Publications by authors named "Jason S Lewis"

274 Publications

Synthesis and Comparative Evaluation of Site-Specifically Labeled Radioimmunoconjugates for DLL3-Targeted ImmunoPET.

Bioconjug Chem 2021 Apr 9. Epub 2021 Apr 9.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.

Delta-like ligand 3 (DLL3) is a therapeutic target for the treatment of small cell lung cancer, neuroendocrine prostate cancer, and isocitrate dehydrogenase mutant glioma. In the clinic, DLL3-targeted Zr-immunoPET has the potential to aid in the assessment of disease burden and facilitate the selection of patients suitable for therapies that target the antigen. The overwhelming majority of Zr-labeled radioimmunoconjugates are synthesized via the random conjugation of desferrioxamine (DFO) to lysine residues within the immunoglobulin. While this approach is admittedly facile, it can produce heterogeneous constructs with suboptimal and behavior. In an effort to circumvent these issues, we report the development and preclinical evaluation of site-specifically labeled radioimmunoconjugates for DLL3-targeted immunoPET. To this end, we modified a cysteine-engineered variant of the DLL3-targeting antibody SC16-MB1 with two thiol-reactive variants of DFO: one bearing a eimide moiety (Mal-DFO) and the other containing a henylxaiazolyl methyl ulfone group (PODS-DFO). In an effort to obtain immunoconjugates with a FO-to-ntibody atio (DAR) of 2, we explored both the reduction of the antibody with tris(2-carboxyethyl) phosphine (TCEP) as well as the use of a combination of glutathione and arginine as reducing and stabilizing agents, respectively. While exerting control over the DAR of the immunoconjugate proved cumbersome using TCEP, the use of glutathione and arginine enabled the selective reduction of the engineered cysteines and thus the formation of homogeneous immunoconjugates. A head-to-head comparison of the resulting Zr-radioimmunoconjugates in mice bearing DLL3-expressing H82 xenografts revealed no significant differences in tumoral uptake and showed comparable radioactivity concentrations in most healthy nontarget organs. However, Zr-DFO-SC16-MB1 produced 30% lower uptake (3.3 ± 0.5 %ID/g) in the kidneys compared to Zr-DFO-SC16-MB1 (4.7 ± 0.5 %ID/g). In addition, H82-bearing mice injected with a Zr-labeled isotype-control radioimmunoconjugate synthesized using PODS exhibited ∼40% lower radioactivity in the kidneys compared to mice administered its maleimide-based counterpart. Taken together, these results demonstrate the improved performance of the PODS-based radioimmunoconjugate and suggest that a stable, well-defined DAR2 radiopharmaceutical may be suitable for the clinical immunoPET of DLL3-expressing cancers.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00121DOI Listing
April 2021

Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer.

ChemMedChem 2021 Apr 1. Epub 2021 Apr 1.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Nuclear medicine is defined as the use of radionuclides for diagnostic and therapeutic applications. The imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on γ-emissions of specific energies. The therapeutic technologies are based on β -particle-, α-particle-, and Auger electron emitters. In oncology, PET and SPECT are used to detect cancer lesions, to determine dosimetry, and to monitor therapy effectiveness. In contrast, radiotherapy is designed to irreparably damage tumor cells in order to eradicate or control the disease's progression. Radiometals are being explored for the development of diagnostic and therapeutic radiopharmaceuticals. Strategies that combine both modalities (diagnostic and therapeutic), referred to as theranostics, are promising candidates for clinical applications. This review provides an overview of the basic concepts behind therapeutic and diagnostic radiopharmaceuticals and their significance in contemporary oncology. Select radiometals that significantly impact current and upcoming cancer treatment strategies are grouped as clinically suitable theranostics pairs. The most important physical and chemical properties are discussed. Standard production methods and current radionuclide availability are provided to indicate whether a cost-efficient use in a clinical routine is feasible. Recent preclinical and clinical developments and outline perspectives for the radiometals are highlighted in each section.
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http://dx.doi.org/10.1002/cmdc.202100135DOI Listing
April 2021

Applications of nuclear-based imaging in gene and cell therapy: probe considerations.

Mol Ther Oncolytics 2021 Mar 4;20:447-458. Epub 2021 Feb 4.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Several types of gene- and cell-based therapeutics are now emerging in the cancer immunotherapy, transplantation, and regenerative medicine landscapes. Radionuclear-based imaging can be used as a molecular imaging tool for repetitive and non-invasive visualization as well as monitoring of therapy success. In this review, we discuss the principles of nuclear-based imaging and provide a comprehensive overview of its application in gene and cell therapy. This review aims to inform investigators in the biomedical field as well as clinicians on the state of the art of nuclear imaging, from probe design to available radiopharmaceuticals and advances of direct (probe-based) and indirect (transgene-based) strategies in both preclinical and clinical settings. Notably, as the nuclear-based imaging toolbox is continuously expanding, it will be increasingly incorporated into the clinical setting where the distribution, targeting, and persistence of a new generation of therapeutics can be imaged and ultimately guide therapeutic decisions.
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http://dx.doi.org/10.1016/j.omto.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907215PMC
March 2021

Exploiting the MUC5AC Antigen for Noninvasive Identification of Pancreatic Cancer.

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

Memorial Sloan Kettering Cancer Center, United States.

Pancreatic cancer (PC) remains the 4th leading cause of cancer death; therefore, there is a clinically unmet need for novel therapeutics and diagnostic markers to treat this devastating disease. Physicians often rely on biopsy or CT for diagnosis, but more specific protein biomarkers are highly desired to assess the stage and severity of PC in a noninvasive manner. Serum biomarkers such as CA19.9 are of particular interest as they are commonly elevated in PC but have exhibited suboptimal performance in the clinic. MUC5AC has emerged as a useful serum biomarker that is specific for PC vs. inflammation. We developed RA96, an anti-MUC5AC antibody, to gauge its utility in PC diagnosis through immunohistochemical (IHC) analysis and whole-body PET in PC. In this study, extensive biochemical characterization determined MUC5AC as the antigen for RA96. We then determined the utility of RA96 for MUC5AC IHC on clinical PC and pre-clinical PC. Finally, we radiolabeled RA96 with zirconium-89 to assess its application as a whole-body PET radiotracer for MUC5AC quantification in PC. Immunohistochemical staining with RA96 distinguished chronic pancreatitis (CP), PanIN, and varying grades of pancreatic ductal adenocarcinoma (PDAC) in clinical samples. [Zr]Zr-DFO-RA96 was able to detect MUC5AC with high specificity in mice bearing capan-2 xenografts. Our study demonstrates that RA96 can differentiate between inflammation and PC, improving the fidelity of PC diagnosis. Our immuno-PET tracer [Zr]Zr-DFO-RA96 shows specific detection of MUC5AC+ tumors in vivo, highlighting the utility of MUC5AC targeting for diagnosis of PC.
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http://dx.doi.org/10.2967/jnumed.120.256776DOI Listing
March 2021

Medical imaging and nuclear medicine: a Lancet Oncology Commission.

Lancet Oncol 2021 04 4;22(4):e136-e172. Epub 2021 Mar 4.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.

The diagnosis and treatment of patients with cancer requires access to imaging to ensure accurate management decisions and optimal outcomes. Our global assessment of imaging and nuclear medicine resources identified substantial shortages in equipment and workforce, particularly in low-income and middle-income countries (LMICs). A microsimulation model of 11 cancers showed that the scale-up of imaging would avert 3·2% (2·46 million) of all 76·0 million deaths caused by the modelled cancers worldwide between 2020 and 2030, saving 54·92 million life-years. A comprehensive scale-up of imaging, treatment, and care quality would avert 9·55 million (12·5%) of all cancer deaths caused by the modelled cancers worldwide, saving 232·30 million life-years. Scale-up of imaging would cost US$6·84 billion in 2020-30 but yield lifetime productivity gains of $1·23 trillion worldwide, a net return of $179·19 per $1 invested. Combining the scale-up of imaging, treatment, and quality of care would provide a net benefit of $2·66 trillion and a net return of $12·43 per $1 invested. With the use of a conservative approach regarding human capital, the scale-up of imaging alone would provide a net benefit of $209·46 billion and net return of $31·61 per $1 invested. With comprehensive scale-up, the worldwide net benefit using the human capital approach is $340·42 billion and the return per dollar invested is $2·46. These improved health and economic outcomes hold true across all geographical regions. We propose actions and investments that would enhance access to imaging equipment, workforce capacity, digital technology, radiopharmaceuticals, and research and training programmes in LMICs, to produce massive health and economic benefits and reduce the burden of cancer globally.
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http://dx.doi.org/10.1016/S1470-2045(20)30751-8DOI Listing
April 2021

Technical Note: Patient-morphed mesh-type phantoms to support personalized nuclear medicine dosimetry - a proof of concept study.

Med Phys 2021 Apr 9;48(4):2018-2026. Epub 2021 Mar 9.

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Current standard practice for clinical radionuclide dosimetry utilizes reference phantoms, where defined organ dimensions represent population averages for a given sex and age. Greater phantom personalization would support more accurate dose estimations and personalized dosimetry. Tailoring phantoms is traditionally accomplished using operator-intensive organ-level segmentation of anatomic images. Modern mesh phantoms provide enhanced anatomical realism, which has motivated their integration within Monte Carlo codes. Here, we present an automatable strategy for generating patient-specific phantoms/dosimetry using intensity-based deformable image registration between mesh reference phantoms and patient CT images. This work demonstrates a proof-of-concept personalized dosimetry workflow, presented in comparison to the manual segmentation approach.

Methods: A linear attenuation coefficient phantom was generated by resampling the PSRK-Man reference phantom onto a voxel grid and defining organ regions with corresponding Hounsfield unit (HU) reference values. The HU phantom was co-registered with a patient CT scan using Plastimatch B-spline deformable registration. In parallel, major organs were manually contoured to generate a "ground truth" patient-specific phantom for comparisons. Monte Carlo derived S-values, which support nuclear medicine dosimetry, were calculated using both approaches and compared.

Results: Application of the derived B-spline transform to the polygon vertices comprising the PSRK-Man yielded a deformed variant more closely matching the patient's body contour and most organ volumes as-evaluated by Hausdorff distance and Dice metrics. S-values computed for fluorine-18 for the deformed phantom using the Particle and Heavy Ion Transport code System showed improved agreement with those derived from the patient-specific analog.

Conclusions: Deformable registration techniques can be used to create a personalized phantom and better support patient-specific dosimetry. This method is shown to be easier and faster than manual segmentation. Our study is limited to a proof-of-concept scope, but demonstrates that integration of personalized phantoms into clinical dosimetry workflows can reasonably be achieved when anatomical images (CT) are available.
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http://dx.doi.org/10.1002/mp.14784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058313PMC
April 2021

A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals.

Eur J Nucl Med Mol Imaging 2021 Jan 25. Epub 2021 Jan 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, MSKCC Zuckerman Building, 417 E 68th St, New York, NY, 10065, USA.

Purpose: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [Lu]-PSMA-617 and other small molecule-based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [Lu]-PSMA-617 in the salivary glands and kidneys.

Methods: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h.

Results: Biodistribution studies at 1 h post-administration revealed that [Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively.

Conclusion: The uptake of [Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.
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http://dx.doi.org/10.1007/s00259-020-05150-wDOI Listing
January 2021

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [Cu]Cu-NOTA-anti-CD8 PET.

Clin Cancer Res 2021 Apr 25;27(7):1958-1966. Epub 2021 Jan 25.

Department of Pharmacology, Weill Cornell Medical College, New York, New York.

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8) T cells using PET.

Experimental Design: We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8 T cells by flow cytometry relative to the [Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8 tumor-infiltrating lymphocytes by IHC. To determine whether [Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8 T cells.

Results: Nontumor-bearing NOG mice injected with human PBMCs showed prominent [Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8 T cells. Radiotracer retention correlated with CD8 T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8 T cells in brain tumors.

Conclusions: Human CD8 T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8 T cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026513PMC
April 2021

Bimodal Imaging of Mouse Peripheral Nerves with Chlorin Tracers.

Mol Pharm 2021 03 6;18(3):940-951. Epub 2021 Jan 6.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.

Almost 17 million Americans have a history of cancer, a number expected to reach over 22 million by 2030. Cancer patients often undergo chemotherapy in the form of antineoplastic agents such as -platin and paclitaxel. Though effective, these agents can induce debilitating side effects; the most common neurotoxic effect, chemotherapy-induced peripheral neuropathy (CIPN), can endure long after treatment ends. Despite the widespread and chronic nature of the dysfunction, no tools exist to quantitatively measure chemotherapy-induced peripheral neuropathy. Such a tool would not only benefit patients but their stratification could also save significant financial and social costs associated with neuropathic pain. In our first step toward addressing this unmet clinical need, we explored a novel dual approach to localize peripheral nerves: Cerenkov luminescence imaging (CLI) and fluorescence imaging (FI). Our approach revolves around the targeting and imaging of voltage-gated sodium channel subtype Na1.7, highly expressed in peripheral nerves from both harvested human and mouse tissues. For the first time, we show that Hsp1a, a radiolabeled Na1.7-selective peptide isolated from spec. Peru, can serve as a targeted vector for delivering a radioactive sensor to the peripheral nervous system. , we observe high signal-to-noise ratios in the sciatic nerves of animals injected with fluorescently labeled Hsp1a and radiolabeled Hsp1a. Moreover, confocal microscopy on fresh nerve tissue shows the same high ratios of fluorescence, corroborating our results. This study indicates that fluorescently labeled and radiolabeled Hsp1a tracers could be used to identify and demarcate nerves in a clinical setting.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920913PMC
March 2021

Predicting CAR-T cell Immunotherapy Success through ImmunoPET.

Clin Cancer Res 2021 Feb 16;27(4):911-912. Epub 2020 Dec 16.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Chimeric antigen receptor (CAR)-T cell therapy has generated unprecedented advances in the treatment of hematologic cancers, but readily translatable imaging approaches to visualize the dynamics of CAR-T cells are lacking. Noninvasive PET imaging is the ideal tool to monitor CAR-T cells..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887102PMC
February 2021

Polyazamacrocycle Ligands Facilitate Zr Radiochemistry and Yield Zr Complexes with Remarkable Stability.

Inorg Chem 2020 Dec 10;59(23):17473-17487. Epub 2020 Nov 10.

Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States.

Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 (Zr: = 78.4 h, β: 22.8%, = 901 keV; EC: 77%, = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the Zr ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2',2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9,15-Tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2',2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [Zr]Zr-PCTA and [Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02722DOI Listing
December 2020

Imaging Early-Stage Metastases Using an F-Labeled VEGFR-1-Specific Single Chain VEGF Mutant.

Mol Imaging Biol 2021 Jun 6;23(3):340-349. Epub 2020 Nov 6.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Purpose: Metastatic breast cancer is the second leading cause of cancer-related death in women. The 5-year survival rate for metastatic breast cancer has remained near 26.9 % for over a decade. The recruitment of hematopoietic stem cells with high expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in early stages of metastasis formation. We propose the use of an F-labeled single-chain version of VEGF121, re-engineered to be selective for VEGFR-1 (scVR1), as a positron emission tomography (PET) imaging agent to non-invasively image early-stage metastases.

Procedures: scVR1 was F-labeled via a biorthogonal click reaction between site-specifically trans-cyclooctene functionalized scVR1 and an AlF labeled tetrazine-NODA (1,4,7-triazacyclononane-1,4-diiacetic acid). The [F]AlF-NODA-scVR1 was purified using a PD10 column and subsequently analyzed on HPLC to determine radiochemical purity. Animal experiments were performed in 6-8-week-old female BALB/c mice bearing orthotopic primary 4T1 breast tumors or 4T1 metastatic lesions. The [F]AlF-NODA-scVR1 tracer was administered via tail vein injection; PET imaging and ex vivo analysis was performed 2 h post-injection.

Results: The [F]AlF-NODA-scVR1 was prepared with a 98.2 ± 1.5 % radiochemical purity and an apparent molar activity of 7.5 ± 1.2 GBq/μmol. The specific binding of scVR1 to VEGFR-1 was confirmed via bead-based assay. The ex vivo biodistribution showed tumor uptake of 3.5 ± 0.5 % ID/g and was readily observable in PET images. Metastasis formation was detected with [F]AlF-NODA-scVR1 tracer showing colocalization with bioluminescent imaging as well as ex vivo autoradiography and immunofluorescent staining of VEGFR-1.

Conclusions: The diagnostic capabilities of the [F]AlF-NODA-scVR1 PET tracer was confirmed in both orthotopic and metastatic murine cancer models. These results support the potential use of [F]AlF-NODA-scVR1 as a PET tracer that could image metastases, providing clinicians with an additional tool to assess a patient's need for adjuvant therapies.
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http://dx.doi.org/10.1007/s11307-020-01555-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099920PMC
June 2021

B7H3-Directed Intraperitoneal Radioimmunotherapy With Radioiodinated Omburtamab for Desmoplastic Small Round Cell Tumor and Other Peritoneal Tumors: Results of a Phase I Study.

J Clin Oncol 2020 12 29;38(36):4283-4291. Epub 2020 Oct 29.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Desmoplastic small round cell tumor (DSRCT), a rare sarcoma of adolescents/young adults primarily involving the peritoneum, has a long-term survival of < 20% despite aggressive multimodality treatment. B7H3 is expressed on DSRCT cell surface, providing a target for antibody-based immunotherapy.

Patients And Methods: In this phase I study, we evaluated the safety, pharmacokinetics, and biodistribution of intraperitoneal (IP) radioimmunotherapy (RIT) with the anti-B7H3 murine monoclonal antibody I-omburtamab in patients with DSRCT or other B7H3-expressing tumors involving the peritoneum. After thyroid blockade, patients received I-omburtamab as a single IP injection at escalated activities from 1.11 to 3.33/GBq/m. A prior tracer dose of IP 74 MBqI-omburtamab was used for radioimmuno-positron emission tomography imaging. Each injection was followed by IP saline infusion.

Results: Fifty-two patients (48, three, and one with DSRCT, peritoneal rhabdomyosarcoma, and Ewing sarcoma, respectively) received IP I-omburtamab administered on an outpatient basis. Maximum tolerated dose was not reached; there were no dose-limiting toxicities. Major related adverse events were transient: grade 4 neutropenia (n = 2 patients) and thrombocytopenia (n = 1), and grade 1 (10%) and grade 2 (52%) pain lasting < 2 hours related to saline infusion. Hypothyroidism was not observed, and antidrug antibody was elicited in 5%. Mean (± SD) projected peritoneal residence time was 22.4 ± 7.9 hours. Mean projected absorbed doses for I-omburtamab based on I-omburtamab dosimetry to normal organs were low and well within tolerable limits. More than 80% I remained protein bound in blood 66 hours after RIT. On the basis of peritoneal dose and feasibility for outpatient administration, the recommended phase II activity was established at 2.96 GBq/m. Patients with DSRCT receiving standard whole-abdominal radiotherapy after RIT did not experience unexpected toxicity.

Conclusion: IP RIT I-omburtamab was well tolerated with minimal toxicities. Radiation exposure to normal organs was low, making combination therapy with other anticancer therapies feasible.
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http://dx.doi.org/10.1200/JCO.20.01974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768336PMC
December 2020

pHLIP ICG for delineation of tumors and blood flow during fluorescence-guided surgery.

Sci Rep 2020 10 27;10(1):18356. Epub 2020 Oct 27.

Physics Department, University of Rhode Island, Kingston, RI, USA.

Fluorescence imaging has seen enduring use in blood flow visualization and is now finding a new range of applications in image-guided surgery. In this paper, we report a translational study of a new fluorescent agent for use in surgery, pHLIP ICG, where ICG (indocyanine green) is a surgical fluorescent dye used widely for imaging blood flow. We studied pHLIP ICG interaction with the cell membrane lipid bilayer, the pharmacology and toxicology in vitro and in vivo (mice and dogs), and the biodistribution and clearance of pHLIP ICG in mice. The pHLIP ICG tumor targeting and imaging efficacy studies were carried out in several murine and human mouse tumor models. Blood vessels were imaged in mice and pigs. Clinical Stryker imaging instruments for endoscopy and open surgery were used in the study. Intravenously administered pHLIP ICG exhibits a multi-hour circulation half-life, offering protracted delineation of vasculature. As it clears from the blood, pHLIP ICG targets tumors and tumor stroma, marking them for surgical removal. pHLIP ICG is non-toxic, marks blood flow for hours after injection, and effectively delineates tumors for improved resection on the day after administration.
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http://dx.doi.org/10.1038/s41598-020-75443-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591906PMC
October 2020

Harnessing Cu/Cu for a theranostic approach to pretargeted radioimmunotherapy.

Proc Natl Acad Sci U S A 2020 11 26;117(45):28316-28327. Epub 2020 Oct 26.

Department of Chemistry, Hunter College, The City University of New York, New York, NY 10021;

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (Cu, = 12.7 h) and beta particle-emitting copper-67 (Cu, = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a Cu-labeled Tz radioligand ([Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [Cu]Cu-MeCOSar-Tz and [Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [Cu]Cu-MeCOSar-Tz.
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http://dx.doi.org/10.1073/pnas.2009960117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668034PMC
November 2020

Antibody-Targeted Imaging of Gastric Cancer.

Molecules 2020 Oct 11;25(20). Epub 2020 Oct 11.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The specificity of antibodies for antigens overexpressed or uniquely expressed in tumor cells makes them ideal candidates in the development of bioconjugates for tumor imaging. Molecular imaging can aid clinicians in the diagnosis of gastric tumors and in selecting patients for therapies targeting receptors with a heterogeneous intratumoral or intertumoral expression. Antibodies labeled with an imaging radiometal can be used to detect primary tumors and metastases using whole-body positron emission tomography (PET) or single photon emission computed tomography (SPECT), both during diagnosis and monitoring disease response. Conjugated with fluorescent dyes, antibodies can image tumors by targeted optical imaging. This review provides an overview of the most recent advances in the use of antibodies labeled with radiometals or conjugated with fluorescent dyes for gastric cancer imaging.
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http://dx.doi.org/10.3390/molecules25204621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587187PMC
October 2020

Acute Statin Treatment Improves Antibody Accumulation in EGFR- and PSMA-Expressing Tumors.

Clin Cancer Res 2020 Dec 30;26(23):6215-6229. Epub 2020 Sep 30.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Statins are cholesterol-depleting drugs used to treat patients with hypercholesterolemia. Preclinically, statins disrupt trafficking of receptors present at the cell membrane. Membrane receptors, defined as tumor biomarkers and therapeutic targets, are often internalized by an endocytic pathway. Indeed, receptor endocytosis and recycling are dynamic mechanisms that often affect receptor density at the cell surface. In therapies using monoclonal antibodies (mAb), a downregulation in receptor density at the cell surface decreases antibody binding to the extracellular domain of the membrane receptor. Here, we determined the potential of lovastatin, simvastatin, and rosuvastatin in preclinically modulating epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) receptor density at the tumor cell surface.

Experimental Design: Small-animal PET was used to study the binding of Zr-labeled antibodies in ectopic xenografts. analyses were performed to determine changes in endocytic proteins, EGFR, and PSMA surface levels.

Results: Acute statin treatment using lovastatin, simvastatin, or rosuvastatin enhanced tumors' avidity for the mAbs panitumumab, cetuximab, and huJ591. Statins temporarily modulated caveolin-1, cavin-1, endophilin, clathrin, and dynamin proteins in EGFR- and PSMA-overexpressing xenografts.

Conclusions: These data show the potential of statins as pharmacologic modulators of endocytic proteins for improved tumors' accumulation of mAbs. The translational significance of these findings lies in the potential of statins to temporarily modulate the heterogeneous presence of receptors at the cell membrane, a characteristic often associated with poor response in tumors to therapeutic antibodies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1960DOI Listing
December 2020

Comparison of Methods for Surface Modification of Barium Titanate Nanoparticles for Aqueous Dispersibility: Toward Biomedical Utilization of Perovskite Oxides.

ACS Appl Mater Interfaces 2020 Nov 3;12(46):51135-51147. Epub 2020 Nov 3.

Department of Chemistry and Biochemistry, The City College of New York, 1024 Marshak, 160 Convent Avenue, New York, New York 10031, United States.

Colloidal perovskite barium titanate (BaTiO, or BT) nanoparticles (NPs), conventionally used for applications in electronics, can also be considered for their potential as biocompatible computed tomography (CT) contrast agents. NPs of BT produced by traditional solid-state methods tend to have broad size distributions and poor dispersibility in aqueous media. Furthermore, uncoated BT NPs can be cytotoxic because of leaching of the heavy metal ion, Ba. Here, we present and compare three approaches for surface modification of BT NPs (8 nm) synthesized by the gel collection method to improve their aqueous stability and dispersibility. The first approach produced citrate-capped BT NPs that exhibited extremely high aqueous dispersibility (up to 50 mg/mL) and a small hydrodynamic size (11 nm). Although the high dispersibility was found to be pH-dependent, such aqueous stability sufficiently enabled a feasibility analysis of BT NPs as CT contrast agents. The second approach, a core/shell design, aimed to encapsulate BT nanoaggregates with a silica layer using a modified Stöber method. A cluster of 7-20 NPs coated with a thick layer (20-100 nm) of SiO was routinely observed, producing larger NPs in the 100-200 nm range. A third approach was developed using a reverse-microemulsion method to encapsulate a single BT core within a thin (10 nm) silica layer, with an overall particle size of 29 nm. The -OH groups on the silica layer readily enabled surface PEGylation, allowing the NPs to remain highly stable in saline solutions. We report that the silica-coated BT NPs in both methods exhibited a low level of Ba leaching (≤3% of total barium in NPs) in phosphate-buffered saline for 48 h compared to the unmodified BT NPs (14.4%).
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http://dx.doi.org/10.1021/acsami.0c10063DOI Listing
November 2020

Aromatic carbohydrate amphiphile disrupts cancer spheroids and prevents relapse.

Nanoscale 2020 Oct;12(37):19088-19092

3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3Bs - PT Government Associate Laboratory, Braga/Guimarães, Portugal.

Spheroids recapitulate the organization, heterogeneity and microenvironment of solid tumors. Herein, we targeted spatiotemporally the accelerated metabolism of proliferative cells located on the spheroid surface that ensure structure maintenance and/or growth. We demonstrate that phosphorylated carbohydrate amphiphile acts as a potent antimetabolite due to glycolysis inhibition and to in situ formation of supramolecular net around spheroid surface where alkaline phosphatase is overexpressed. The efficiency of the treatment is higher in spheroids as compared to the conventional 2D cultures because of the 2-fold higher expression of glucose transporter 1 (GLUT1). Moreover, treated spheroids do not undergo following relapse.
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http://dx.doi.org/10.1039/d0nr05008cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541621PMC
October 2020

Leveraging synthetic chlorins for bio-imaging applications.

Chem Commun (Camb) 2020 Oct;56(83):12608-12611

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. and Department of Chemistry, Hunter College of The City University of New York, 695 Park Avenue, New York, NY 10065, USA.

Synthetic chlorins are not only fluorescent, the modulation of the tetrapyrrole system can also chelate metal ions. Conjugation of linkers at their pyrrolidines allows for conjugation to bio-molecules to create target specificity. By altering these chemo-photophysical properties, this work facilitates the use of chlorins in fluorescent imaging and positron emission tomography (PET).
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http://dx.doi.org/10.1039/d0cc05494aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907923PMC
October 2020

ImmunoPET Imaging of Pancreatic Tumors with Zr-Labeled Gold Nanoparticle-Antibody Conjugates.

Mol Imaging Biol 2021 02 9;23(1):84-94. Epub 2020 Sep 9.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Targeted delivery in vivo remains an immense roadblock for the translation of nanomaterials into the clinic. The greatest obstacle is the mononuclear phagocyte system (MPS), which sequesters foreign substances from general circulation and causes accumulation in organs such as the liver and spleen. The purpose of this study was to determine whether attaching an active targeting antibody, 5B1, to the surface of gold nanoparticles and using clodronate liposomes to deplete liver and splenic macrophages could help to minimize uptake by MPS organs, increase targeted delivery to CA19.9-positive pancreatic tumors, and enhance pancreatic tumor delineation.

Procedures: To produce the antibody-gold nanoparticle conjugate (Ab-AuNP), the Ab was conjugated to p-isothiocyanatobenzyl-desferrioxamine (p-SCN-DFO) and subsequently conjugated to NHS-activated gold nanoparticles. The Ab-AuNP was characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Modified Lindmo assay was performed to assess binding affinity and internalization potential in vitro. The Ab-AuNP was radiolabeled with Zr and injected into CA19.9-positive BxPc-3 pancreatic orthotopic tumor-bearing mice pretreated with or without clodronate liposomes for PET imaging and biodistribution studies. Inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis was used to confirm delivery of gold nanoparticles to BxPc-3 pancreatic subcutaneous xenografts.

Results: Mice pretreated with clodronate liposomes in an orthotopic setting demonstrated decreased liver uptake at early time points (12.2 ± 2.3 % ID/g vs. 22.8 ± 3.8 % ID/g at 24 h) and increased tumor uptake at 120 h (13.8 ± 8.0 % ID/g vs. 6.0 ± 1.2 % ID/g). This allowed for delineation of orthotopic pancreatic xenografts in significantly more mice treated with clodronate (6/6) than in mice not treated with clodronate (2/6) or mice injected with gold nanoparticles labeled with a nonspecific antibody (0/5).

Conclusions: The combination of clodronate liposomes and an active targeting antibody on the surface of gold nanoparticles allowed for PET/CT imaging of subcutaneous and orthotopic pancreatic xenografts in mice.
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http://dx.doi.org/10.1007/s11307-020-01535-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785666PMC
February 2021

A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89.

Inorg Chem 2020 Aug 28;59(16):11715-11727. Epub 2020 Jul 28.

Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.

Herein we report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). Our new chelator-DFO2-is acyclic and was designed and synthesized with the purpose of improving the coordination chemistry and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([Zr]Zr) has found wide use for positron emission tomography (PET) imaging when it is coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination number of 12, which uniquely positions this chelator for binding large, high-valent, and oxophilic metal ions. Following synthesis of the DFO2 chelator and the [Zr]Zr-(DFO2) complex we performed density functional theory calculations to study its coordination sphere, followed by zirconium-89 radiolabeling experiments for comparisons with the "gold standard" chelator DFO. DFO (CN 6) can coordinate with zirconium in a hexadentate fashion, leaving two open coordination sites where water is thought to coordinate (total CN 8). DFO2 (potential CN 12, dodecadentate) can saturate the coordination sphere of zirconium with four hydroxamate groups (CN 8), with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quantitative radiolabeling with zirconium-89, the preformed [Zr]Zr-(DFO) and [Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of stability challenges, including human blood serum, -transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to determine if the increased denticity of DFO2 over that of DFO imparted improved complex stability, and another was to determine which of these assays is most relevant to perform with future chelators. In all of the assays DFO2 showed superior stability with zirconium-89, except for the iron challenge, where both DFO2 and DFO were identical. Substantial differences in stability were observed for human blood serum using a precipitation method of analysis, -transferrin, hydroxyapatite, and EDTA challenges. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochemistry with even larger radionuclides, which we anticipate will expand the utility of DFO2 into theranostic applications.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01629DOI Listing
August 2020

Oncology-Inspired Treatment Options for COVID-19.

J Nucl Med 2020 12 17;61(12):1720-1723. Epub 2020 Jul 17.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

CR3022 is a human antibody that binds to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we explore the use of CR3022 as a molecularly targeted radiotherapeutic. CR3022 was labeled with I and purified, yielding I-CR3022. Using a magnetic bead assay and a recombinant SARS-CoV-2 spike protein fragment, we tested binding of I-CR3022 in the presence and absence of CR3022. We conjugated the antibody CR3022 with a purity of more than 98% and a specific activity of more than 292 MBq/mg. Using a bead-based assay, we confirmed that binding of I-CR3022 is selective and is significantly reduced in the presence of unlabeled antibody (3.14% ± 0.14% specific uptake and 0.10% ± 0.01% specific uptake, respectively; < 0.0001). Our results confirm the potential of CR3022 as a molecularly targeted probe for SARS-CoV-2. A labeled version of CR3022 could potentially be used for Auger radiotherapy or noninvasive imaging.
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http://dx.doi.org/10.2967/jnumed.120.249748DOI Listing
December 2020

Head-to-Head Evaluation of F-FES and F-FDG PET/CT in Metastatic Invasive Lobular Breast Cancer.

J Nucl Med 2021 03 17;62(3):326-331. Epub 2020 Jul 17.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.

Invasive lobular carcinoma (ILC) demonstrates lower conspicuity on F-FDG PET than the more common invasive ductal carcinoma. Other molecular imaging methods may be needed for evaluation of this malignancy. As ILC is nearly always (95%) estrogen receptor (ER)-positive, ER-targeting PET tracers such as 16α-F-fluoroestradiol (F-FES) may have value. We reviewed prospective trials at Memorial Sloan Kettering Cancer Center using F-FES PET/CT to evaluate metastatic ILC patients with synchronous F-FDG and F-FES PET/CT imaging, which allowed a head-to-head comparison of these 2 PET tracers. Six prospective clinical trials using F-FES PET/CT in patients with metastatic breast cancer were performed at Memorial Sloan Kettering Cancer Center from 2008 to 2019. These trials included 92 patients, of whom 14 (15%) were of ILC histology. Seven of 14 patients with ILC had F-FDG PET/CT performed within 5 wk of the research F-FES PET/CT and no intervening change in management. For these 7 patients, the F-FES and F-FDG PET/CT studies were analyzed to determine the total number of tracer-avid lesions, organ systems of involvement, and SUV of each organ system for both tracers. In the 7 comparable pairs of scans, there were a total of 254 F-FES-avid lesions (SUV, 2.6-17.9) and 111 F-FDG-avid lesions (SUV, 3.3-9.9) suggestive of malignancy. For 5 of 7 (71%) ILC patients, F-FES PET/CT detected more metastatic lesions than F-FDG PET/CT. In the same 5 of 7 patients, the SUV of F-FES-avid lesions was greater than the SUV of F-FDG-avid lesions. One patient had F-FES-avid metastases with no corresponding F-FDG-avid metastases. There were no patients with F-FDG-avid distant metastases without F-FES-avid distant metastases, although in one patient liver metastases were evident on F-FDG but not on F-FES PET. F-FES PET/CT compared favorably with F-FDG PET/CT for detection of metastases in patients with metastatic ILC. Larger prospective trials of F-FES PET/CT in ILC should be considered to evaluate ER-targeted imaging for clinical value in patients with this histology of breast cancer.
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http://dx.doi.org/10.2967/jnumed.120.247882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049349PMC
March 2021

Immuno-PET Detects Changes in Multi-RTK Tumor Cell Expression Levels in Response to Targeted Kinase Inhibition.

J Nucl Med 2021 03 9;62(3):366-371. Epub 2020 Jul 9.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Receptor tyrosine kinase (RTK) coexpression facilitates tumor resistance due to redundancies in the phosphatidylinositol-3'-kinase/protein kinase B and KRAS/extracellular-signal-regulated kinase signaling pathways, among others. Crosstalk between the oncogenic RTK hepatocyte growth factor receptor (MET), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) are involved in tumor resistance to RTK-targeted therapies. In a relevant renal cell carcinoma patient-derived xenograft model, we use the Zr-labeled anti-RTK antibodies (immuno-PET) onartuzumab, panitumumab, and trastuzumab to monitor MET, EGFR, and HER2 protein levels, respectively, during treatment with agents to which the model was resistant (cetuximab) or sensitive (INC280 and trametinib). Cetuximab treatment resulted in continued tumor growth, as well as an increase in all RTK protein levels at the tumor in vivo on immuno-PET and ex vivo at the cellular level. Conversely, after dual MET/mitogen-activated protein kinase inhibition, tumor growth was significantly blunted and corresponded to a decrease in RTK levels. These data show the utility of RTK-targeted immuno-PET to annotate RTK changes in protein expression and inform tumor response to targeted therapies.
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http://dx.doi.org/10.2967/jnumed.120.244897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049345PMC
March 2021

A Molecularly Targeted Intraoperative Near-Infrared Fluorescence Imaging Agent for High-Grade Serous Ovarian Cancer.

Mol Pharm 2020 08 16;17(8):3140-3147. Epub 2020 Jul 16.

Department of Chemistry, Hunter College, City University of New York, New York, New York 10021, United States.

Ovarian cancer is the fifth leading cause of cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. The foundation of its management consists of cytoreductive surgery (CRS) followed by systemic chemotherapy, with the completeness of surgical resection consistently identified as one of the most important prognostic factors for the disease. The goal of our investigation is the development of a near-infrared fluorescence (NIRF) imaging agent for the intraoperative imaging of high-grade serous ovarian cancer (HGSOC). As surgeons are currently limited to the visual and manual assessment of tumor tissue during CRS, this technology could facilitate more complete resections as well as serve important functions at other points in the surgical management of the disease. Elevated levels of cancer antigen 125 (CA125) have proven a useful biomarker of HGSOC, and the CA125-targeting antibody B43.13 has shown potential as a platform for immunoPET imaging in murine models of ovarian cancer. Herein, we report the development of a NIRF imaging agent based on B43.13: B43.13-IR800. We site-specifically modified the heavy chain glycans of B43.13 with the near-infrared dye IRDye 800CW using a chemoenzymatic approach developed in our laboratories. SDS-PAGE analysis confirmed the specificity of the conjugation reaction, and flow cytometry, immunostaining, and fluorescence microscopy verified the specific binding of B43.13-IR800 to CA125-expressing OVCAR3 human ovarian cancer cells. NIRF imaging studies demonstrated that B43.13-IR800 can be used to image CA125-expressing HGSOC tumors in subcutaneous, orthotopic, and patient-derived xenograft mouse models. Finally, analyses confirmed that B43.13-IR800 can bind and identify CA125-expressing cells in primary tumor and metastatic lymph node samples from human patients with HGSOC.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961817PMC
August 2020

Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted Zr-Pertuzumab PET/CT.

Radiology 2020 08 9;296(2):370-378. Epub 2020 Jun 9.

From the Department of Radiology (G.A.U., J.A.C., C.C.R., R.Y., V.H., B.M.Z., S.K.L., J.S.L.), Department of Pathology (D.S.R.), Department of Medicine (K.J., S.C., D.M.H.), and Molecular Pharmacology Program (B.M.Z., J.S.L.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 77, New York, NY 10065; Departments of Radiology (G.A.U., J.A.C., C.C.R., R.Y., V.H., S.K.L., J.S.L.) and Medicine (K.J., S.C., D.M.H.), Weill Cornell Medical College, New York, NY; and Department of Chemistry, Hunter College, City University of New York, New York, NY (B.M.Z.).

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies are successful in patients with HER2-positive malignancies; however, spatial and temporal heterogeneity of HER2 expression may prevent identification of optimal patients for these therapies. Purpose To determine whether imaging with the HER2-targeted PET tracer zirconium 89 (Zr)-pertuzumab can depict HER2-positive metastases in women with HER2-negative primary breast cancer. Materials and Methods From January to June 2019, women with biopsy-proven HER2-negative primary breast cancer and biopsy-proven metastatic disease were enrolled in a prospective clinical trial ( NCT02286843) and underwent Zr-pertuzumab PET/CT for noninvasive whole-biopsy evaluation of potential HER2-positive metastases. Zr-pertuzumab-avid foci that were suspicious for HER2-positive metastases were tissue sampled and examined by pathologic analysis to document HER2 status. Results Twenty-four women (mean age, 55 years ± 11 [standard deviation]) with HER2-negative primary breast cancer were enrolled. Six women demonstrated foci at Zr-pertuzumab PET/CT that were suspicious for HER2-positive disease. Of these six women, three had biopsy-proven HER2-positive metastases, two had pathologic findings that demonstrated HER2-negative disease, and one had a fine-needle aspirate with inconclusive results. Conclusion Human epidermal growth factor receptor 2 (HER2)-targeted imaging with zirconium 89-pertuzumab PET/CT was successful in detecting HER2-positive metastases in women with HER2-negative primary breast cancer. This demonstrates the ability of targeted imaging to identify patients for targeted therapies that might not otherwise be considered. © RSNA, 2020 See the editorial by Mankoff and Pantel in this issue.
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http://dx.doi.org/10.1148/radiol.2020192828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543717PMC
August 2020

Zr-PET imaging of DNA double-strand breaks for the early monitoring of response following α- and β-particle radioimmunotherapy in a mouse model of pancreatic ductal adenocarcinoma.

Theranostics 2020 27;10(13):5802-5814. Epub 2020 Apr 27.

Department of Radiology, Memorial Sloan Kettering Cancer Center, NY, USA.

: The evaluation of early treatment response is critical for patient prognosis and treatment planning. When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated histone γH2AX in the context of pancreatic cancer targeted radionuclide therapy. Pancreatic ductal adenocarcinoma has a poor patient prognosis due to the absence of curative treatment for patients with advanced disease. There is therefore a critical need for the fast clinical translation of new therapeutic options. In line with these observations, our group has been focusing on the development of radiotheranostic agents based on a fully human monoclonal antibody (5B1) with exceptional affinity for CA19.9, an antigen overexpressed in PDAC. Two on-going clinical trials resulted from these efforts, one with Zr (diagnosis) and one with Lu (β-particle therapy). More recently, we successfully developed and evaluated in PDAC mouse models a targeted α-therapy strategy with high clinical translation potential. We aim to expedite the clinical translation of the developed radioimmunotherapy approaches by investigating the early therapeutic response and effect of radiation therapy in a PDAC mouse model via PET imaging. : Mice bearing BxPC3 tumor xenografts were treated with α- and β-particle pretargeted radioimmunotherapy (PRIT), external beam radiotherapy (EBRT), or sham-treated (vehicle). The phosphorylated histone γH2AX produced as a response to DNA double strand breaks was quantified with the PET radiotracer, [Zr]Zr-DFO-anti-γH2AX-TAT. : PET imaging studies in BxPC3 PDAC mouse models demonstrated increased uptake of [Zr]Zr-DFO-anti-γH2AX-TAT (6.29 ± 0.15 %IA/g) following β-PRIT in BxPC3 PDAC xenografts as compared to the saline control group (4.58 ± 0.76 %IA/g) and EBRT control group (5.93 ± 0.76 %IA/g). Similarly, significantly higher uptake of [Zr]Zr-DFO-anti-γH2AX-TAT was observed in tumors of the Ac-PRIT and EBRT (10 Gy) cohorts (7.37 ± 1.23 and 6.80 ± 1.24 %IA/g, respectively) compared to the negative control cohort (5.08 ± 0.95 %IA/g). γH2AX immunohistochemistry and immunofluorescence analysis correlated with Zr-anti-γH2AX PET/CT imaging with increased γH2AX positive cell and γH2AX foci per cell in the treated cohorts. When α-PRIT resulted in prolonged overall survival of treated animals (107.5 days) as compared to β-PRIT (73.0 days), no evidence of difference in [Zr]Zr-DFO-anti-γH2AX-TAT uptake at the tumor site was observed, highlighting that DNA damage is not the sole radiobiology paradigm and that off-targeted (bystander) effects should be considered. : PET imaging studies with [Zr]Zr-DFO-anti-γH2AX-TAT following α- and β-particle PRIT in a BxPC3 PDAC subcutaneous xenograft mouse model allowed the monitoring of tumor radiobiological response to treatment.
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http://dx.doi.org/10.7150/thno.44772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255009PMC
April 2020