90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin’s Lymphoma

Hernandez, Reinier; Walker, Kevin R.; Grudzinski, Joseph; Aluicio‐Sarduy, Eduardo; Patel, Ravi B.; Zahm, Christopher D.; Pinchuk, Anatoly N.; Massey, Christopher; Bitton, Ariana; Brown, Ryan; Sondel, Paul M.; Morris, Zachary S.; Engle, Jonathan W.; Capitini, Christian M.; Weichert, Jamey P.

doi:10.1038/s42003-019-0327-4

Cited by 46 publications

(62 citation statements)

References 41 publications

(37 reference statements)

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“…The vehicle used for MTRT, 2-(trimethylammonio)ethyl(18-(4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)phenyl)octadecyl) phosphate (NM600), was kindly provided by Archeus Technologies (Madison, WI). The radiolabeling and characterization of [ 90 Y]NM600 and its positron emission tomographydetectible counterpart [ 86 Y]NM600 has been described elsewhere (29,33). Briefly, 510 mCi of 90 YCl 3 was buffered in 0.1 M NaOAc (pH 5.5), and 1015 nmol/mCi of NM600 was added to the mixture.…”

Section: External Beam Radiation Molecularly Targeted Radionuclide Preparation and Administrationmentioning

confidence: 99%

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

Carlson

Mohan

Patel

et al. 2021

The Journal of Immunology

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Most shared resource flow cytometry facilities do not permit analysis of radioactive samples. We are investigating low-dose molecular targeted radionuclide therapy (MTRT) as an immunomodulator in combination with in situ tumor vaccines and need to analyze radioactive samples from MTRT-treated mice using flow cytometry. Further, the sudden shutdown of core facilities in response to the COVID-19 pandemic has created an unprecedented work stoppage. In these and other research settings, a robust and reliable means of cryopreservation of immune samples is required. We evaluated different fixation and cryopreservation protocols of disaggregated tumor cells with the aim of identifying a protocol for subsequent flow cytometry of the thawed sample, which most accurately reflects the flow cytometric analysis of the tumor immune microenvironment of a freshly disaggregated and analyzed sample. Cohorts of C57BL/6 mice bearing B78 melanoma tumors were evaluated using dual lymphoid and myeloid immunophenotyping panels involving fixation and cryopreservation at three distinct points during the workflow. Results demonstrate that freezing samples after all staining and fixation are completed most accurately matches the results from noncryopreserved equivalent samples. We observed that cryopreservation of living, unfixed cells introduces a nonuniform alteration to PD1 expression. We confirm the utility of our cryopreservation protocol by comparing tumors treated with in situ tumor vaccines, analyzing both fresh and cryopreserved tumor samples with similar results. Last, we use this cryopreservation protocol with radioactive specimens to demonstrate potentially beneficial effector cell changes to the tumor immune microenvironment following administration of a novel MTRT in a dose- and time-dependent manner.

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Section: External Beam Radiation Molecularly Targeted Radionuclide Preparation and Administrationmentioning

confidence: 99%

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

Carlson

Mohan

Patel

et al. 2021

The Journal of Immunology

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“…Metabolically stable alkylphospholipid derivatives, including alkylphosphocholines, are structural mimics of cell membrane phospholipids that selectively accumulate in glycosphingolipidand cholesterol-rich cellular membrane microdomains, known as lipid rafts (5,6). Lipid rafts, which play important roles in cancer cell proliferation, survival, and metastasis, are markedly overexpressed by malignant cells compared with normal cells, constituting a promising mechanism for cancer-targeted therapies (7)(8)(9)(10)(11). Leveraging such a nearly universal, receptor-independent targeting mechanism, we have developed several alkylphosphocholine analogs displaying selective tumor uptake and retention in a wide variety of cancer types, including breast cancer.…”

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confidence: 99%

¹⁷⁷Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer

et al. 2019

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There is a clinically unmet need for effective treatments for triplenegative 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 86 Y for PET imaging and 177 Lu for targeted radionuclide therapy. 86 Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n 5 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 177 Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177 Lu-NM600 toxicity in naïve BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n 5 5-6) received excipient or 9.25 or 18.5 MBq of 177 Lu-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 86 Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86 Y-NM600 as a surrogate for 177 Lu-NM600. 177 Lu-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 177 Lu-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 177 Lu-NM600 targeted radionuclide therapy has potential for TNBC and merits further exploration in a clinical setting.

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“…It is hypothesized but not confirmed yet that the observed effect was based on radiation-induced changes in the tumor microenvironment. This may include CD8+ T cell infiltration and recruitment of innate immune cells as it was previously reported in preclinical studies that used radioconjugates to enhance the response to ICIs in mouse models of melanoma [ 19 , 46 ], non-Hodgkin lymphoma [ 47 ], and colon cancer [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

Guzik

Siwowska

Fang

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

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90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin’s Lymphoma

Cited by 46 publications

References 41 publications

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

¹⁷⁷Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer

Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

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90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin’s Lymphoma

Cited by 46 publications

References 41 publications

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice

177Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer

Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

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¹⁷⁷Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer