Imaging Pseudoprogression in Cancer Therapy: A Comparison of FDG PET and CD8 ImmunoPET

Introduction

Pseudoprogression (PsP) is a critical challenge in cancer treatment response assessment, particularly in immuno-oncology (IO) and CAR T-cell therapies. Characterized by an initial apparent increase in tumor size or new lesion appearance followed by regression, PsP can be misinterpreted as true disease progression, leading to unnecessary treatment discontinuation or modification (Chiou & Burotto, 2015).

Functional imaging techniques such as 18F-fluorodeoxyglucose (FDG) PET/CT and CD8 ImmunoPET (89Zr-crefmirlimab berdoxam) have emerged as potential tools to differentiate PsP from true progression. While FDG PET is widely used in oncology for metabolic imaging, CD8 ImmunoPET offers a more specific approach by directly targeting CD8+ T-cell infiltration (Zhang et al., 2024). This article explores the strengths and limitations of each imaging modality and their potential use cases in assessing PsP in patients undergoing immunotherapy.

FDG PET in Imaging Pseudoprogression

FDG PET/CT is a well-established imaging modality that assesses glucose metabolism in tissues. Since cancer cells exhibit increased glucose uptake compared to normal tissues, FDG PET is commonly used to detect active malignancies (Hung et al., 2020). However, in the context of immunotherapy, elevated glucose metabolism may result from inflammatory responses rather than tumor progression, leading to challenges in distinguishing PsP from true progression.

Pros of FDG PET

• Broad Availability and Clinical Integration – FDG PET is widely available and integrated into clinical workflows, allowing for easy adoption in most oncology centers (Osman et al., 2010).
• High Sensitivity – The technique detects metabolic activity with high sensitivity, identifying changes in tumor metabolism before anatomical alterations appear.
• Quantitative Metrics – Standardized uptake values (SUV) provide quantitative assessment of metabolic activity, which can aid in longitudinal monitoring of treatment response (Chiou & Burotto, 2015).

Cons of FDG PET

• Lack of Specificity – Increased FDG uptake is not exclusive to malignancies; inflammation, infection, and immune cell activation may also exhibit high glucose metabolism, complicating differentiation between PsP and true progression.
• High Background Signal – Tissues with inherently high glucose metabolism, such as the brain and heart, can yield false-positive results, limiting interpretation in these regions.

CD8 ImmunoPET in Imaging Pseudoprogression

CD8 ImmunoPET is an emerging imaging modality designed to visualize CD8+ T-cell infiltration in tumors. Unlike FDG PET, which relies on metabolic activity, CD8 ImmunoPET employs radiolabeled antibodies targeting CD8+ T cells, enabling direct visualization of immune responses (Zhang et al., 2024).

Pros of CD8 ImmunoPET

• Immune-Specific Imaging – CD8 ImmunoPET directly tracks CD8+ T-cell activity, potentially making it a more precise tool for distinguishing PsP from true progression (Zhang et al., 2024).
• Lower False-Positive Rates – By targeting T-cell infiltration rather than metabolic activity, CD8 ImmunoPET reduces false-positive findings associated with inflammatory responses unrelated to tumor progression. (Mohr et al., 2024)
• Potential for Personalized Treatment – Longitudinal imaging with CD8 ImmunoPET may inform researchers about the dynamics of immune responses, potentially aiding in patient stratification and treatment considerations (Huang et al., 2021).

Cons of CD8 ImmunoPET

• Limited Availability – Unlike FDG PET, CD8 ImmunoPET is not yet widely available and requires specialized radiotracers that are still undergoing clinical validation. However, utilization of these specialized, immune imaging agents is possible through collaborations within the context of a clinical trial.
• Longer Preparation Time – The production of radiolabeled CD8 antibodies is more complex than FDG and typically requires a 1-2 week notice to the manufacturer, typically centrally located within a geographic location. Within the context of clinical trials, sponsors and investigators will have a planned timeline of events and meeting the required timelines for obtaining these manufactured on demand products is generally not an issue.
• Higher Cost – The development and implementation of CD8 ImmunoPET remain costly, potentially limiting accessibility in resource-constrained settings. As manufacturer demands increase, the cost of CD8 ImmunoPET is likely to decrease significantly.

Use Cases: When to Choose FDG PET vs. CD8 ImmunoPET

The choice between FDG PET and CD8 ImmunoPET depends on the clinical scenario, availability, and specific diagnostic needs.

When FDG PET is Preferred:

• Routine Oncology Imaging: Given its availability, FDG PET remains the standard for assessing tumor metabolic activity in most oncology cases.

• Rapid Turnaround Needs: When quick decision-making is required, FDG PET’s widespread accessibility allows for faster imaging and interpretation.

• Non-Immunotherapy Settings: For tumors not treated with immune-based therapies, FDG PET remains a reliable modality for evaluating progression.

When CD8 ImmunoPET is Preferred:

• Immunotherapy Monitoring: Since CD8 ImmunoPET provides a direct assessment of T-cell infiltration, it is particularly valuable in patients receiving checkpoint inhibitors or varying forms of cell therapy (Tavare, R, et al. 2016).

• Differentiating PsP from True Progression: In cases where PsP is suspected, CD8 ImmunoPET may offer a more accurate assessment of immune-related changes.

• Personalized Medicine Approaches: For patients enrolled in clinical trials or receiving novel immunotherapies, CD8 ImmunoPET may provide crucial insights into treatment efficacy and immune dynamics.

Conclusion

Both FDG PET and CD8 ImmunoPET offer insightful tools for imaging patients undergoing immunotherapy, yet each has its strengths and limitations. FDG PET remains the most widely used and accessible imaging modality, but its lack of specificity for distinguishing pseudoprogression from true progression presents challenges. CD8 ImmunoPET, though still in early stages of clinical implementation, provides a more targeted approach by visualizing CD8+ T-cell infiltration, thereby potentially enhancing the accuracy of pseudoprogression assessment.

As immunotherapies continue to evolve, the integration of CD8 ImmunoPET alongside FDG PET may offer a more comprehensive imaging strategy, enabling precise differentiation of treatment-related immune responses from true disease progression. Future studies and broader clinical implementation of CD8 ImmunoPET will be crucial in optimizing its role in oncologic imaging.

References

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• Osman, M., Chaar, B., Muzaffar, R., et al. (2010) 18F-FDG PET/CT of Patients with Cancer: Comparison of Whole-Body and Limited Whole-Body Technique. (American Journal of Roentgenology. Vol 195, Issue 6)

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• Zhang, J., Du, B., Wang, Y., et al. (2024). The role of CD8 PET imaging in guiding immunotherapy. Frontiers in Immunology. (Frontiers in Medicine Vol. 15).