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Theranostics 2024; 14(3):911-923. doi:10.7150/thno.89206 This issue Cite

Research Paper

[89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models

Carlos A. Gallegos1, Yun Lu2,3, Jennifer C. Clements4, Patrick N. Song2,3, Shannon E. Lynch2,3, Alessandro Mascioni5, Fang Jia5, Yolanda E. Hartman2, Adriana V. F. Massicano2, Hailey A. Houson2, Suzanne E. Lapi1,6,7, Jason M. Warram7,8, James M. Markert4,7, Anna G. Sorace1,2,7✉

1. Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA.
2. Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
3. Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
4. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
5. Imaginab, Inc, Inglewood, CA, USA.
6. Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA.
7. O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
8. Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, AL, USA.

✉ Corresponding author: Anna G. Sorace, PhD., Associate Professor, Departments of Radiology and Biomedical Engineering, University of Alabama at Birmingham, Volker Hall G082, 1670 University Boulevard, Birmingham, AL 35294, USA; Telephone: 1-205-934-3 More

Citation:
Gallegos CA, Lu Y, Clements JC, Song PN, Lynch SE, Mascioni A, Jia F, Hartman YE, Massicano AVF, Houson HA, Lapi SE, Warram JM, Markert JM, Sorace AG. [89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models. Theranostics 2024; 14(3):911-923. doi:10.7150/thno.89206. https://www.thno.org/v14p0911.htm
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Abstract

Graphic abstract

Rationale: Novel immune-activating therapeutics for the treatment of glioblastoma multiforme (GBM) have shown potential for tumor regression and increased survival over standard therapies. However, immunotherapy efficacy remains inconsistent with response assessment being complicated by early treatment-induced apparent radiological tumor progression and slow downstream effects. This inability to determine early immunotherapeutic benefit results in a drastically decreased window for alternative, and potentially more effective, treatment options. The objective of this study is to evaluate the effects of combination immunotherapy on early CD8+ cell infiltration and its association with long term response in orthotopic syngeneic glioblastoma models.

Methods: Luciferase positive GBM orthotopic mouse models (GSC005-luc) were imaged via [89Zr]-CD8 positron emission tomography (PET) one week following treatment with saline, anti-PD1, M002 oncolytic herpes simplex virus (oHSV) or combination immunotherapy. Subsequently, brains were excised, imaged via [89Zr]-CD8 ImmunoPET and evaluated though autoradiography and histology for H&E and CD8 immunohistochemistry. Longitudinal immunotherapeutic effects were evaluated through [89Zr]-CD8 PET imaging one- and three-weeks following treatment, with changes in tumor volume monitored on a three-day basis via bioluminescence imaging (BLI). Response classification was then performed based on long-term BLI signal changes. Statistical analysis was performed between groups using one-way ANOVA and two-sided unpaired T-test, with p < 0.05 considered significant. Correlations between imaging and biological validation were assessed via Pearson's correlation test.

Results: [89Zr]-CD8 PET standardized uptake value (SUV) quantification was correlated with ex vivo SUV quantification (r = 0.61, p < 0.01), autoradiography (r = 0.46, p < 0.01), and IHC tumor CD8+ cell density (r = 0.55, p < 0.01). Classification of therapeutic responders, via bioluminescence signal, revealed a more homogeneous CD8+ immune cell distribution in responders (p < 0.05) one-week following immunotherapy.

Conclusions: Assessment of early CD8+ cell infiltration and distribution in the tumor microenvironment provides potential imaging metrics for the characterization of oHSV and checkpoint blockade immunotherapy response in GBM. The combination therapies showed enhanced efficacy compared to single agent immunotherapies. Further development of immune-focused imaging methods can provide clinically relevant metrics associated with immune cell localization that can inform immunotherapeutic efficacy and subsequent treatment response in GBM patients.

Keywords: glioblastoma stem cell, cytotoxic T cell, ImmunoPET, molecular imaging, oncolytic herpes simplex virus

Citation styles

APA
Gallegos, C.A., Lu, Y., Clements, J.C., Song, P.N., Lynch, S.E., Mascioni, A., Jia, F., Hartman, Y.E., Massicano, A.V.F., Houson, H.A., Lapi, S.E., Warram, J.M., Markert, J.M., Sorace, A.G. (2024). [89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models. Theranostics, 14(3), 911-923. https://doi.org/10.7150/thno.89206.

ACS
Gallegos, C.A.; Lu, Y.; Clements, J.C.; Song, P.N.; Lynch, S.E.; Mascioni, A.; Jia, F.; Hartman, Y.E.; Massicano, A.V.F.; Houson, H.A.; Lapi, S.E.; Warram, J.M.; Markert, J.M.; Sorace, A.G. [89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models. Theranostics 2024, 14 (3), 911-923. DOI: 10.7150/thno.89206.

NLM
Gallegos CA, Lu Y, Clements JC, Song PN, Lynch SE, Mascioni A, Jia F, Hartman YE, Massicano AVF, Houson HA, Lapi SE, Warram JM, Markert JM, Sorace AG. [89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models. Theranostics 2024; 14(3):911-923. doi:10.7150/thno.89206. https://www.thno.org/v14p0911.htm

CSE
Gallegos CA, Lu Y, Clements JC, Song PN, Lynch SE, Mascioni A, Jia F, Hartman YE, Massicano AVF, Houson HA, Lapi SE, Warram JM, Markert JM, Sorace AG. 2024. [89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models. Theranostics. 14(3):911-923.

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