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

Nagle, Veronica L.; Henry, Kelly E.; Hertz, Charli Ann J.; Graham, Maya Srikanth; Campos, Carl; Parada, Luis F.; Pandit‐Taskar, Neeta; Schietinger, Andrea; Mellinghoff, Ingo K.; Lewis, Jason S.

doi:10.1158/1078-0432.ccr-20-3243

Cited by 29 publications

(19 citation statements)

References 29 publications

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“…The patterns of activity retained in target brain regions of mice in the present studies are consistent with the hypothesis that M002 oHSV treatment mediated the specific retention of [ 89 Zr]-malDFO-169 cDb in the treated glioma tumors. The very low uptake of [ 89 Zr]-malDFO-169 cDb in normal brain regions was consistent with results from alternative radiolabeled polypeptide imaging agents that do not cross the BBB and show below 0.2% ID/g in normal brains of mice 40 , 41 . As all groups of mice received i.c.…”

Section: Discussionsupporting

confidence: 80%

“…Alternative CD8-targeted scaffolds (single-domain or F(ab)′2 antibody fragments) have shown correlations between PET signals and CD8 + cell infiltration as well as response to checkpoint immunotherapy in syngeneic murine non-CNS tumors 40 , 42 , 46 , 47 . A recent study showed that an anti-human CD8α-targeted minibody (IAB22M2C) labeled with 64 Cu specifically localized in orthotopic patient derived xenograft GBM tumors implanted in brain striatum of humanized mice; the PET signal in the tumor directly correlated with the number of human CD8 + cells that had trafficked into the tumors after systemic injection of human peripheral blood monocytes into the humanized mice 41 . While that study did not investigate response to treatment, the findings support the rationale for non-invasive PET imaging to detect localization of CD8 + cells in intracranial glioma models.…”

Section: Discussionmentioning

confidence: 99%

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Positron emission tomography imaging with 89Zr-labeled anti-CD8 cys-diabody reveals CD8+ cell infiltration during oncolytic virus therapy in a glioma murine model

Kasten

Houson

Coleman

et al. 2021

Sci Rep

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Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p < 0.001). Radioactive probe accumulation in brains was consistent with CD8+ cell trafficking patterns after oHSV treatment. This PET imaging strategy could aid in distinguishing responders from non-responders during immunotherapy of GBM.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Positron emission tomography imaging with 89Zr-labeled anti-CD8 cys-diabody reveals CD8+ cell infiltration during oncolytic virus therapy in a glioma murine model

Kasten

Houson

Coleman

et al. 2021

Sci Rep

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“…MRI was performed by Animal Imaging MRI core at MSKCC using previously published methods (21). Briefly, MRIs were acquired two days before radiotracer injection.…”

Section: Mrimentioning

confidence: 99%

Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe

Nie

Kalidindi

Nagle

et al. 2021

Clinical Cancer Research

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◥Purpose: Abnormal Notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting g-secretase, a pivotal regulator in the Notch pathway, has yielded numerous g-secretase inhibitors (GSIs) for clinical investigation in the last 2 decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess g-secretase activity and its inhibition in vivo.Experimental Design: We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine-labeled analogues [ 131 I]-or [ 124 I]-PN67 from corresponding trimethyl-tin precursors. Both membrane-and cell-based ligand-binding assays were performed using [ 131 I]-PN67 to determine the binding affinity and specificity for g-secretase in vitro. Moreover, we evaluated [ 124 I]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models. Results:The probe was synthesized through iodo-destannylation using chloramine-T as an oxidant with a high labeling yield and efficiency. In vitro binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant (P < 0.05) increased in the uptake of [ 124 I]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 allograft, MMTV-PyMT breast cancer, and U87 glioblastoma allograft. Ex vivo biodistribution and autoradiography corroborate these results, indicating g-secretase specific tumor accumulation of [ 124 I]-PN67.Conclusions: [ 124 I]-PN67 is a novel PET imaging agent that enables assessment of g-secretase activity and target engagement of clinical GSIs.

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“…Advanced quantitative imaging-based methods that enable non-invasive and repeated whole-tumor interrogation are highly desirable. A recent study presents such an attempt based on PET imaging [ 4 ]. However, we are not aware of any CT imaging of TL burden.…”

Section: Introductionmentioning

confidence: 99%

Photon Counting CT and Radiomic Analysis Enables Differentiation of Tumors Based on Lymphocyte Burden

et al. 2022

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The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrast-enhancement can differentiate tumors based on lymphocyte burden. High mutational load transplant soft tissue sarcomas were initiated in Rag2+/− and Rag2−/− mice to model varying lymphocyte burden. Mice received radiation therapy (20 Gy) to the tumor-bearing hind limb and were injected with a liposomal iodinated contrast agent. Five days later, animals underwent conventional micro-CT imaging using an energy integrating detector (EID) and spectral micro-CT imaging using a photon-counting detector (PCD). Tumor volumes and iodine uptakes were measured. The radiomic features (RF) were grouped into feature-spaces corresponding to EID, PCD, and spectral decomposition images. The RFs were ranked to reduce redundancy and increase relevance based on TL burden. A stratified repeated cross validation strategy was used to assess separation using a logistic regression classifier. Tumor iodine concentration was the only significantly different conventional tumor metric between Rag2+/− (TLs present) and Rag2−/− (TL-deficient) tumors. The RFs further enabled differentiation between Rag2+/− and Rag2−/− tumors. The PCD-derived RFs provided the highest accuracy (0.68) followed by decomposition-derived RFs (0.60) and the EID-derived RFs (0.58). Such non-invasive approaches could aid in tumor stratification for cancer therapy studies.

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

Cited by 29 publications

References 29 publications

Positron emission tomography imaging with 89Zr-labeled anti-CD8 cys-diabody reveals CD8+ cell infiltration during oncolytic virus therapy in a glioma murine model

Positron emission tomography imaging with 89Zr-labeled anti-CD8 cys-diabody reveals CD8+ cell infiltration during oncolytic virus therapy in a glioma murine model

Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe

Photon Counting CT and Radiomic Analysis Enables Differentiation of Tumors Based on Lymphocyte Burden

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