Targeted Radionuclide Therapy

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Joseph Grudzinski - One of the best experts on this subject based on the ideXlab platform.

  • low dose Targeted Radionuclide Therapy renders immunologically cold tumors responsive to immune checkpoint blockade
    Science Translational Medicine, 2021
    Co-Authors: Ravi Patel, Reinier Hernandez, Joseph Grudzinski, Peter M Carlson, Amber M Bates, Justin C Jagodinsky, Amy K Erbe, Ian Marsh, Ian S Arthur, Eduardo Aluiciosarduy
    Abstract:

    Molecular and cellular effects of radioTherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using Targeted Radionuclide Therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radioTherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

  • Protocol schema for tumor-bearing companion dogs receiving external beam radiation Therapy in combination with intratumoral hu14.18-IL2 immunocytokine and 86/90Y-NM600 Targeted Radionuclide Therapy.
    'Public Library of Science (PLoS)', 2021
    Co-Authors: Kara Magee, Joseph Grudzinski, Ian R. Marsh, Michelle M. Turek, Eduardo Aluicio-sarduy, Jonathan W. Engle, Ilene D. Kurzman, Cindy L. Zuleger, Elizabeth A. Oseid, Christine Jaskowiak
    Abstract:

    Protocol schema for tumor-bearing companion dogs receiving external beam radiation Therapy in combination with intratumoral hu14.18-IL2 immunocytokine and 86/90Y-NM600 Targeted Radionuclide Therapy.

  • abstract 903 in vivo efficacy of bempegaldesleukin immune checkpoint inhibition and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer
    Immunology, 2020
    Co-Authors: Gustavo A Sosa, Reinier Hernandez, Joseph Grudzinski, Ravi Patel, Amber M Bates, Ian Marsh, Bryan Bednarz, Alexander A Pieper, Erin J Nystuen, Sarah E Emma
    Abstract:

    In preclinical studies, we have demonstrated that delivering low dose radiation Therapy to all sites of metastatic cancer using Targeted Radionuclide Therapy (TRT) can improve the response to immune checkpoint blockade. NM600 is a tumor-targeting alkylphosphocholine radiolabeled with 90Y. Following intravenous administration, NM600 is selectively taken up and retained in most murine and human cancer cells. Bempegaldesleukin (NKTR-214) is a first in class, CD122-preferential interleukin-2 (IL2) pathway agonist being studied for its ability to influence the IL2 pathway and selectively stimulate an immune response. The primary objective of this study was to test the hypothesis that NKTR-214 and 90Y-NM600 would increase the response to immune checkpoint blockade in the immunologically “cold” MOC2 syngeneic mouse model of head and neck squamous cell carcinoma (HNSCC). C57BL/6 female mice were engrafted with MOC2, a murine HNSCC cell line, in the right flank. When mean tumor volume reached ~100mm3, mice were randomized into eight treatment groups using a 2 × 2 × 2 study design for combinations of NKTR-214, 90Y-NM600, and anti-CTLA4. 100 µCi 90Y-NM600 was administered intravenously (IV, treatment day 1). Prior in vivo dosimetry performed using the Monte Carlo based RAPID platform following serial 86Y-NM600 PET/CT imaging demonstrated that this activity delivered ~8Gy to the MOC2 tumor. 200 µg anti-CTLA4 was delivered by intraperitoneal injection on days 4, 7, and 10. 16 µg NKTR-214 was given IV on days 6, 15, and 24. Tumor growth was monitored. In a parallel study, cohorts of mice were treated with PBS (control), NKTR-214, 90Y-NM600, or NKTR-214 + 90Y-NM600, and tumors were collected at day 14 for flow cytometry analysis. In the spontaneously metastatic, immunologically “cold” MOC2 HNSCC tumor model, 62.5% of mice treated with the combination of 90Y-NM600, NKTR-214, and anti-CTLA4 experienced complete tumor response, and these mice showed no observable primary or metastatic disease 60 days after treatment initiation. No mice receiving single or dual Therapy combinations exhibited complete tumor response (p = Citation Format: Gustavo A. Sosa, Amber M. Bates, Ravi Patel, Reinier Hernandez, Joseph J. Grudzinski, Ian Marsh, Bryan Bednarz, Alexander Pieper, Erin Nystuen, Sarah Emma, Elizabeth G. Sumiec, Jamey P. Weichert, Zachary S. Morris. In vivo efficacy of bempegaldesleukin, immune checkpoint inhibition, and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 903.

  • abstract 2262 low dose Targeted Radionuclide Therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model
    Immunology, 2020
    Co-Authors: Hemanth Potluri, Reinier Hernandez, Joseph Grudzinski, Christopher Massey, Jamey P Weichert, Christopher D Zahm, Douglas G Mcneel
    Abstract:

    Introduction: Prostate cancer remains the second leading cause of cancer-related death in American men because of its metastatic, incurable form. Prostate cancer responds poorly to checkpoint blockade likely due to its immunosuppressive microenvironment with relatively few infiltrating CD8+ T cells, limited mutational burden, and activity of myeloid-derived suppressor cells (MDSCs). External beam radioTherapy (EBRT) has been shown to help overcome this suppressive state, but EBRT is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can be used to deliver radiation to all sites of disease simultaneously in an approach called Targeted Radionuclide Therapy (TRT). However, the effects of TRT on immune populations within prostate tumors are not yet well described. In this study, we examined the effects of TRT in the form of 90Y-NM600 on mice bearing Myc-CaP prostate tumors. Methods: 6-week old male FVB mice were implanted subcutaneously with Myc-CaP cells, then given a single intravenous injection of either 50 (“low-dose”) or 250 (“high-dose”) μCi of 90Y-NM600, estimated to deliver 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. Groups of mice (n=3) were then euthanized at several timepoints following TRT administration. Their tumors and spleens were collected for analysis by flow cytometry and Luminex cytokine analysis. A separate group (n=5) were followed for survival to 2000 mm3. Results: Flow cytometry of splenocytes revealed that high-dose, but not low-dose TRT caused a 6-fold increase in numbers of MDSCs (p = 0.002) at Day 21 compared to baseline. Additionally, low-dose TRT caused a 2-fold (p = 0.005) increase in CD8+ T cells at Day 21 compared to baseline, unlike in the high-dose condition. These CD8+ T cells in the low-dose TRT condition were predominantly proliferating naive T cells. Flow cytometry of tumor infiltrating lymphocytes showed a 13% increase in CD8+ T cells in both dose conditions at Day 14 (p = 0.03). Returning CD8+ T cells displayed high expression of PD-1, CTLA-4, and LAG-3. Within the tumor, there was an 8-fold increase in chemokines including CXCL1, Rantes, and MIP2 at Day 21, suggesting that there may be further recruitment of tumor infiltrating cells even three weeks following treatment. Mice treated with high-dose TRT (median survival 37 days, p = .029) had significantly improved median survival compared to control (median survival 23 days), unlike low-dose treated mice (median survival 29 days, p =.250). Conclusions: These data suggest that low-dose TRT is superior for immunomodulation because, although it has little effect on tumor growth, it increases intratumoral CD8+ T cell infiltration while avoiding deleterious systemic immune effects. We hypothesize that immunomodulatory TRT combined with checkpoint blockade will improve anti-tumor efficacy compared to high-dose TRT. Citation Format: Hemanth Kumar Potluri, Reinier Hernandez, Christopher D. Zahm, Joseph Grudzinski, Christopher Massey, Jamey Weichert, Douglas G. McNeel. Low-dose Targeted Radionuclide Therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2262.

  • 177lu nm600 Targeted Radionuclide Therapy extends survival in syngeneic murine models of triple negative breast cancer
    The Journal of Nuclear Medicine, 2020
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Ray R Zhang, Aakarsha V Rao, Gopal Iyer
    Abstract:

    There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for Targeted Radionuclide Therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for Targeted Radionuclide Therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3–5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naive BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5–6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 Targeted Radionuclide Therapy has potential for TNBC and merits further exploration in a clinical setting.

Roger Schibli - One of the best experts on this subject based on the ideXlab platform.

  • terbium 161 for psma Targeted Radionuclide Therapy of prostate cancer
    European Journal of Nuclear Medicine and Molecular Imaging, 2019
    Co-Authors: Cristina Muller, Roger Schibli, Peter Bernhardt, Christoph A Umbricht, Nadezda Gracheva, Viviane J Tschan, Giovanni Pellegrini, Jan Rijn Zeevaart, U Koster
    Abstract:

    The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for Radionuclide Therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβav = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile. 161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in Therapy studies using PC-3 PIP tumor-bearing mice. 161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu. 161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC.

  • inhibition of mnk pathways enhances cancer cell response to chemoTherapy with temozolomide and Targeted Radionuclide Therapy
    Cellular Signalling, 2016
    Co-Authors: Roger Schibli, Michal Grzmil, Jan Seebacher, Daniel Hess, Martin Behe, Gerald Moncayo, Stephan Frank, Brian A Hemmings
    Abstract:

    Current standard-of-care treatment for malignant cancers includes radioTherapy and adjuvant chemoTherapy. Here, we report increased MAP kinase-interacting kinase (MNK)-regulated phosphorylation of translation initiation factor 4E (eIF4E) in glioma cells upon temozolomide (TMZ) treatment and in medullary thyroid carcinoma (MTC) cells in response to Targeted Radionuclide Therapy. Depletion of MNK activity by using two MNK inhibitors, CGP57380 or cercosporamide, as well as by MNK1-specific knockdown sensitized glioblastoma (GBM) cells and GBM-derived spheres to TMZ. Furthermore, CGP57380 treatment enhanced response of MTC cells to (177)Lu-labeled gastrin analogue. In order to understand how MNK signaling pathways support glioma survival we analyzed putative MNK substrates by quantitative phosphoproteomics in normal condition and in the presence of TMZ. We identified MNK inhibitor-sensitive phosphorylation sites on eIF4G1, mutations of which either influenced eIF4E phosphorylation or glioma cell response to TMZ, pointing to altered regulation of translation initiation as a resistance mechanism. Pharmacological inhibition of overexpressed MNK1 by CGP57380 reduced eIF4E phosphorylation and induced association of inactive MNK1 with eIF4G1. Taken together, our data show an activation of MNK-mediated survival mechanisms in response to either glioma chemoTherapy or MTC Targeted radiation and suggest that inhibition of MNK activity represents an attractive sensitizing strategy for cancer treatments.

  • folate receptor Targeted Radionuclide Therapy preclinical investigation of anti tumor effects and potential radionephropathy
    Nuclear Medicine and Biology, 2015
    Co-Authors: Stephanie Haller, Roger Schibli, Josefine Reber, Simone Brandt, Peter Bernhardt, Viola Groehn, Cristina Muller
    Abstract:

    Abstract Introduction Application of therapeutic folate radioconjugates is a promising option for the treatment of folate receptor (FR)-positive tumors, although high uptake of radiofolates in the kidneys remains a critical issue. Recently, it was shown that enhancing the blood circulation of radiofolates results in increased tumor uptake and reduced retention of radioactivity in the kidneys. In this study, we investigated and compared the anti-tumor effects and potential long-term damage to the kidneys after application of an albumin-binding ( 177 Lu-cm09), and a conventional ( 177 Lu-EC0800) folate radioconjugate. Methods In vivo studies were performed with KB tumor-bearing nude mice. 177 Lu-EC0800 and 177 Lu-cm09 were applied at variable quantities (10–30MBq/mouse), and the tumor growth was monitored over time. Mice without tumors were injected with the same radiofolates and investigated over eight months by determination of creatinine and blood urea nitrogen plasma levels and by measuring renal uptake of 99m Tc-DMSA using SPECT. At the study end, the morphological changes were examined on renal tissue sections using variable staining methods. Results Compared to untreated controls, dose-dependent tumor growth inhibition and prolonged survival was observed in all treated mice. In line with the resulting absorbed dose, the treatment was more effective with 177 Lu-cm09 than with 177 Lu-EC0800, enabling complete tumor remission after application of ≥20MBq (≥28Gy). Application of radiofolates with an absorbed renal dose ≥23Gy showed increased levels of renal plasma parameters and reduced renal uptake of 99m Tc-DSMA. Morphological changes observed on tissue sections confirmed radionephropathy of variable stages. Conclusions 177 Lu-cm09 showed more favorable anti-tumor effects and significantly less damage to the kidneys compared to 177 Lu-EC0800 as was expected based on improved tumor-to-kidney ratios. It was demonstrated that enhancing the blood circulation time of radiofolates was favorable regarding the risk–benefit profile of a therapeutic application. These results hold promise for future translation of the albumin-binder concept to the clinics, potentially enabling FR-Targeted Radionuclide Therapy in patients.

  • prospects in folate receptor Targeted Radionuclide Therapy
    Frontiers in Oncology, 2013
    Co-Authors: Cristina Muller, Roger Schibli
    Abstract:

    Targeted Radionuclide Therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed towards a specific tumor-associated target. Accumulation of the radiopharmaceutical in Targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-Targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g. ovarian, lung, brain, renal and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new Therapy concepts. Due to its high FR-binding affinity (KD < 10-9 M) the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based Radionuclide Therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical Therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic.

Reinier Hernandez - One of the best experts on this subject based on the ideXlab platform.

  • low dose Targeted Radionuclide Therapy renders immunologically cold tumors responsive to immune checkpoint blockade
    Science Translational Medicine, 2021
    Co-Authors: Ravi Patel, Reinier Hernandez, Joseph Grudzinski, Peter M Carlson, Amber M Bates, Justin C Jagodinsky, Amy K Erbe, Ian Marsh, Ian S Arthur, Eduardo Aluiciosarduy
    Abstract:

    Molecular and cellular effects of radioTherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using Targeted Radionuclide Therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radioTherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

  • abstract 903 in vivo efficacy of bempegaldesleukin immune checkpoint inhibition and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer
    Immunology, 2020
    Co-Authors: Gustavo A Sosa, Reinier Hernandez, Joseph Grudzinski, Ravi Patel, Amber M Bates, Ian Marsh, Bryan Bednarz, Alexander A Pieper, Erin J Nystuen, Sarah E Emma
    Abstract:

    In preclinical studies, we have demonstrated that delivering low dose radiation Therapy to all sites of metastatic cancer using Targeted Radionuclide Therapy (TRT) can improve the response to immune checkpoint blockade. NM600 is a tumor-targeting alkylphosphocholine radiolabeled with 90Y. Following intravenous administration, NM600 is selectively taken up and retained in most murine and human cancer cells. Bempegaldesleukin (NKTR-214) is a first in class, CD122-preferential interleukin-2 (IL2) pathway agonist being studied for its ability to influence the IL2 pathway and selectively stimulate an immune response. The primary objective of this study was to test the hypothesis that NKTR-214 and 90Y-NM600 would increase the response to immune checkpoint blockade in the immunologically “cold” MOC2 syngeneic mouse model of head and neck squamous cell carcinoma (HNSCC). C57BL/6 female mice were engrafted with MOC2, a murine HNSCC cell line, in the right flank. When mean tumor volume reached ~100mm3, mice were randomized into eight treatment groups using a 2 × 2 × 2 study design for combinations of NKTR-214, 90Y-NM600, and anti-CTLA4. 100 µCi 90Y-NM600 was administered intravenously (IV, treatment day 1). Prior in vivo dosimetry performed using the Monte Carlo based RAPID platform following serial 86Y-NM600 PET/CT imaging demonstrated that this activity delivered ~8Gy to the MOC2 tumor. 200 µg anti-CTLA4 was delivered by intraperitoneal injection on days 4, 7, and 10. 16 µg NKTR-214 was given IV on days 6, 15, and 24. Tumor growth was monitored. In a parallel study, cohorts of mice were treated with PBS (control), NKTR-214, 90Y-NM600, or NKTR-214 + 90Y-NM600, and tumors were collected at day 14 for flow cytometry analysis. In the spontaneously metastatic, immunologically “cold” MOC2 HNSCC tumor model, 62.5% of mice treated with the combination of 90Y-NM600, NKTR-214, and anti-CTLA4 experienced complete tumor response, and these mice showed no observable primary or metastatic disease 60 days after treatment initiation. No mice receiving single or dual Therapy combinations exhibited complete tumor response (p = Citation Format: Gustavo A. Sosa, Amber M. Bates, Ravi Patel, Reinier Hernandez, Joseph J. Grudzinski, Ian Marsh, Bryan Bednarz, Alexander Pieper, Erin Nystuen, Sarah Emma, Elizabeth G. Sumiec, Jamey P. Weichert, Zachary S. Morris. In vivo efficacy of bempegaldesleukin, immune checkpoint inhibition, and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 903.

  • abstract 2262 low dose Targeted Radionuclide Therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model
    Immunology, 2020
    Co-Authors: Hemanth Potluri, Reinier Hernandez, Joseph Grudzinski, Christopher Massey, Jamey P Weichert, Christopher D Zahm, Douglas G Mcneel
    Abstract:

    Introduction: Prostate cancer remains the second leading cause of cancer-related death in American men because of its metastatic, incurable form. Prostate cancer responds poorly to checkpoint blockade likely due to its immunosuppressive microenvironment with relatively few infiltrating CD8+ T cells, limited mutational burden, and activity of myeloid-derived suppressor cells (MDSCs). External beam radioTherapy (EBRT) has been shown to help overcome this suppressive state, but EBRT is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can be used to deliver radiation to all sites of disease simultaneously in an approach called Targeted Radionuclide Therapy (TRT). However, the effects of TRT on immune populations within prostate tumors are not yet well described. In this study, we examined the effects of TRT in the form of 90Y-NM600 on mice bearing Myc-CaP prostate tumors. Methods: 6-week old male FVB mice were implanted subcutaneously with Myc-CaP cells, then given a single intravenous injection of either 50 (“low-dose”) or 250 (“high-dose”) μCi of 90Y-NM600, estimated to deliver 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. Groups of mice (n=3) were then euthanized at several timepoints following TRT administration. Their tumors and spleens were collected for analysis by flow cytometry and Luminex cytokine analysis. A separate group (n=5) were followed for survival to 2000 mm3. Results: Flow cytometry of splenocytes revealed that high-dose, but not low-dose TRT caused a 6-fold increase in numbers of MDSCs (p = 0.002) at Day 21 compared to baseline. Additionally, low-dose TRT caused a 2-fold (p = 0.005) increase in CD8+ T cells at Day 21 compared to baseline, unlike in the high-dose condition. These CD8+ T cells in the low-dose TRT condition were predominantly proliferating naive T cells. Flow cytometry of tumor infiltrating lymphocytes showed a 13% increase in CD8+ T cells in both dose conditions at Day 14 (p = 0.03). Returning CD8+ T cells displayed high expression of PD-1, CTLA-4, and LAG-3. Within the tumor, there was an 8-fold increase in chemokines including CXCL1, Rantes, and MIP2 at Day 21, suggesting that there may be further recruitment of tumor infiltrating cells even three weeks following treatment. Mice treated with high-dose TRT (median survival 37 days, p = .029) had significantly improved median survival compared to control (median survival 23 days), unlike low-dose treated mice (median survival 29 days, p =.250). Conclusions: These data suggest that low-dose TRT is superior for immunomodulation because, although it has little effect on tumor growth, it increases intratumoral CD8+ T cell infiltration while avoiding deleterious systemic immune effects. We hypothesize that immunomodulatory TRT combined with checkpoint blockade will improve anti-tumor efficacy compared to high-dose TRT. Citation Format: Hemanth Kumar Potluri, Reinier Hernandez, Christopher D. Zahm, Joseph Grudzinski, Christopher Massey, Jamey Weichert, Douglas G. McNeel. Low-dose Targeted Radionuclide Therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2262.

  • 177lu nm600 Targeted Radionuclide Therapy extends survival in syngeneic murine models of triple negative breast cancer
    The Journal of Nuclear Medicine, 2020
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Ray R Zhang, Aakarsha V Rao, Gopal Iyer
    Abstract:

    There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for Targeted Radionuclide Therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for Targeted Radionuclide Therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3–5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naive BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5–6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 Targeted Radionuclide Therapy has potential for TNBC and merits further exploration in a clinical setting.

  • 90y nm600 Targeted Radionuclide Therapy induces immunologic memory in syngeneic models of t cell non hodgkin s lymphoma
    Communications Biology, 2019
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Kirsti L Walker, Christopher D Zahm, Ryan J Brown
    Abstract:

    Finding improved therapeutic strategies against T-cell Non-Hodgkin’s Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for Targeted Radionuclide Therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease. Hernandez et al. show the effectiveness of 90Y for Targeted radionucleotide Therapy of T-cell Non-Hodgkin’s Lymphoma (NHL). This study suggests that delivering radiation to all NHL disease sites elicits minimal toxicity and induces a memory T-cell response, inviting combination therapies with immune activating agents.

Sophie Besse - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Targeted Radionuclide Therapy using 131i icf01012 in 3d pigmented braf and nras mutant melanoma models and in vivo nras mutant melanoma
    Cancers, 2021
    Co-Authors: Hussein Akil, Sophie Besse, Valentin Benboubker, Philippe Auzeloux, Mercédès Quintana, Jeremy Raymond, Tommy Billoux, Veronique Delmas
    Abstract:

    Purpose: To assess the efficiency of Targeted Radionuclide Therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.

  • immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma Targeted Radionuclide Therapy
    Cancer Immunology Immunotherapy, 2020
    Co-Authors: Jacques Rouanet, Sophie Besse, Valentin Benboubker, Hussein Akil, Ana Hennino, Philippe Auzeloux, Bruno Pereira, Solene Delorme, S Mansard, M Dincan
    Abstract:

    In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma Targeted Radionuclide Therapy (TRT), we explore the interplay between immune system and the melanin ligand [131I]ICF01012 alone or combined with immunoTherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [131I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [131I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [131I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [131I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [131I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p < 0.0001) compared to TRT alone. Specifically, [131I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26 days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.

  • Targeted Radionuclide Therapy Decreases Melanoma Lung Invasion by Modifying Epithelial-Mesenchymal Transition-Like Mechanisms
    Translational Oncology, 2019
    Co-Authors: Hussein Akil, Jean-michel Chezal, Sophie Besse, Jacques Rouanet, Philippe Auzeloux, Claire Viallard, Elisabeth Miot-noirault, Mercédès Quintana, Françoise Degoul
    Abstract:

    Melanin-radiolabeled molecules for Targeted Radionuclide Therapy (TRT) provide a promising approach for the treatment of pigmented melanoma. Among these radiolabeled molecules, the iodinated melanin-specific binding molecule ([ 131 I]ICF01012) has shown a significant antitumor effect on metastatic melanoma preclinical models. We report herein that [ 131 I]ICF01012 decreases the epithelial-mesenshymal transition-like (EMT-like) markers in both in vivo and in vitro three-dimensional (3D) melanoma spheroid models. [ 131 I]ICF01012 spheroids irradiation resulted in reduced clonogenic capacity of all pigmented spheroids accompanied by increased protein expression levels of phosphorylated H2A.X, p53 and its downstream target p21. In addition, [ 131 I]ICF01012 treatment leads to a significant increase of cell pigmentation as demonstrated in SK-MEL3 human xenograft model. We also showed that [ 131 I]ICF01012 decreases the size and the number of melanoma lung colonies in the syngeneic murine B16BL6 in vivo model assessing its potentiality to kill circulating tumor cells. Taken together, these results indicate that [ 131 I]ICF01012 reduces metastatic capacity of melanoma cells presumably through EMT-like reduction and cell differentiation induction.

  • Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy
    Journal of Mammary Gland Biology and Neoplasia, 2017
    Co-Authors: Latifa Rbah-vidal, Emilie M F Billaud, Aurelien Vidal, Sophie Besse, Florence Mishellany, Isabelle Ranchon-cole, Yann Perrot, Lydia Maigne, Nicole Moins, Jean-luc Guerquin-kern
    Abstract:

    PURPOSE: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound. METHODS: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for Targeted Radionuclide Therapy (TRT). TRT efficacy was assessed by tumor volume measurement, with mechanistics and dosimetry parameters being determined in the B16BL6 model. Intracellular localization of ICF15002 was characterized by secondary ion mass spectrometry (SIMS). RESULTS: PET imaging with [ 18 F]ICF15002 evidenced tumoral uptake of 14.33 ± 2.11%ID/g and 4.87 ± 0.93%ID/g in pigmented B16BL6 and SK-MEL-3 models, respectively, at 1 hour post inoculation. No accumulation was observed in the unpigmented A375 melanoma. SIMS demonstrated colocalization of ICF15002 signal with melanin polymers in melanosomes of the B16BL6 tumors. TRT with two doses of 20 MBq [ 131 I]ICF15002 delivered an absorbed dose of 102.3 Gy to B16BL6 tumors, leading to a significant tumor growth inhibition [doubling time (DT) of 2.9 ± 0.5 days in treated vs 1.8 ± 0.3 in controls] and a prolonged median survival (27 days vs 21 in controls). P53S15 phosphorylation and P21 induction were associated with a G2/M blockage, suggesting mitotic catastrophe. In the human SK-MEL-3 model, three doses of 25 MBq led also to a DT increase (26.5 ± 7.8 days vs 11.0 ± 3.8 in controls) and improved median survival (111 days vs 74 in controls). CONCLUSION: Results demonstrate that ICF15002 fulfills suitable properties for bimodal imaging/TRT management of patients with pigmented melanoma.

  • synthesis radiolabeling and preliminary in vivo evaluation of multimodal radiotracers for pet imaging and Targeted Radionuclide Therapy of pigmented melanoma
    European Journal of Medicinal Chemistry, 2015
    Co-Authors: Emilie M F Billaud, Aurelie Maisonialbesset, Latifa Rbahvidal, Aurelien Vidal, Sophie Besse
    Abstract:

    Abstract Melanin pigment represents an attractive target to address specific treatment to melanoma cells, such as cytotoxic Radionuclides. However, less than half of the patients have pigmented metastases. Hence, specific marker is required to stratify this patient population before proceeding with melanin-Targeted Radionuclide Therapy. In such a context, we developed fluorinated analogues of a previously studied melanin-targeting ligand, N -(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide ( ICF01012 ). These latter can be labeled either with 18 F or 131 I/ 125 I for positron emission tomography imaging (melanin-positive patient selection) and Targeted Radionuclide Therapy purposes. Here we describe the syntheses, radiosyntheses and preclinical evaluations on melanoma-bearing mice model of several iodo- and fluoro(hetero)aromatic derivatives of the ICF01012 scaffold. After preliminary planar gamma scintigraphic and positron emission tomography imaging evaluations, [ 125 I]- and [ 18 F]- N -[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamides ([ 125 I] 4 , [ 18 F] 4 ) were found to be chemically and biologically stable with quite similar tumor uptakes at 1 h p.i. (9.7 ± 2.6% ID/g and 6.8 ± 1.9% ID/g, respectively).

Ravi Patel - One of the best experts on this subject based on the ideXlab platform.

  • low dose Targeted Radionuclide Therapy renders immunologically cold tumors responsive to immune checkpoint blockade
    Science Translational Medicine, 2021
    Co-Authors: Ravi Patel, Reinier Hernandez, Joseph Grudzinski, Peter M Carlson, Amber M Bates, Justin C Jagodinsky, Amy K Erbe, Ian Marsh, Ian S Arthur, Eduardo Aluiciosarduy
    Abstract:

    Molecular and cellular effects of radioTherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using Targeted Radionuclide Therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radioTherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

  • abstract 903 in vivo efficacy of bempegaldesleukin immune checkpoint inhibition and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer
    Immunology, 2020
    Co-Authors: Gustavo A Sosa, Reinier Hernandez, Joseph Grudzinski, Ravi Patel, Amber M Bates, Ian Marsh, Bryan Bednarz, Alexander A Pieper, Erin J Nystuen, Sarah E Emma
    Abstract:

    In preclinical studies, we have demonstrated that delivering low dose radiation Therapy to all sites of metastatic cancer using Targeted Radionuclide Therapy (TRT) can improve the response to immune checkpoint blockade. NM600 is a tumor-targeting alkylphosphocholine radiolabeled with 90Y. Following intravenous administration, NM600 is selectively taken up and retained in most murine and human cancer cells. Bempegaldesleukin (NKTR-214) is a first in class, CD122-preferential interleukin-2 (IL2) pathway agonist being studied for its ability to influence the IL2 pathway and selectively stimulate an immune response. The primary objective of this study was to test the hypothesis that NKTR-214 and 90Y-NM600 would increase the response to immune checkpoint blockade in the immunologically “cold” MOC2 syngeneic mouse model of head and neck squamous cell carcinoma (HNSCC). C57BL/6 female mice were engrafted with MOC2, a murine HNSCC cell line, in the right flank. When mean tumor volume reached ~100mm3, mice were randomized into eight treatment groups using a 2 × 2 × 2 study design for combinations of NKTR-214, 90Y-NM600, and anti-CTLA4. 100 µCi 90Y-NM600 was administered intravenously (IV, treatment day 1). Prior in vivo dosimetry performed using the Monte Carlo based RAPID platform following serial 86Y-NM600 PET/CT imaging demonstrated that this activity delivered ~8Gy to the MOC2 tumor. 200 µg anti-CTLA4 was delivered by intraperitoneal injection on days 4, 7, and 10. 16 µg NKTR-214 was given IV on days 6, 15, and 24. Tumor growth was monitored. In a parallel study, cohorts of mice were treated with PBS (control), NKTR-214, 90Y-NM600, or NKTR-214 + 90Y-NM600, and tumors were collected at day 14 for flow cytometry analysis. In the spontaneously metastatic, immunologically “cold” MOC2 HNSCC tumor model, 62.5% of mice treated with the combination of 90Y-NM600, NKTR-214, and anti-CTLA4 experienced complete tumor response, and these mice showed no observable primary or metastatic disease 60 days after treatment initiation. No mice receiving single or dual Therapy combinations exhibited complete tumor response (p = Citation Format: Gustavo A. Sosa, Amber M. Bates, Ravi Patel, Reinier Hernandez, Joseph J. Grudzinski, Ian Marsh, Bryan Bednarz, Alexander Pieper, Erin Nystuen, Sarah Emma, Elizabeth G. Sumiec, Jamey P. Weichert, Zachary S. Morris. In vivo efficacy of bempegaldesleukin, immune checkpoint inhibition, and Targeted Radionuclide Therapy in immunocompetent murine model of head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 903.

  • 177lu nm600 Targeted Radionuclide Therapy extends survival in syngeneic murine models of triple negative breast cancer
    The Journal of Nuclear Medicine, 2020
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Ray R Zhang, Aakarsha V Rao, Gopal Iyer
    Abstract:

    There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for Targeted Radionuclide Therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for Targeted Radionuclide Therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3–5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naive BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5–6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 Targeted Radionuclide Therapy has potential for TNBC and merits further exploration in a clinical setting.

  • 90y nm600 Targeted Radionuclide Therapy induces immunologic memory in syngeneic models of t cell non hodgkin s lymphoma
    Communications Biology, 2019
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Kirsti L Walker, Christopher D Zahm, Ryan J Brown
    Abstract:

    Finding improved therapeutic strategies against T-cell Non-Hodgkin’s Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for Targeted Radionuclide Therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease. Hernandez et al. show the effectiveness of 90Y for Targeted radionucleotide Therapy of T-cell Non-Hodgkin’s Lymphoma (NHL). This study suggests that delivering radiation to all NHL disease sites elicits minimal toxicity and induces a memory T-cell response, inviting combination therapies with immune activating agents.

  • 90 y nm600 Targeted Radionuclide Therapy induces immunologic memory in syngeneic models of t cell non hodgkin s lymphoma
    Communications biology, 2019
    Co-Authors: Reinier Hernandez, Joseph Grudzinski, Eduardo Aluiciosarduy, Christopher Massey, Anatoly Pinchuk, Ariana N Bitton, Ravi Patel, Kirsti L Walker, Christopher D Zahm, Ryan J Brown
    Abstract:

    Finding improved therapeutic strategies against T-cell Non-Hodgkin’s Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for Targeted Radionuclide Therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease. Hernandez et al. show the effectiveness of 90Y for Targeted radionucleotide Therapy of T-cell Non-Hodgkin’s Lymphoma (NHL). This study suggests that delivering radiation to all NHL disease sites elicits minimal toxicity and induces a memory T-cell response, inviting combination therapies with immune activating agents.

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