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Group Members
Dr. Klaus Spohr (PI)
Dr. Domenico Doria
Our project in collaboration with the Prof. Dr Monica Neagu's group at the Victor Babes Institute for Pathlogy focused on advancing cancer therapy through the development and production of lutetium-177 (177Lu) for radiologic treatments, particularly targeting metastatic castration-resistant prostate cancer (mCRPC) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Key points to be addressed include:
Current State of Cancer Therapy:
The introduction of 177Lu-based treatments, such as Novartis' Pluvicto® and Lutathera®, has shown significant promise in targeting cancer cells with high precision. These therapies utilize the unique properties of 177Lu, which emits beta particles to maximize therapeutic effects while minimizing damage to healthy tissue.Production Challenges: There is a growing demand for 177Lu, with current production methods unable to meet this need. The document emphasizes the necessity for alternative production routes, particularly through high-power laser systems (HPLS), to ensure a stable supply of this isotope.
Project Objectives:
The project aims to enhance the production of 177Lu using laser-driven techniques and improve therapeutic delivery mechanisms. It is divided into two main parts:Part I focuses on experimental production of 177Lu using HPLS and optimizing neutron generation techniques.Part II involves in vitro studies to evaluate the efficacy of 177Lu therapies on various prostate cancer cell lines, comparing them to existing treatments.
Methodology: The project will explore two production methods for 177Lu: carrier-added (c.a.) and non-carrier-added (n.c.a.), with a focus on minimizing the production of unwanted isotopes like 177mLu. It will also investigate the use of genetically modified T-cells as delivery mechanisms for enhanced therapeutic precision.
Expected Outcomes: The project anticipates significant advancements in the production and application of 177Lu, including:Development of compact neutron sources for efficient isotope production.Improved therapeutic outcomes through innovative delivery systems.Long-term studies on the biological impact of 177Lu therapies on cancer cells.Overall, the document presents a detailed plan to leverage cutting-edge technology in nuclear physics and oncology to address critical challenges in cancer treatment, aiming for breakthroughs that could revolutionize patient care in this field.
5. Milestones and expected resultsPart I•
Pulse compression achieved for the 200 TW system at the CLPU Salamanca from 25 fs to 6 fs– Duration: 1 year from start of the grant (Experiment at CLPU already in May 2024, PIs: KS & GBwill progress agenda of the grant proposal)– Expected Results: Shortening pulse by a factor of 4 by the optics installation at the CLPU in Sala-manca. The method will be employed at the HPLS installations at ELI-NP in due course• Design, built, and commissioning of small-scale moderator for the production of thermal & epithermalneutrons at ELI-NP HPLS beamlines– Duration: 2 years from the start of the grant– Expected Results: State-of-the-art compact neutron moderator and provision of 107 Nn per shot atELI-NP HPLS installations with the highest possible repetition rate• Production of 177Lu at the Triga reactor at the ICN Pites,ti– Duration: 2 years from the start of the grant7– Expected Results: High yield provision of 177Lu and supression of the production of intruding 177mLu.This will allow us to estimate the improvement of the therapeutic efficiency for 177Lu−production withcompact HPLS-based neutron generators in the future• Exposing 176Lu−nanoparticles, uploaded by our patented method in T-cell carrier to an epithermal flux ofneutrons for the in-situ creation of 177Lu at the Triga reactor at the ICN Pites,ti– Duration: 2.5 years from the start of the grant– Expected Results: Creating in-situ loads of carriers of 177Lu with the aim to evaluate the efficiency oflocalized production of the medical commodity, thus paving the way for an advanced therapyPart II• In vitro exposure of prostate cancer cell lines SerBob, Bob, & Shmac 5 and a control one normal HPrECcell culture to 177Lu loading and tested for their cellular viability using MTS and LDH tests as previouslydescribed in Part 4.– Duration: 1 year from the start of the grant– Expected Results: Derving cellular viability using MTS and LDH tests as previously described in 4integrity• Flow-cytometry to derive the apoptosis profile of exposed cell lines– Duration: 2 years from the start of the grant, following the progress of the 177Lu production– Expected Results: Deriving distributions of viable, early apoptotic, late apoptotic, and necrotic cellu-lar cells in comparison between Lutathera® and Pluictor and our ICN Pites,ti and potentially ELI-NPlaser-driven produced 177Lu.• Cell cycle analysis– Duration: 2 years from the start of the grant, following the progress of the 177Lu production– Expected Results: Evaluating the proliferation of cells with respect to the crucial on-target (= oncancer cells) expansion• Testing the dynamics of the proliferative capacity of cells after 177Lu loading via impedance measurementwith xCeLLigence– Duration: 2 years from the start of the grant, following the progress of the 177Lu production– Expected Results: Proliferation of the 177Lu in the tumor environment.• Measuring the influence of the intruding radioactivity in a long-term study (> 1 y)– Duration: 2.5 years years from the start of the grant– Expected Results: Evidence of the enhanced therapeutics with our 177Lu specimen• Determination of the treatment’s efficacy and related radiation dose rates using our patented T-cell carriers– Duration: 2.5 years years from the start of the grant for final analysis and report– Evidencing therapeutic progress with our T-cell carrier method by reducing dose rates and increasingmalignant cell apoptosis
[1] M. W. Mortensen et al. “Next Generation Adoptive Immunotherapy - Human T Cells as Carriers of Therapeutic Nanoparticles”. In: Journal of Nanoscience and Nanotechnology 7.12 (2007), pages 4575–4580. DOI: doi:10.1166/jnn.2007.18108
[2] J. R. Lindner. “Microbubbles in medical imaging: current applications and future directions”. In: Nature Reviews Drug Discovery 3.6 (June 2004), pages 527–533. DOI: 10.1038/nrd1417.
[3] J. Collis et al. “Cavitation microstreaming and stress fields created by microbubbles”. In: Ultrasonics 50.2 (Feb. 2010), pages 273–279. DOI: 10.1016/j.ultras. 2009.10.002.
[4] F. Prada et al. “Quantitative analysis of in-vivo microbubble distribution in the human brain”. In: Scientific Reports 11.1 (June 2021), page 11797. ISSN: 2045-2322. DOI: 10.1038/s41598-021-91252-w.
[5] Z. Wang et al. “Analytical solutions of the Rayleigh-Plesset equation for N-dimensional spherical bubbles”. In: Science China Physics, Mechanics & Astronomy 60.10 (Aug. 2017), page 104721. ISSN: 1869-1927. DOI: 10.1007/s11433-017-9074-x.
[6] M. W. Mortensen et al. “Functionalization and Cellular Uptake of Boron Carbide Nanoparticles. The First Step toward T Cell-Guided Boron Neutron Capture Therapy”. In: Bioconjugate Chemistry 17.2 (Mar. 2006), pages 284–290. ISSN: 1043- 1802. DOI: 10.1021/bc050206v.
[7] J. P. Fisher et al. “γδ T cells for cancer immunotherapy”. In: OncoImmunology 3.1 (Jan. 2014), e27572. DOI: 10.4161/onci.27572.
[8] J. C. Ribot et al. “γδ T cells in tissue physiology and surveillance”. In: Nature Reviews Immunology 21.4 (Oct. 2020), pages 221–232. DOI: 10.1038/s41577-020- 00452-4.
[9] D. Kabelitz et al. “Cancer immunotherapy with γδ T cells: many paths ahead of us”. In: Cellular & Molecular Immunology 17.9 (July 2020), pages 925–939. DOI: 10.1038/s41423-020-0504-x.
[10] M. Leek et al. “Patent: MODIFIED GAMMA DELTA T CELLS AND USES THEREOF”. In: Espacenet (www.epsacenet.com) WO2016166544A1 (2016).
[11] J. Doyen et al. “Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments”. In: Frontiers in Oncology 10 (2021), page 2963. DOI: 10.3389/fonc. 2020.613089.
[12] S. van de Water et al. “Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates”. In: Acta Oncologica 58.10 (June 2019), pages 1463–1469. DOI: 10 . 1080 / 0284186x . 2019 . 1627416.
[13] S. R. Mirfayzi et al. “Proof-of-principle experiment for laser-driven cold neutron source”. In: Scientific Reports 10.1 (Nov. 2020), page 20157. ISSN: 2045-2322. DOI: 10.1038/s41598-020-77086-y.
[14] D. Doria. Private Communication. 2021.
[15] S. Balascuta. Private Communication. 2021.
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[1] M. W. Mortensen et al. “Next Generation Adoptive Immunotherapy - Human T Cells as Carriers of Therapeutic Nanoparticles”. In: Journal of Nanoscience and Nanotechnology 7.12 (2007), pages 4575–4580. DOI: doi:10.1166/jnn.2007.18108
[2] J. R. Lindner. “Microbubbles in medical imaging: current applications and future directions”. In: Nature Reviews Drug Discovery 3.6 (June 2004), pages 527–533. DOI: 10.1038/nrd1417.
[3] J. Collis et al. “Cavitation microstreaming and stress fields created by microbubbles”. In: Ultrasonics 50.2 (Feb. 2010), pages 273–279. DOI: 10.1016/j.ultras. 2009.10.002.
[4] F. Prada et al. “Quantitative analysis of in-vivo microbubble distribution in the human brain”. In: Scientific Reports 11.1 (June 2021), page 11797. ISSN: 2045-2322. DOI: 10.1038/s41598-021-91252-w.
[5] Z. Wang et al. “Analytical solutions of the Rayleigh-Plesset equation for N-dimensional spherical bubbles”. In: Science China Physics, Mechanics & Astronomy 60.10 (Aug. 2017), page 104721. ISSN: 1869-1927. DOI: 10.1007/s11433-017-9074-x.
[6] M. W. Mortensen et al. “Functionalization and Cellular Uptake of Boron Carbide Nanoparticles. The First Step toward T Cell-Guided Boron Neutron Capture Therapy”. In: Bioconjugate Chemistry 17.2 (Mar. 2006), pages 284–290. ISSN: 1043- 1802. DOI: 10.1021/bc050206v.
[7] J. P. Fisher et al. “γδ T cells for cancer immunotherapy”. In: OncoImmunology 3.1 (Jan. 2014), e27572. DOI: 10.4161/onci.27572.
[8] J. C. Ribot et al. “γδ T cells in tissue physiology and surveillance”. In: Nature Reviews Immunology 21.4 (Oct. 2020), pages 221–232. DOI: 10.1038/s41577-020- 00452-4.
[9] D. Kabelitz et al. “Cancer immunotherapy with γδ T cells: many paths ahead of us”. In: Cellular & Molecular Immunology 17.9 (July 2020), pages 925–939. DOI: 10.1038/s41423-020-0504-x.
[10] M. Leek et al. “Patent: MODIFIED GAMMA DELTA T CELLS AND USES THEREOF”. In: Espacenet (www.epsacenet.com) WO2016166544A1 (2016).
[11] J. Doyen et al. “Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments”. In: Frontiers in Oncology 10 (2021), page 2963. DOI: 10.3389/fonc. 2020.613089.
[12] S. van de Water et al. “Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates”. In: Acta Oncologica 58.10 (June 2019), pages 1463–1469. DOI: 10 . 1080 / 0284186x . 2019 . 1627416.
[13] S. R. Mirfayzi et al. “Proof-of-principle experiment for laser-driven cold neutron source”. In: Scientific Reports 10.1 (Nov. 2020), page 20157. ISSN: 2045-2322. DOI: 10.1038/s41598-020-77086-y.
[14] D. Doria. Private Communication. 2021.
[15] S. Balascuta. Private Communication. 2021.
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References
[1] M. W. Mortensen et al. “Next Generation Adoptive Immunotherapy - Human T Cells as Carriers of Therapeutic Nanoparticles”. In: Journal of Nanoscience and Nanotechnology 7.12 (2007), pages 4575–4580. DOI: doi:10.1166/jnn.2007.18108
[2] J. R. Lindner. “Microbubbles in medical imaging: current applications and future directions”. In: Nature Reviews Drug Discovery 3.6 (June 2004), pages 527–533. DOI: 10.1038/nrd1417.
[3] J. Collis et al. “Cavitation microstreaming and stress fields created by microbubbles”. In: Ultrasonics 50.2 (Feb. 2010), pages 273–279. DOI: 10.1016/j.ultras. 2009.10.002.
[4] F. Prada et al. “Quantitative analysis of in-vivo microbubble distribution in the human brain”. In: Scientific Reports 11.1 (June 2021), page 11797. ISSN: 2045-2322. DOI: 10.1038/s41598-021-91252-w.
[5] Z. Wang et al. “Analytical solutions of the Rayleigh-Plesset equation for N-dimensional spherical bubbles”. In: Science China Physics, Mechanics & Astronomy 60.10 (Aug. 2017), page 104721. ISSN: 1869-1927. DOI: 10.1007/s11433-017-9074-x.
[6] M. W. Mortensen et al. “Functionalization and Cellular Uptake of Boron Carbide Nanoparticles. The First Step toward T Cell-Guided Boron Neutron Capture Therapy”. In: Bioconjugate Chemistry 17.2 (Mar. 2006), pages 284–290. ISSN: 1043- 1802. DOI: 10.1021/bc050206v.
[7] J. P. Fisher et al. “γδ T cells for cancer immunotherapy”. In: OncoImmunology 3.1 (Jan. 2014), e27572. DOI: 10.4161/onci.27572.
[8] J. C. Ribot et al. “γδ T cells in tissue physiology and surveillance”. In: Nature Reviews Immunology 21.4 (Oct. 2020), pages 221–232. DOI: 10.1038/s41577-020- 00452-4.
[9] D. Kabelitz et al. “Cancer immunotherapy with γδ T cells: many paths ahead of us”. In: Cellular & Molecular Immunology 17.9 (July 2020), pages 925–939. DOI: 10.1038/s41423-020-0504-x.
[10] M. Leek et al. “Patent: MODIFIED GAMMA DELTA T CELLS AND USES THEREOF”. In: Espacenet (www.epsacenet.com) WO2016166544A1 (2016).
[11] J. Doyen et al. “Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments”. In: Frontiers in Oncology 10 (2021), page 2963. DOI: 10.3389/fonc. 2020.613089.
[12] S. van de Water et al. “Towards FLASH proton therapy: the impact of treatment planning and machine characteristics on achievable dose rates”. In: Acta Oncologica 58.10 (June 2019), pages 1463–1469. DOI: 10 . 1080 / 0284186x . 2019 . 1627416.
[13] S. R. Mirfayzi et al. “Proof-of-principle experiment for laser-driven cold neutron source”. In: Scientific Reports 10.1 (Nov. 2020), page 20157. ISSN: 2045-2322. DOI: 10.1038/s41598-020-77086-y.
[14] D. Doria. Private Communication. 2021.
[15] S. Balascuta. Private Communication. 2021.
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