‘Tolerant fraction’ metric IDs those at risk for immunotherapy-related toxicity
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Researchers at UT Southwestern's Simmons Cancer Center have introduced a new metric that may be useful in predicting which patients are likely to develop immunotherapy toxicity.
The metric, known as the “tolerant fraction,” represents the percentage of T cells not expected to attack healthy cells or tissues.
In a study published in Journal for ImmunoTherapy of Cancer, the researchers developed and tested the parameter in 77 patients treated with immune checkpoint inhibitor therapy. Additionally, they used publicly accessible data from patients with autoimmune disease and 786 healthy individuals.
“Immune-related adverse events occur in a substantial proportion of patients. These autoimmune toxicities may affect almost every organ system,” David Gerber, MD, professor in the department of internal medicine at UT Southwestern Medical Center and a member of its division of hematology/oncology, told Healio. “In contrast to the well-defined toxicities of conventional chemotherapy and molecularly targeted therapies, immune-related adverse events remain entirely unpredictable.”
Gerber spoke with Healio about developing this novel approach, the results of his group’s study and how he hopes this innovation will impact the future of immunotherapy treatment.
Healio: How much of an issue are immune-related adverse events? Why is it useful to predict who will experience these events?
Gerber: As combination immunotherapy regimens become more common, immune-related adverse events will become a greater clinical issue — because immune-related adverse event frequency and severity are greater with these treatments. For example, regimens such as ipilimumab [Yervoy, Bristol Myers Squibb] plus nivolumab [Opdivo, Bristol Myers Squibb] may cause clinically significant immune-related adverse events in more than one-third of patients.
The increasing use of immune checkpoint inhibitors for early-stage cancer also brings concerns about immune-related adverse events to the forefront. These are patients who may be cured even without immunotherapy, so the possibility of severe or chronic immune-related adverse events is especially worrisome.
The ability to predict which patients are at risk for immune-related adverse events could help clinicians select treatments or customize monitoring. For instance, an oncologist might feel more comfortable prescribing combination immunotherapy if a patient is unlikely to develop immune-related adverse events. Alternatively, if a patient is predicted to have high risk for immune-related adverse events, more intensive clinical, laboratory and radiographic monitoring for toxicities might be considered.
Healio: How did you develop the new metric, and how does it work?
Gerber: The “tolerant fraction” is a novel approach to characterizing T cells. Earlier research has looked at other ways of characterizing T cells in the peripheral blood — such as T-cell receptor diversity and clonality — for the prediction of immunotherapy outcomes, including immune-related adverse events. The tolerant fraction represents the proportion of T cells that are not expected to attack normal cells or tissues. We hypothesized that nontolerant T cells — which we defined as having nonproductive T-cell receptor gene sequences — would be associated with immune-related adverse events. To develop this parameter, we examined T-cell receptor sequences from healthy subjects, from patients with autoimmune diseases and from subjects with both thymic and peripheral blood T-cell samples.
Healio: How did the tolerant fraction perform in predicting immunotherapy toxicity?
Gerber: As we hypothesized, the tolerant fraction was significantly lower in patients who went on to develop clinically significant immune-related adverse events. To determine the accuracy of the tolerant fraction, we calculated the area under the receiver operating curve (AUC), which was 0.79. In the same patient cohort, T-cell receptor clonality had an AUC of 0.62 and T-cell receptor diversity had an AUC of 0.6 for predicting immune-related adverse events. These results suggest that — if validated in other populations — the tolerant fraction may be useful for immune-related adverse event prediction.
Healio: Do you have further research planned in this area?
Gerber: Our team’s further research falls into three main categories: 1) discovery of new biomarkers for the prediction, diagnosis and characterization of immune-related adverse events; 2) validation of our early discoveries; and 3) expanding our study cohort to diverse, generalizable populations. We are focusing primarily on blood-based biomarkers, as these are readily collected and can provide insight into multiple aspects of immune function.
Healio: What do you hope will be the long-term implications of your findings?
Gerber: Ultimately, we hope that our and other research into immune-related adverse events will improve the reach and outcomes of cancer immunotherapy. Being able to predict which patients are at greatest risk for immune-related adverse events may help oncologists give more effective immunotherapy regimens to more patients more safely.
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For more information:
David Gerber, MD, can be reached at UT Southwestern Medical Center, 6202 Harry Hines Blvd., 9th Floor, Dallas, TX 75235; email: david.gerber@utsouthwestern.edu.
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