon our strengths in materials science, nanotechnology, biomedical engineering and interventional oncology, we seek to develop a powerful new approach for image-guided catheter-directed delivery of MEAN to liver tumors. This pre-clinical project will address the following Specific Aims in a well-established rat model of liver cancer: Aim 1: To determine the relationship between micro-fluidic MEAN-MNC synthesis protocols and resulting MEAN loading, release kinetics, and magnetic resonance imaging (MRI) properties. Aim 2: To compare a) tumor responses following transcatheter infusion of MEAN-MNCs and IV administration of MEAN and b) MRI measurements of MEAN-MNC delivery to the elicited response.
NCI R01CA159178 – $1,975,000
Quantitative MRI-Guided Nanoembolization of Liver Cancer
Role: Co-investigator
PIs: Andrew C. Larson and Reed A. Omary
09/01/2013-08/01/2015
The broad, long-term objective of this proposal is to improve the prognosis of patients with unresectable hepatocellular carcinoma (HCC). For these patients, transarterial chemoembolization (TACE) is the most widely accepted local treatment because of its proven survival benefit in patients with preserved liver function. However, benefit to patients with advanced disease or poor liver function is still limited. The optimal dose for TACE also remains unknown. To address the need to expand patient eligibility and optimize dosing protocols for TACE, the investigators propose: a) developing the next generation of TACE by using nanoparticles (NP) as drug delivery vehicles for doxorubicin (DOX) and b) devising a new magnetic resonance imaging (MRI) system to predict and monitor dosimetry for this locally delivered therapy. The proposed improvement to TACE employs therapeutic nanoparticles (NP) in a new procedure termed nanoembolization (NE). NE is the local delivery of therapeutic NPs, together with embolic agents, into the tumor blood supply to increase intratumoral drug uptake. The investigators’ NP platform employs a central superparamagnetic oxide (SPIO) core that can be imaged with MRI, enclosed within a gold (Au) shell that is attached to DOX as the therapeutic agent. The proposal will test the utility of an MRI-monitoring system for the delivery of Au-SPIOs in the VX2 rabbit model of HCC. This system will enable the prediction of dosimetry prior to drug delivery, real-time monitoring during drug delivery, and feedback after delivery to verify that desired intratumoral drug concentrations have been reached. Specific Aim 1 will develop a model that predicts tissue concentrations of Au-SPIOs before delivery and provides imaging parameters for dosimetry. It is hypothesized that quantitative MRI parameters can be used to predict the biodistribution of injected Au-SPIOs before delivery and to provide dosimetry for NE. The health relevance will be to personalize liver tumor therapies for patients based upon local tumor perfusion. Specific Aim 2 will develop a real-time projection MRI fluoroscopy technique that can monitor Au-SPIO delivery in real-time during NE. It is hypothesized that Au-SPIO delivery during NE can be monitored in real-time with dynamic projection MRI. The health relevance is to develop a real-time imaging method that ensures injected NPs reach their intended tumor target. Specific Aim 3 will use MRI to quantify tissue concentrations of Au-SPIOs after NE. It is hypothesized that MRI R2* mapping accurately quantifies tissue concentrations of Au-SPIOs after NE. The health relevance is to provide quantitative intra-procedural feedback during drug delivery, with the goal of maximizing intratumoral drug concentrations, while minimizing toxicity to adjacent liver tissue.
Eisenberger Fundation 2019 – $50,000
MRI-Guided Electroporation-Enhanced Immunotherapy for Pancreatic Cancer
09/01/2019 – 08/31/2020
Role: Principle investigator
PI: Zhuoli Zhang
We propose to investigate whether IRE treatment improves the efficacy of DC vaccination.
MSTP Student Awards – $5000
2018 RSNA Medical Student Grant, RSNA Student Travel Award
2019 Fishel Fellowship, Northwestern University
Role: Mentor
PI: Junjie Shangguan
2016 Pilot Funds, Radiology of Northwestern University – $5,000
Image-guided DC vaccination for pancreatic cancer treatment
Role: Co-investigator
PI: Vahid Yaghmai
2015 Cancer Center Bridge Funds, Northwestern University – $40,000
Imaged-guided combination of IRE and DC vaccine for pancreatic cancer therapy
Role: Principal investigator
PI: Zhuoli Zhang
American Cancer Society Grant (185025) – $200,000
MRI-Monitored Electroporation-Mediated Immunotherapy for Pancreatic Cancer
02/01/2011 – 02/01/2014
Role: Principal investigator
PI: Zhuoli Zhang
We propose to optimize clinically translatable MRI approaches to optimize and amplify immune responses of combination therapy of DC vaccine and IRE treatment. Based on a previously developed MRI method, this proposal optimizes and validates the imaging protocol in animal models and focuses on clinical validation and translation of the MRI methods.