Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Kanojia, Deepak; Balyasnikova, Irina V.; Morshed, Ramin A.; Frank, R.T.; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A.; Kim, Julius W.; Han, Yu; Yu, Dihua; Ahmed, Atique U.; Aboody, Karen S.; Lesniak, Maciej S.

doi:10.1002/stem.2109

Cited by 47 publications

(31 citation statements)

References 39 publications

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“…This model was established as described [33] by implanting ~6 × 10 5 BT474M1BrM3-Fluc cells in the mouse brain and allowing tumors to grow for about 8 weeks prior microPET/CT imaging. Tumor growth was monitored by bioluminescence imaging (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation

et al. 2017

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Purpose Our previous studies with F-18-labeled anti-HER2 single-domain antibodies (sdAbs) utilized 5F7, which binds to the same epitope on HER2 as trastuzumab, complicating its use for positron emission tomography (PET) imaging of patients undergoing trastuzumab therapy. On the other hand, sdAb 2Rs15d binds to a different epitope on HER2 and thus might be a preferable vector for imaging in these patients. The aim of this study was to evaluate the tumor targeting of F-18 -labeled 2Rs15d in HER2-expressing breast carcinoma cells and xenografts. Procedures sdAb 2Rs15d was labeled with the residualizing labels N-succinimidyl 3-((4-(4-[18F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([18F]RL-I) and N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), and the purity and HER2-specific binding affinity and immunoreactivity were assessed after labeling. The biodistribution of I-125- and F-18-labeled 2Rs15d was determined in SCID mice bearing subcutaneous BT474M1 xenografts. MicroPET/x-ray computed tomograph (CT) imaging of [18F]RL-I-2Rs15d was performed in this model and compared to that of nonspecific sdAb [18F]RL-I-R3B23. MicroPET/CT imaging was also done in an intracranial HER2-positive breast cancer brain metastasis model after administration of 2Rs15d-, 5F7-, and R3B23-[18F]RL-I conjugates. Results [18F]RL-I was conjugated to 2Rs15d in 40.8 ± 9.1 % yield and with a radiochemical purity of 97–100 %. Its immunoreactive fraction (IRF) and affinity for HER2-specific binding were 79.2 ± 5.4 % and 7.1 ± 0.4 nM, respectively. [125I]SGMIB was conjugated to 2Rs15d in 58.4 ± 8.2 % yield and with a radiochemical purity of 95–99 %; its IRF and affinity for HER2-specific binding were 79.0 ± 12.9 % and 4.5 ± 0.8 nM, respectively. Internalized radioactivity in BT474M1 cells in vitro for [18F]RL-I-2Rs15d was 43.7 ± 3.6, 36.5 ± 2.6, and 21.7 ± 1.2 % of initially bound radioactivity at 1, 2, and 4 h, respectively, and was similar to that seen for [125I]SGMIB-2Rs15d. Uptake of [18F]RL-I-2Rs15d in subcutaneous xenografts was 16–20 %ID/g over 1–3 h. Subcutaneous tumor could be clearly delineated by microPET/CT imaging with [18F]RL-I-2Rs15d but not with [18F]RL-I-R3B23. Intracranial breast cancer brain metastases could be visualized after intravenous administration of both [18F]RL-I-2Rs15d and [18F]RL-I-5F7. Conclusions Although radiolabeled 2Rs15d conjugates exhibited lower tumor cell retention both in vitro and in vivo than that observed previously for 5F7, given that it binds to a different epitope on HER2 from those targeted by the clinically utilized HER2-targeted therapeutic antibodies trastuzumab and pertuzumab, F-18-labeled 2Rs15d has potential for assessing HER2 status by PET imaging after trastuzumab and/or pertuzumab therapy.

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Section: Methodsmentioning

confidence: 99%

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation

et al. 2017

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“…NSCs, originally present in the central nervous system, can self-renew and generate new neurons and glial cells. They have been broadly tested to treat both primary and metastatic breast, lung, and prostate cancers in murine models [16][17][18].…”

Section: Adult Stem Cells (Ascs)mentioning

confidence: 99%

Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications

Chu

Nguyen

Tien

et al. 2020

Cells

153

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The insufficient and unspecific target of traditional therapeutic approaches in cancer treatment often leads to therapy resistance and cancer recurrence. Over the past decades, accumulating discoveries about stem cell biology have provided new potential approaches to cure cancer patients. Stem cells possess unique biological actions, including self-renewal, directional migration, differentiation, and modulatory effects on other cells, which can be utilized as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. In this review, we emphasize the mechanisms underlying the use of various types of stem cells in cancer treatment. In addition, we summarize recent progress in the clinical applications of stem cells, as well as common risks of this therapy. We finally give general directions for future studies, aiming to improve overall outcomes in the fight against cancer.

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“…To overcome these obstacles, the development of stem cells that express small single-chain antibody (scFv) on their surface has been pursued. Antibodies targeting cancer-exclusive genetic mutation EGFRvIII [70,98] and HER2 [72] have been previously investigated for stem-cell-based GBM treatment; bispecific α-carcinoembryonic antigen (αCEA)/αCD3 diabody-secreting MSCs have been investigated for the treatment of colon cancer [71]. The viability of antibodies from genetically modified stem cells must be evaluated in the context of time and explored further in order for a successful transition into the clinic.…”

Section: Effector Functions Of Therapeutic Stem Cellsmentioning

confidence: 99%

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

Bonamici

Dey

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Glioblastoma (GBM) is the most aggressive malignant brain cancer in adults, and its poor prognosis and resistance to the existing standard of care require the development of innovative therapeutic modalities. The local delivery of stem cells as therapeutic carriers against glioma has produced encouraging results, but encounters obstacles with regards to the repeatability and invasiveness of administration. Intranasal delivery of therapeutic stem cells could overcome these obstacles, among others, as a noninvasive and easily repeatable mode of administration. Areas covered This review describes nasal anatomy, routes of stem cell migration, and factors affecting stem cell delivery to hard-to-reach tumors. Furthermore, this review discusses the molecular mechanisms underlying stem cell migration following delivery, as well as possible stem cell effector functions to be considered in combination with intranasal delivery. Expert opinion Further research is necessary to elucidate the dynamics of stem cell effector functions in the context of intranasal delivery and optimize their therapeutic potency. Nonetheless, the technique represents a promising tool against brain cancer and has the potential to be expanded for use against other brain pathologies.

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Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Cited by 47 publications

References 39 publications

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation

Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

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