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UTSW finds potential key to predict immunotherapy toxicity

New metric may make it possible to distinguish which cancer patients are at higher risk of adverse events

This illustration shows a T cell (orange), which plays a central role in immune response, attached to a cancer cell. (Photo Credit: Getty Images)

DALLAS – Aug. 14, 2023 – Researchers at UT Southwestern Medical Center have identified a novel parameter of T cells that could help oncologists anticipate which patients would be most likely to develop immunotherapy toxicity. The findings, published in the Journal for ImmunoTherapy of Cancer, could lead to improved treatments for a variety of cancers.

Immunotherapy has grown rapidly in recent years as a treatment for a wide range of common cancers. Some patients, however, acquire toxicities known as immune-related adverse events (irAEs), which can affect almost any organ system at any point during or after treatment. In rare cases, they can be fatal.

David Gerber, M.D.
David Gerber, M.D., is Professor of Internal Medicine in the Division of Hematology and Oncology and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern. He holds the David Bruton, Jr. Professorship in Clinical Cancer Research.

“The ability to predict which patients may develop significant immunotherapy toxicity would be extremely useful in the selection of patients, treatments, and monitoring,” said David Gerber, M.D., Professor of Internal Medicine in the Division of Hematology and Oncology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern. “Our metric – which we call the ‘tolerant fraction’ – could play a role in making that a reality.”

The tolerant fraction represents the proportion of T cells — white blood cells that are primarily responsible for immune responses — not expected to attack normal cells or tissues. To develop and test this parameter, UTSW researchers profiled the receptors of T cells in 77 patients treated with immunotherapy. They also used publicly available data from patients with autoimmune disease and 786 healthy subjects.

“When we compared the new metric to previously studied parameters, the tolerant fraction predicted future immunotherapy toxicity more accurately,” noted Dr. Gerber, who is also a member of UTSW’s Harold C. Simmons Comprehensive Cancer Center. “Patients with a higher percentage of tolerant T cells appear less likely to develop an irAE.”

The team’s findings are preliminary and will need to be confirmed by larger prospective studies, but they hold promise for the development of a novel approach to prevent irAEs.

“Today, immunotherapy toxicities are entirely unpredictable, and there isn’t a clear standard for how to monitor patients for potential irAEs,” Dr. Gerber added. “As a result, some clinicians may be reluctant to use immunotherapy for early-stage cancers or to recommend the most aggressive and potentially toxic treatments, such as combination immunotherapy regimens. The ability to understand a patient’s risk for these toxicities and customize clinical monitoring could lead to more patients receiving more effective treatments more safely.”

The study was funded in part by the National Institute of Allergy and Infectious Diseases (1U01AI156189-01); an American Cancer Society-Melanoma Research Alliance Team Award (MRAT-18-114-01-LIB); a V Foundation Robin Roberts Cancer Survivorship Award (DT2019-007); the University of Texas Lung Cancer Specialized Program of Research Excellence (SPORE) (P50CA070907-21); a Mary Kay Ash International Fellowship; the University of Texas Stimulating Access to Research in Residency (UT-StARR, R38HL150214); and the Harold C. Simmons Comprehensive Cancer Center Data Science Shared Resource (1P30 CA 142543-03).

The study’s first author is Jared Ostmeyer, Ph.D., formerly an Assistant Professor at UTSW. Other UTSW researchers who contributed to the study are Jason Y. Park, M.D., Ph.D., Professor of Pathology; David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology; Farjana Fattah, Ph.D., Assistant Professor, Simmons Cancer Center; Shaheen Khan, Ph.D., Assistant Professor of Pathology; Prithvi Raj, Ph.D., Assistant Professor of Immunology; Edward K. Wakeland, Ph.D., Professor of Immunology; Yang Xie, Ph.D., Professor in the O’Donnell School of Public Health; Rodrigo Catalan, M.D., postdoctoral fellow of Pharmacology; Mitchell von Itzstein, M.D., medical oncology fellow; and Mary Gwin, M.D., second-year resident of Internal Medicine.

Dr. Gerber holds the David Bruton, Jr. Professorship in Clinical Cancer Research. Dr. Xie holds the Raymond D. and Patsy R. Nasher Distinguished Chair in Cancer Research, in Honor of Eugene P. Frenkel, M.D. 

About UT Southwestern Medical Center  
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 19 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.