Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Thakrar, Ricky; Sage, Elizabeth K.; Janes, Sam M.

doi:10.1080/14712598.2016.1188074

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…Targeted stem cells expressing TRAIL as therapy for lung cancer (TACTICAL) is a prospective, randomised phase I/II trial to assess the safety and efficacy of third party, pooled human allogeneic umbilical cord-derived MSCs expressing TRAIL (MSCTRAIL) in combination with pembrolizumab, cisplatin, and pemetrexed as firstline therapy for metastatic lung adenocarcinoma [6,7] (ClinicalTrials.gov Identifier: NCT03298763). TNFrelated apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells via binding to cell surface death receptors (DR4, DR5), thereby activating the extrinsic apoptotic pathway [8].…”

Section: Introductionmentioning

confidence: 99%

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

et al. 2020

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Background: MSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate 89 Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma. Methods: MSCTRAIL were radiolabelled with 89 Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of 89 Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo. Results: MSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of 89 Zr-oxine labelling on cell proliferation rate was amountand time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections. Conclusions: 89 Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.

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Section: Introductionmentioning

confidence: 99%

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

et al. 2020

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“…[4] In recent years, much effort has been devoted to the use of TRAIL as a therapeutic agent to treat cancer. [5][6][7][8] TRAIL is a type II transmembrane protein able to selectively trigger apoptosis in cancer cells, while not affecting normal cells due to multiple redundant pathways in the non-malignant cells. [9] The soluble form of TRAIL (sTRAIL) has been studied extensively and tested in clinical trials, [10,11] however, low bioavailability, poor pharmacokinetics, short half-life, and resistance to TRAIL resulted in unsatisfactory clinical performance.…”

Section: Trail Coated Genetically Engineered Immunotherapeutic Nano-ghosts Vesicles Target Human Melanoma-avoiding the Need For High Effementioning

confidence: 99%

TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

Levy

Davidov

Kolluri

et al. 2021

Adv Funct Materials

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Cancer cell therapy using cytotoxic T lymphocytes (CTL) or mesenchymal stem cells (MSC) possesses hurdles due to the cells, susceptibility to host induced changes. Here, versatile inanimate broadly applicable nanovesicles, termed immunotherapeutic-nano-ghosts (iNGs), are armed with inherent surface-associated targeting and therapeutic capabilities in which the promise and benefits of MSC therapy and T cell immunotherapy are combined into one powerful off-the-shelf approach for treating malignant diseases. To mimic the cytotoxic or immunosuppressive functions of T cells, iNG are produced from MSC that were genetically engineered (GE) or metabolically manipulated to express additional membrane-bound proteins, endowing the NGs derived therefrom with additional surface-associated functions such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). iNGs from GE-MSCs (GE-iNGs) show superior TRAIL retention and induce apoptosis in different cancer cell lines in vitro. In vivo studies on a human melanoma model demonstrate that a systemic, three-day frequency, administration of GE-iNGs result in tumor inhibition comparable to a six orders of magnitude higher concentration of soluble TRAIL. The iNGs are therefore a promising nanovesicle platform that can affect tumors in a non-immunogenic manner while avoiding the need for a highly effective therapeutic concentration.

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“…TACTICAL (Targeted stem cells expressing TRAIL as therapy for lung cancer) is a prospective, randomised phase I/II trial to assess the safety and efficacy of third party, pooled allogeneic MSCs expressing TRAIL (MSCTRAIL) in combination with Pembrolizumab, Cisplatin and Pemetrexed as first line therapy for metastatic lung adenocarcinoma [6, 7] (ClinicalTrials.gov Identifier: NCT03298763). TRAIL (TNF-Related Apoptosis-Inducing Ligand) selectively induces apoptosis in cancer cells via binding to cell surface death receptors, thereby activating the extrinsic apoptotic pathway [8].…”

Section: Introductionmentioning

confidence: 99%

⁸⁹Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy

Patrick

Kolluri

Thin

et al. 2019

Preprint

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PurposeMSCTRAIL is a new stem cell-based therapy for lung cancer, currently in phase I evaluation (ClinicalTrials.gov ref: NCT03298763). Biodistribution of cell therapies is rarely assessed in clinical trials, despite cell delivery to the target site often being critical to presumed mechanism of action. This preclinical study demonstrates that MSCTRAIL biodistribution dynamics can be detected non-invasively using 89Zr-oxine labelling and PET imaging, thus supporting use of this cell tracking technology in phase II evaluation.MethodsMSCTRAIL were radiolabelled with a range of 89Zr-oxine doses, and assayed for cell viability, phenotype and therapeutic efficacy post-labelling. Cell biodistribution was imaged in a mouse model of lung cancer using PET imaging and bioluminescence imaging (BLI) to confirm cell viability and location in vivo up to 1 week post-injection.ResultsMSCTRAIL retained therapeutic efficacy and MSC phenotype at doses up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was dose and time-dependent. PET imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer, with PET signal correlating with the presence of viable cells as assessed by bioluminescence imaging, ex vivo autoradiography and matched fluorescence imaging on lung tissue sections. Human dosimetry estimates were produced using simulations and preclinical biodistribution data.Conclusion89Zr-oxine labelling and PET imaging present an attractive method of evaluating the biodistribution of new cell-therapies, such as MSCTRAIL. This offers to improve understanding of mechanism of action, migration dynamics and interpatient variability of MSCTRAIL and other cell-based therapies.

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Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Cited by 4 publications

References 19 publications

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

⁸⁹Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy

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Combined cell-gene therapy for lung cancer: rationale, challenges and prospects

Cited by 4 publications

References 19 publications

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

89Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy

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⁸⁹Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy