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Researchers Find Pembrolizumab Alone Has Limited Effect in Patients With Rare Neuroendocrine Tumors
PHILADELPHIA (March 12, 2021)—Researchers at Fox Chase Cancer Center recently conducted a study that showed the immunotherapy drug pembrolizumab, also known by the brand name Keytruda, has limited treatment efficacy when used alone in the treatment of high-grade neuroendocrine neoplasms (G3 NENs).
G3 NENs are aggressive, rare malignancies found in the gastrointestinal tract, pancreas, and other locations that have a high capability of spreading. “We wanted to investigate the reasons for poor activity of immunotherapy drugs in these cancers and identify potential new immunologic targets,” said Namrata “Neena” Vijayvergia, MD, co-author and assistant professor in the Department of Hematology/Oncology at Fox Chase.
“The associated clinical trial was conducted to see if in this particular cancer, whether treating with the PD1-blocking antibody pembrolizumab would improve patient outcomes by allowing T-cells to be reactivated toward the tumor and eliminate it,” said Campbell.
Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. According to the authors, one patient achieved partial response, two had stable disease, and 18 exhibited progressive disease following treatment.
“In this study, we looked at what immune changes occurred. We looked at the initial immune system in each patient and then how it changed in response to the treatment. We then tried to identify particular traits in patients, namely immune phenotype biomarkers in blood that could potentially define which patients would respond,” said Campbell.
“We were also looking for immune biomarkers that are targetable. In this case we looked at immune inhibitory receptors such as TIGIT and TIM-3. Together with PD-1, these receptors are called immune checkpoints involved in shutting down immune responses,” he added. Targeting these checkpoint receptors with therapeutic antibodies, like pembrolizumab, reverses their inhibition to reinvigorate the immune response.
Campbell said the researchers found that patients who responded best to treatment with pembrolizumab were the ones who had a higher baseline T-cell count. Additionally, those patients also had lower activation of naïve T-cells and natural killer (NK) cells, which control cancer and viral infections.
Alternatively, the patients with the worst response to therapy had high expression of TIM-3 on T cells. Furthermore, pembrolizumab treatment increased expression of TIGIT on T cells. The results suggested that blocking the PD-1 checkpoint alone was ineffective due to increased expression of the other inhibitory checkpoints, such as TIGIT and TIM-3, that may still be holding back an immune response toward the G3 NENs.
“Unfortunately, our study, and a few other studies, have shown that a single-agent treatment has very poor response rates in our patients,” said Vijayvergia. She added that although this study did not show many clinical benefits for patients treated with pembrolizumab, it may help determine that combination strategies, such as blocking multiple immune checkpoints, may be a more effective way to treat these rare cancers rather than using single agents.
“Even though this is a very rare cancer, a concentrated effort for this disease can lead to meaningful answers quickly, and more studies are needed to address these unmet needs,” said Vijayvergia.
The study, “Impacts of Pembrolizumab Therapy on Immune Phenotype in Patients With High-Grade Neuroendocrine Neoplasms,” was published in the journal Cancer Immunology, Immunotherapy.
Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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