Dataset Information

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [⁶⁴Cu]Cu-NOTA-anti-CD8 PET.

ABSTRACT:

Purpose

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8⁺) T cells using PET.

Experimental design

We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8⁺ T cells by flow cytometry relative to the [⁶⁴Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8⁺ tumor-infiltrating lymphocytes by IHC. To determine whether [⁶⁴Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8⁺ T cells.

Results

Nontumor-bearing NOG mice injected with human PBMCs showed prominent [⁶⁴Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8⁺ T cells. Radiotracer retention correlated with CD8⁺ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [⁶⁴Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8⁺ T cells in brain tumors.

Conclusions

Human CD8⁺ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [⁶⁴Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8⁺ T cells.

SUBMITTER: Nagle VL

PROVIDER: S-EPMC8026513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

Dataset Information

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [⁶⁴Cu]Cu-NOTA-anti-CD8 PET.

Purpose

Experimental design

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET.

Purpose

Experimental design

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [⁶⁴Cu]Cu-NOTA-anti-CD8 PET.