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Volpe A, Adusumilli PS, Schöder H, Ponomarev V. Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients. J Immunother Cancer 2022; 10:jitc-2022-004902. [PMID: 36137649 PMCID: PMC9511655 DOI: 10.1136/jitc-2022-004902] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2022] [Indexed: 01/26/2023] Open
Abstract
Cellular immunotherapies have emerged as a successful therapeutic approach to fight a wide range of human diseases, including cancer. However, responses are limited to few patients and tumor types. An in-depth understanding of the complexity and dynamics of cellular immunotherapeutics, including what is behind their success and failure in a patient, the role of other immune cell types and molecular biomarkers in determining a response, is now paramount. As the cellular immunotherapy arsenal expands, whole-body non-invasive molecular imaging can shed a light on their in vivo fate and contribute to the reliable assessment of treatment outcome and prediction of therapeutic response. In this review, we outline the non-invasive strategies that can be tailored toward the molecular imaging of cellular immunotherapies and immune-related components, with a focus on those that have been extensively tested preclinically and are currently under clinical development or have already entered the clinical trial phase. We also provide a critical appraisal on the current role and consolidation of molecular imaging into clinical practice.
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Affiliation(s)
- Alessia Volpe
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA,Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA,Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Vladimir Ponomarev
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA,Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA,Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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2
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Abstract
MRI is a widely available clinical tool for cancer diagnosis and treatment monitoring. MRI provides excellent soft tissue imaging, using a wide range of contrast mechanisms, and can non-invasively detect tissue metabolites. These approaches can be used to distinguish cancer from normal tissues, to stratify tumor aggressiveness, and to identify changes within both the tumor and its microenvironment in response to therapy. In this review, the role of MRI in immunotherapy monitoring will be discussed and how it could be utilized in the future to address some of the unique clinical questions that arise from immunotherapy. For example, MRI could play a role in identifying pseudoprogression, mixed response, T cell infiltration, cell tracking, and some of the characteristic immune-related adverse events associated with these agents. The factors to be considered when developing MRI imaging biomarkers for immunotherapy will be reviewed. Finally, the advantages and limitations of each approach will be discussed, as well as the challenges for future clinical translation into routine clinical care. Given the increasing use of immunotherapy in a wide range of cancers and the ability of MRI to detect the microstructural and functional changes associated with successful response to immunotherapy, the technique has great potential for more widespread and routine use in the future for these applications.
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Affiliation(s)
- Doreen Lau
- Centre for Immuno-Oncology, University of Oxford, Oxford, UK
| | - Pippa G Corrie
- Department of Oncology, Addenbrooke's Hospital, Cambridge, UK
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3
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Lim TX, Ahamed M, Reutens DC. The aryl hydrocarbon receptor: A diagnostic and therapeutic target in glioma. Drug Discov Today 2021; 27:422-435. [PMID: 34624509 DOI: 10.1016/j.drudis.2021.09.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 07/29/2021] [Accepted: 09/29/2021] [Indexed: 12/19/2022]
Abstract
Glioblastoma multiforme (GBM) is a deadly disease; 5-year survival rates have shown little improvement over the past 30 years. In vivo positron emission tomography (PET) imaging is an important method of identifying potential diagnostic and therapeutic molecular targets non-invasively. The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates multiple genes involved in immune response modulation and tumorigenesis. The AhR is an attractive potential drug target and studies have shown that its activation by small molecules can modulate innate and adaptive immunity beneficially and prevent AhR-mediated tumour promotion in several cancer types. In this review, we provide an overview of the role of the AhR in glioma tumorigenesis and highlight its potential as an emerging biomarker for glioma therapies targeting the tumour immune response and PET diagnostics.
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Affiliation(s)
- Ting Xiang Lim
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Muneer Ahamed
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - David C Reutens
- ARC Centre for Innovation in Biomedical Imaging Technology, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.
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4
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Iyalomhe O, Farwell MD. Immune PET Imaging. Radiol Clin North Am 2021; 59:875-886. [PMID: 34392924 PMCID: PMC8371717 DOI: 10.1016/j.rcl.2021.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Fluorodeoxyglucose (FDG) PET/CT is sensitive to metabolic, immune-related, and structural changes that can occur in tumors in cancer immunotherapy. Unique mechanisms of immune checkpoint inhibitors (ICIs) occasionally make response evaluation challenging, because tumors and inflammatory changes are both FDG avid. These response patterns and sequelae of ICI immunotherapy, such as immune-related adverse events, are discussed. Immune-specific PET imaging probes at preclinical stage or in early clinical trials, which may help guide clinical management of cancer patients treated with immunotherapy and likely have applications outside of oncology for other diseases in which the immune system plays a role, are reviewed.
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Affiliation(s)
- Osigbemhe Iyalomhe
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael D. Farwell
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
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5
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Shao F, Long Y, Ji H, Jiang D, Lei P, Lan X. Radionuclide-based molecular imaging allows CAR-T cellular visualization and therapeutic monitoring. Am J Cancer Res 2021; 11:6800-6817. [PMID: 34093854 PMCID: PMC8171102 DOI: 10.7150/thno.56989] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is a new and effective form of adoptive cell therapy that is rapidly entering the mainstream for the treatment of CD19-positive hematological cancers because of its impressive effect and durable responses. Huge challenges remain in achieving similar success in patients with solid tumors. The current methods of monitoring CAR-T, including morphological imaging (CT and MRI), blood tests, and biopsy, have limitations to assess whether CAR-T cells are homing to tumor sites and infiltrating into tumor bed, or to assess the survival, proliferation, and persistence of CAR-T cells in solid tumors associated with an immunosuppressive microenvironment. Radionuclide-based molecular imaging affords improved CAR-T cellular visualization and therapeutic monitoring through either a direct cellular radiolabeling approach or a reporter gene imaging strategy, and endogenous cell imaging is beneficial to reflect functional information and immune status of T cells. Focusing on the dynamic monitoring and precise assessment of CAR-T therapy, this review summarizes the current applications of radionuclide-based noninvasive imaging in CAR-T cells visualization and monitoring and presents current challenges and strategic choices.
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6
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Volpe A, Nagle VL, Lewis JS, Ponomarev V. Predicting CAR-T cell Immunotherapy Success through ImmunoPET. Clin Cancer Res 2021; 27:911-912. [PMID: 33328345 PMCID: PMC7887102 DOI: 10.1158/1078-0432.ccr-20-4297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/01/2020] [Accepted: 12/14/2020] [Indexed: 11/16/2022]
Abstract
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 in vivo dynamics of CAR-T cells are lacking. Noninvasive PET imaging is the ideal tool to monitor CAR-T cells.See related article by Simonetta et al., p. 1058.
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Affiliation(s)
- Alessia Volpe
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vladimir Ponomarev
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
- Weill Cornell Medical College, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
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7
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Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria. Mol Imaging Biol 2021; 22:47-65. [PMID: 31049831 DOI: 10.1007/s11307-019-01361-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"
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8
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Arlauckas S, Oh N, Li R, Weissleder R, Miller MA. Macrophage imaging and subset analysis using single-cell RNA sequencing. Nanotheranostics 2021; 5:36-56. [PMID: 33391974 PMCID: PMC7738942 DOI: 10.7150/ntno.50185] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/19/2020] [Indexed: 12/12/2022] Open
Abstract
Macrophages have been associated with drug response and resistance in diverse settings, thus raising the possibility of using macrophage imaging as a companion diagnostic to inform personalized patient treatment strategies. Nanoparticle-based contrast agents are especially promising because they efficiently deliver fluorescent, magnetic, and/or radionuclide labels by leveraging the intrinsic capacity of macrophages to accumulate nanomaterials in their role as professional phagocytes. Unfortunately, current clinical imaging modalities are limited in their ability to quantify broad molecular programs that may explain (a) which particular cell subsets a given imaging agent is actually labeling, and (b) what mechanistic role those cells play in promoting drug response or resistance. Highly multiplexed single-cell approaches including single-cell RNA sequencing (scRNAseq) have emerged as resources to help answer these questions. In this review, we query recently published scRNAseq datasets to support companion macrophage imaging, with particular focus on using dextran-based nanoparticles to predict the action of anti-cancer nanotherapies and monoclonal antibodies.
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Affiliation(s)
- Sean Arlauckas
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA
| | - Nuri Oh
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA
| | - Ran Li
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA.,Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA.,Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.,Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Miles A Miller
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA.,Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA
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Development of [ 89Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma. Eur J Nucl Med Mol Imaging 2020; 48:1302-1311. [PMID: 33179150 DOI: 10.1007/s00259-020-05097-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/26/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [89Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models. METHODS Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [89Zr]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [89Zr]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [18F]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [89Zr]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [89Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. RESULTS [89Zr]DFO-elotuzumab was produced with high specific activity (56 ± 0.75 MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1S-CG cells. Compared to [89Zr]DFO-IgG, [89Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [89Zr]DFO-elotuzumab in the bones. Importantly, while [18F]FDG demonstrated similar uptake in the bone and muscle, [89Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones. CONCLUSION These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
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Schmitzer B, Schafers KP, Wirth B. Dynamic Cell Imaging in PET With Optimal Transport Regularization. IEEE TRANSACTIONS ON MEDICAL IMAGING 2020; 39:1626-1635. [PMID: 31751230 DOI: 10.1109/tmi.2019.2953773] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
We propose a novel dynamic image reconstruction method from PET listmode data that could be particularly suited to tracking single or small numbers of cells. In contrast to conventional PET reconstruction our method combines the information from all detected events not only to reconstruct the dynamic evolution of the radionuclide distribution, but also to improve the reconstruction at each single time point by enforcing temporal consistency. This is achieved via optimal transport regularization where in principle, among all possible temporally evolving radionuclide distributions consistent with the PET measurement, the one is chosen with least kinetic motion energy. The reconstruction is found by convex optimization so that there is no dependence on the initialization of the method. We study its behaviour on simulated data of a human PET system and demonstrate its robustness even in settings with very low radioactivity. In contrast to previously reported cell tracking algorithms, our technique is oblivious to the number of tracked cells. Without any additional complexity one or multiple cells can be reconstructed, and the model automatically determines the number of particles. For instance, four radiolabelled cells moving at a velocity of 3.1 mm/s and a PET recorded count rate of 1.1 cps (for each cell) could be simultaneously tracked with a tracking accuracy of 5.3 mm inside a simulated human body.
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11
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Lan Q, Ji C, Yao Y. [Basis of Tumor Microenvironment Relevant to Immunotherapies for Brain Metastases of NSCLC]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 22:512-519. [PMID: 31451142 PMCID: PMC6717868 DOI: 10.3779/j.issn.1009-3419.2019.08.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
脑是非小细胞肺癌(non-small cell lung cancer, NSCLC)最常见的远处转移部位，脑转移也是晚期肺癌致残致死的主要原因。近年来，小分子酪氨酸激酶抑制剂的应用和疗效奠定了驱动基因突变阳性的NSCLC脑转移的治疗基础。随着程序性死亡受体1(programmed cell death protein 1, PD-1)/程序性死亡受体配体1(programmed cell death protein ligand 1, PD-L1)抑制剂及相应联合疗法的不断发展，免疫治疗已成为驱动基因突变泛阴性的NSCLC脑转移患者的重要选择，相关生物标志物的价值也日益凸显。由于NSCLC脑转移肿瘤及其微环境的免疫病理特征具有一定的特殊性，本文旨在回顾相关研究进展，并为免疫治疗联合策略的探索与新型免疫疗法的开发提供参考。
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Affiliation(s)
- Qing Lan
- Immunology Laboratory, Neurosurgical Institute of Fudan University; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Chunxia Ji
- Immunology Laboratory, Neurosurgical Institute of Fudan University; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yu Yao
- Immunology Laboratory, Neurosurgical Institute of Fudan University; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
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12
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Ahmed S, Nakaji-Hirabayashi T, Rajan R, Zhao D, Matsumura K. Cytosolic delivery of quantum dots mediated by freezing and hydrophobic polyampholytes in RAW 264.7 cells. J Mater Chem B 2019; 7:7387-7395. [PMID: 31697291 DOI: 10.1039/c9tb01184f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Quantum dots (QDs) can be delivered efficiently inside macrophages using a freeze-concentration approach. In this study, we introduced a new, facile, high concentration-based freezing technology of low toxicity. We also developed QD-conjugated new hydrophobic polyampholytes using poly-l-lysine (PLL), a naturally derived polymer, which showed sustained biocompatibility, stability over one week, and enhanced intracellular delivery. When freeze-concentration was applied, the QD-encapsulated hydrophobic polyampholytes showed a higher tendency to adsorb onto the cell membrane than the non-frozen molecules. Interestingly, we observed that the efficacy of adsorption of QDs on RAW 264.7 macrophages was higher than that on fibroblasts. Furthermore, the intracellular delivery of QDs using hydrophobic polyampholytes was higher than those of PLL and QDs. In vitro studies revealed the efficient endosomal escape of QDs in the presence of hydrophobic polyampholytes and freeze-concentration. Collectively, these observations indicated that the promising combination of freeze-concentration and hydrophobic polyampholytes may act as an effective and versatile strategy for the intracellular delivery of QDs, which can be used for biological diagnosis and therapeutic applications.
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Affiliation(s)
- Sana Ahmed
- School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), Nomi, Ishikawa 923-1292, Japan. and Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, Toyama 930-8555, Japan
| | - Tadashi Nakaji-Hirabayashi
- Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, Toyama 930-8555, Japan and Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama, Toyama 930-8555, Japan
| | - Robin Rajan
- School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), Nomi, Ishikawa 923-1292, Japan.
| | - Dandan Zhao
- School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), Nomi, Ishikawa 923-1292, Japan.
| | - Kazuaki Matsumura
- School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), Nomi, Ishikawa 923-1292, Japan.
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Minn I, Rowe SP, Pomper MG. Enhancing CAR T-cell therapy through cellular imaging and radiotherapy. Lancet Oncol 2019; 20:e443-e451. [PMID: 31364596 DOI: 10.1016/s1470-2045(19)30461-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/13/2022]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is one of the most remarkable advances in cancer therapy in the last several decades. More than 300 adoptive T-cell therapy trials are ongoing, which is a testament to the early success and hope engendered by this line of investigation. Despite the enthusiasm, application of CAR T-cell therapy to solid tumours has had little success, although positive outcomes are increasingly being reported for these diseases. In this Series paper, we discuss the short-term strategies to improve CAR T-cell therapy responses, particularly for solid tumours, by combining CAR T-cell therapy with radiotherapy through the use of careful monitoring and non-invasive imaging. Through the use of imaging, we can gain greater mechanistic insights into the cascade of events that must unfold to enable tumour eradication by CAR T-cell therapy.
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Affiliation(s)
- Il Minn
- Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Steven P Rowe
- Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Martin G Pomper
- Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Krebs S, Ponomarev V, Slovin S, Schöder H. Imaging of CAR T-Cells in Cancer Patients: Paving the Way to Treatment Monitoring and Outcome Prediction. J Nucl Med 2019; 60:879-881. [PMID: 31053682 PMCID: PMC12079154 DOI: 10.2967/jnumed.119.227561] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Simone Krebs
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vladimir Ponomarev
- Radiochemistry and Molecular Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York; and
| | - Susan Slovin
- Guam Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Heiko Schöder
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
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15
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Man F, Lim L, Volpe A, Gabizon A, Shmeeda H, Draper B, Parente-Pereira AC, Maher J, Blower PJ, Fruhwirth GO, T M de Rosales R. In Vivo PET Tracking of 89Zr-Labeled Vγ9Vδ2 T Cells to Mouse Xenograft Breast Tumors Activated with Liposomal Alendronate. Mol Ther 2019; 27:219-229. [PMID: 30429045 PMCID: PMC6318719 DOI: 10.1016/j.ymthe.2018.10.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 10/03/2018] [Accepted: 10/08/2018] [Indexed: 12/19/2022] Open
Abstract
Gammadelta T (γδ-T) cells are strong candidates for adoptive immunotherapy in oncology due to their cytotoxicity, ease of expansion, and favorable safety profile. The development of γδ-T cell therapies would benefit from non-invasive cell-tracking methods and increased targeting to tumor sites. Here we report the use of [89Zr]Zr(oxinate)4 to track Vγ9Vδ2 T cells in vivo by positron emission tomography (PET). In vitro, we showed that 89Zr-labeled Vγ9Vδ2 T cells retained their viability, proliferative capacity, and anti-cancer cytotoxicity with minimal DNA damage for amounts of 89Zr ≤20 mBq/cell. Using a mouse xenograft model of human breast cancer, 89Zr-labeled γδ-T cells were tracked by PET imaging over 1 week. To increase tumor antigen expression, the mice were pre-treated with PEGylated liposomal alendronate. Liposomal alendronate, but not placebo liposomes or non-liposomal alendronate, significantly increased the 89Zr signal in the tumors, suggesting increased homing of γδ-T cells to the tumors. γδ-T cell trafficking to tumors occurred within 48 hr of administration. The presence of γδ-T cells in tumors, liver, and spleen was confirmed by histology. Our results demonstrate the suitability of [89Zr]Zr(oxinate)4 as a cell-labeling agent for therapeutic T cells and the potential benefits of liposomal bisphosphonate treatment before γδ-T cell administration.
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Affiliation(s)
- Francis Man
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK
| | - Lindsay Lim
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK
| | - Alessia Volpe
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK
| | - Alberto Gabizon
- Oncology Institute, Shaare Zedek Medical Center and Hebrew University-School of Medicine, Jerusalem 9103102, Israel
| | - Hilary Shmeeda
- Oncology Institute, Shaare Zedek Medical Center and Hebrew University-School of Medicine, Jerusalem 9103102, Israel
| | - Benjamin Draper
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London SE1 9RT, UK
| | - Ana C Parente-Pereira
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London SE1 9RT, UK
| | - John Maher
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital, London SE1 9RT, UK
| | - Philip J Blower
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK
| | - Gilbert O Fruhwirth
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK
| | - Rafael T M de Rosales
- School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, UK.
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Fruhwirth GO, Kneilling M, de Vries IJM, Weigelin B, Srinivas M, Aarntzen EHJG. The Potential of In Vivo Imaging for Optimization of Molecular and Cellular Anti-cancer Immunotherapies. Mol Imaging Biol 2018; 20:696-704. [PMID: 30030697 PMCID: PMC6153672 DOI: 10.1007/s11307-018-1254-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This review aims to emphasize the potential of in vivo imaging to optimize current and upcoming anti-cancer immunotherapies: spanning from preclinical to clinical applications. Immunotherapies are an emerging class of treatments for a variety of diseases. The agents include molecular and cellular therapeutics, which aim to treat the disease through re-education of the host immune system, often via complex mechanisms of action. In vivo imaging has the potential to contribute in several different ways: (1) as a drug development tool to improve our understanding of their complex mechanisms of action, (2) as a tool to predict efficacy, for example, to stratify patients into probable responders and likely non-responders, and (3) as a non-invasive treatment response biomarker to guide efficient immunotherapy use and to recognize early signs of potential loss of efficacy or resistance in patients. Areas where in vivo imaging is already successfully implemented in onco-immunology research will be discussed and domains where its use offers great potential will be highlighted. The focus of this article is on anti-cancer immunotherapy as it currently is the most advanced immunotherapy area. However, the described concepts can also be paralleled in other immune-mediated disorders and for conditions requiring immunotherapeutic intervention. Importantly, we introduce a new study group within the European Society of Molecular Imaging with the goal to facilitate and enhance immunotherapy development through the use of in vivo imaging.
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Affiliation(s)
- Gilbert O Fruhwirth
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, Kings' College London, London, UK
| | - Manfred Kneilling
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tuebingen, Germany
- Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
| | - I Jolanda M de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Bettina Weigelin
- Genitourinary Medical Oncology and Koch Center, MD Anderson Cancer Center, Houston, USA
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Mangala Srinivas
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Erik H J G Aarntzen
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein 10, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
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