Common Immune Related Adverse Event Detection Methods in Immuno-oncology Therapies

Background

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing the body's immune response against tumors. These therapies, known as immuno-oncology (IO) therapies, target molecules such as CTLA-4, PD-1, and PD-L1 to prevent tumors from evading immune detection. While effective in many cases, IO therapies can also lead to a unique set of side effects known as immune-related adverse events (irAEs). Unlike traditional chemotherapy, which primarily affects rapidly dividing cells, irAEs result from immune activation against normal tissues, mirroring autoimmune disorders. IrAEs can affect any organ system, with common targets including the skin, gastrointestinal tract, liver, lungs, and endocrine glands.

The incidence and severity of irAEs vary depending on the specific checkpoint inhibitor used, the type of cancer being treated, and individual patient factors. Given the broad range of potential organ systems involved and the sometimes severe or life-threatening nature of irAEs, early identification and management are crucial for improving patient outcomes. This underscores the importance of a thorough understanding of irAEs among oncologists, patients, and clinical teams involved in administering IO therapies.

The detection of irAEs remains a clinical challenge, as symptoms may mimic other conditions, appear long after treatment has started, or even after therapy has been discontinued. Consequently, the development of reliable and non-invasive methods for identifying irAEs is critical in optimizing treatment plans, minimizing interruptions, and reducing morbidity. This blog explores several methods for identifying irAEs, including traditional clinical observation, imaging techniques, and emerging molecular imaging modalities such as CD8 ImmunoPET.

Methods of Identifying irAEs

1. Clinical Observation

The most straightforward method for identifying irAEs is through clinical observation, where physicians rely on patients' reports of symptoms and routine monitoring. Common irAEs, such as rash, diarrhea, or thyroid dysfunction, can often be detected through physical exams, laboratory tests, and patient interviews.

Pros

• Non-invasive and cost-effective: Clinical observation is low-cost and requires no specialized equipment.
• Readily accessible: Almost all healthcare providers can implement this method as part of routine clinical care.
• Immediate intervention: When symptoms are identified early through direct observation, immediate steps can be taken to mitigate their progression.

Cons

• Subjectivity: The method relies heavily on patient-reported symptoms, which may be vague or inconsistent.
• Late detection: Many irAEs can present insidiously, with symptoms only becoming apparent when significant damage has occurred.
• Non-specificity: Some symptoms, such as fatigue or joint pain, could result from multiple causes, making it difficult to definitively attribute them to IO therapy.

2. Laboratory Tests

Routine blood tests are often used to monitor for irAEs, especially those affecting endocrine organs, liver, or kidneys. Abnormalities in thyroid function tests, liver enzymes, or kidney function can provide early clues of developing irAEs.

Pros

• Objective measurements: Unlike patient-reported symptoms, blood tests provide objective data on organ function.
• Routine monitoring: Many cancer centers have integrated regular laboratory testing into the treatment plans for patients receiving IO therapy.

Cons

• Non-specific markers: While elevated liver enzymes or changes in thyroid function may indicate an irAE, they do not provide information on which part of the immune system is responsible.
• Limited scope: Laboratory tests are effective for detecting specific organ-related irAEs but may not be helpful for irAEs affecting organs like the skin or lungs, which require other diagnostic modalities.

3. Radiologic Imaging

Traditional radiologic imaging, such as CT scans, MRIs, or PET scans, is frequently employed to monitor tumor progression or response to therapy in cancer patients. These imaging methods can also reveal certain irAEs, especially those affecting the lungs, liver, or gastrointestinal tract. For instance, pneumonitis (inflammation of lung tissue) may present as ground-glass opacities on a CT scan, while colitis (inflammation of the colon) can manifest as bowel wall thickening.

Pros

• Whole-body assessment: Radiologic imaging provides a comprehensive view of multiple organ systems, allowing clinicians to potentially detect irAEs in areas that patients may not report symptoms for.
• Non-invasive: Imaging is non-invasive and can be repeated as needed to monitor changes over time.

Cons

• Radiation exposure: Some imaging modalities, such as CT scans, expose patients to ionizing radiation, which can increase long-term cancer risk, especially in young patients or those requiring frequent scans.
• Non-specific findings: Changes seen on imaging may not always be due to irAEs and can sometimes be indistinguishable from infections, tumor progression, or other conditions.

4. CD8 ImmunoPET

An emerging method for detecting potential irAEs involves the use of CD8 ImmunoPET, a molecular imaging technique designed to visualize CD8+ T-cell activity throughout the body. Since CD8+ T cells are key mediators of the immune response activated by IO therapies, tracking their distribution and activity may provide insights into both the anti-tumor response and the occurrence of irAEs.

CD8 ImmunoPET uses a radiolabeled antibody or antibody fragment that is designed to bind specifically to CD8 molecules on the surface of T cells. By visualizing areas of high CD8+ T-cell activity, this technique may help clinicians identify irAEs at an earlier stage, potentially before symptoms appear.

Pros

• Early detection: CD8 ImmunoPET may potentially detect irAEs before clinical symptoms develop, allowing for earlier intervention .
• Specificity: This imaging agent is designed to directly visualize the immune cells responsible for mediating irAEs, positioning it to potentially be more specific than traditional imaging or laboratory tests.
• Comprehensive immune monitoring: CD8 ImmunoPET provides a unique opportunity to assess the overall immune landscape, helping researchers to potentially distinguish between tumor response and off-target immune effects.

Cons

• Limited availability: CD8 ImmunoPET is not yet widely available and remains a drug development tool in clinical trials until it is commercially approved.
• Cost: Molecular imaging techniques and are covered by most insurance providers, however CD8 ImmunoPET is not, as it is still considered an investigational imaging agent.

Radiation exposure: Like other PET scansCD8 ImmunoPET involves exposure to ionizing radiation but given its relatively quick excretion and low administered dose, the overall radiation exposure is minimized, considered moderate and medically safe.

Results

As IO therapies become more prevalent, the importance of identifying and managing irAEs is increasingly recognized. Several studies have demonstrated that early identification and intervention are key to minimizing the impact of irAEs on patients' quality of life and ensuring that IO therapy can continue without interruption. A multi-modal approach, combining clinical observation, laboratory tests, imaging, and advanced molecular techniques like CD8 ImmunoPET, may offer the best chance of detecting irAEs at an early stage.

Research into CD8 ImmunoPET has shown promising results, with early clinical trials demonstrating its ability to visualize T-cell activity in both tumors and normal tissues affected by irAEs. For example, studies have reported that CD8 ImmunoPET may detect pneumonitis, colitis, and other irAEs before they manifest as clinical symptoms, allowing for preemptive management strategies.

Conclusion

Identifying irAEs early in the course of IO therapy is critical to ensuring the best possible outcomes. While traditional methods such as clinical observation and laboratory tests remain essential components of irAE management, they have limitations in specificity and sensitivity. Radiologic imaging offers more comprehensive monitoring but lacks the specificity needed to differentiate irAEs from other conditions.

Emerging technologies like CD8 ImmunoPET may offer a promising avenue for potentially detecting irAEs with greater precision and at earlier stages. By visualizing the immune cells responsible for these events, CD8 ImmunoPET has the potential to improve outcomes by enabling clinicians to tailor their interventions more effectively. As research advances and these methods become more accessible, the management of irAEs will likely become more proactive and personalized, leading to better experiences for patients undergoing IO therapy.

Further Reading

“Early detection of side effects in patients with metastatic melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [89Zr] crefmirlimab berdoxam PET.”

References:

1. Early detection of side effects in patients with metastatic melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [89Zr] crefmirlimab berdoxam PET.

DISCLAIMER: THIS CONTENT IS FOR INDIVIDUALS IN THE PHARMA OR BIOTECH INDUSTRY AND IS FOR EDUCATIONAL PURPOSES ONLINE. CD8 IMMUNOPET IS AN INVESTIGATIONAL PRODUCT AND HAS NOT YET BEEN APPROVED BY THE FDA.

Click here for a copy of this article.