Talk at SGO Conference on Women’s Cancer highlights importance of measuring both senescent and ‘exhausted’ T cells
- Both overall and progression-free survival affected by T-cell phenotypes
- Findings could have implications for timing of immunotherapy
- Clinical trial results presented at SGO Annual Conference on Women’s Cancer
BUFFALO, N.Y. — Research conducted at Roswell Park Comprehensive Cancer Center shows that the types of T cells circulating in the blood of patients with recurrent ovarian cancer may predict the likelihood that their disease will respond to an anti-PD1 immunotherapy. The findings, which grew out of a phase 2 clinical trial led by Emese Zsiros, MD, PhD, FACOG, Chair and Director of Research, Department of Gynecologic Oncology, will be highlighted at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, March 25-28 in Tampa, Florida.
The clinical trial evaluated a novel treatment regimen that combined two immunotherapies — pembrolizumab (brand name Keytruda) and bevacizumab (brand name Avastin) — plus the chemotherapy drug cyclophosphamide (brand name Cytoxan). Pembrolizumab is an anti-PD1 therapy, designed to boost the immune system’s ability to attack cancer cells.
Results of the clinical trial, published in JAMA Oncology in November 2020, were highly encouraging: of 40 participants, 19 (47.5%) responded to treatment, including three who achieved a complete response. The disease remained stable in another 19 patients (47.5%), for a clinical benefit of 95% overall — far superior to outcomes achieved with approved therapies or newer immunotherapies used by themselves.
But why did some patients respond to the regimen while others did not? That question will be explored by Nicole Gaulin, MD, Fellow in Gynecologic Oncology at Roswell Park and presenting author for “T-cell senescence and T-cell exhaustion as potential biomarkers of progression-free and overall survival in patients with recurrent ovarian cancer treated with anti-PD1 combination therapy” Monday, March 27, at the SGO meeting. It will be part of the focused plenary session On the Horizon: Emerging Therapeutics, which begins at 3:15 p.m. ET.
Chemotherapy accelerates immune system aging
Previous research shows that patients who have undergone extensive chemotherapy treatments typically exhibit a weaker response to immunotherapy than those with fewer chemotherapy cycles.
“While traditional cytotoxic chemotherapy is an effective primary treatment for recurrent ovarian cancer, multiple treatment cycles can quickly age a patient’s immune system,” explains Dr. Zsiros, a gynecologic oncologist and senior author on the new study. “This damage adds to the natural decline of the immune system that comes with age, with the average age of ovarian cancer diagnosis being 63.”
When such patients are later enrolled in clinical trials involving immunotherapy, she adds, the treatment is less likely to have a significant impact due to the weakened state of patients’ immune systems.
Dr. Zsiros and team hypothesized that the varied responses observed during the clinical trial could be attributed to the patients’ T cells. T cells are part of the immune system, and a specific type called CD8+ T cells has the ability to destroy cancer cells. The researchers questioned whether weakened CD8+ T cells could be responsible for the unfavorable outcomes.
To investigate this, they measured the levels of so-called “exhausted” and senescent, or aging, CD8+ T cells in blood samples provided by patients before and during their participation in the clinical trial. Exhausted T cells have been weakened by continuous antigen exposure due to their previous activity in fighting tumors or viral infections. Although these cells can no longer multiply or produce the cytokines essential for anticancer immune activity, their presence signifies that an anti-tumor immune response is in progress.
Senescent T cells, on the other hand, have been damaged by cytotoxic chemotherapy, typically resulting in shortened telomeres — parts of chromosomes that protect DNA from degradation. Shortened telomeres contribute to genomic instability and are associated with aging, an increased risk of cancer and poor survival rates.
Outcomes hinge on volumes of exhausted or senescent T cells
Through flow cytometry, a technique used to assess cell properties, the scientists focused on two distinct types of impaired CD8+ T cells by examining blood samples from patients before and during their participation in a clinical study. They discovered that the more chemotherapy treatments a patient had undergone before joining the study, the higher the number of senescent T cells (aged and nonfunctional) and the lower the number of exhausted T cells (tired and less effective) in their blood circulation.
The scientists observed that patients carrying a BRCA gene mutation generally had lower numbers of senescent T cells in their bloodstream compared to individuals with a normal (wild-type) BRCA gene. However, there was no noticeable difference in exhausted T-cell levels between those with the wild-type BRCA gene and those with the BRCA mutation. On average, patients with the wild-type BRCA gene were older (mean age of 63.3) than those with the BRCA mutation (mean age of 60.2).
“We saw that patients who showed a positive response to the combined treatment had a higher count of exhausted T cells and a lower count of senescent T cells in their blood, while the opposite was observed in non-responders,” notes Dr. Gaulin.
Those with fewer senescent T cells in circulation experienced longer progression-free survival (PFS) of 20.2 months, compared to 7.1 months for patients with a higher count of these cells. Moreover, patients with a higher number of circulating exhausted T cells had a PFS of 10.2 months, whereas those with lower counts experienced a PFS of 7.1 months.
A notable increase in overall survival (OS) was observed in patients with fewer senescent T cells in their bloodstream, with a survival rate of 19.4 months compared to 9.1 months for those with higher counts of these cells. While not statistically significant, there was a tendency towards better OS in patients with a greater number of circulating exhausted T cells.
“Our findings tell us that the levels of circulating senescent and exhausted T cells could potentially act as a biomarker, signaling that a patient’s immune system is still generating an anti-tumor response, and that immunotherapy might thus be a viable treatment option,” says Dr. Zsiros.
Because introducing immunotherapy earlier in the treatment plan for patients with recurrent ovarian cancer could lead to better outcomes, she advises against waiting until patients have undergone multiple chemotherapy treatments.
Dr. Zsiros and her team plan to broaden their research in upcoming clinical trials by monitoring senescent and exhausted T cell levels in blood samples from patients on future immunotherapy clinical trials.
Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.
Rebecca Vogt, Media Relations Specialist