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Tumor profiling may predict response to anti–PD-1 therapy for metastatic melanoma
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Greater abundance of tumor-infiltrating CD8–positive T cells that expressed high levels of PD-1 and CTLA-4 increased the likelihood that a person with metastatic melanoma would respond to anti–PD-1 therapy, according to study results.
This information may help improve patient selection by identifying patients most likely to achieve clinical response to PD-1 pathway inhibition, researchers wrote.
Adil I. Daud
“Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment,” Adil I. Daud, MD, clinical professor in the department of medicine at University of California, San Francisco, and director of melanoma clinical research at UCSF Helen Diller Family Comprehensive Cancer Center, and colleagues wrote. “The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.”
Daud and colleagues performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 40 patients prior to anti–PD-1 therapy. Researchers assessed clinical response by tumor immune phenotype.
They assessed CD45, CD3, CD4, CD8 and FOXP3 expression to quantify the percentages of CD4–positive effector T cells, CD4–positive regulatory T cells (Tregs) and CD8–positive cytotoxic T lymphocytes that infiltrated each tumor. The researchers also evaluated PD-1, PD-L1, CTLA-4 and MHC class II expression on each subset.
Daud and colleagues used RECIST criteria to evaluate response. Patients who achieved complete or partial response were considered responders; those with stable or progressive disease were not.
A discovery cohort (n = 20) included 14 patients whose cytotoxic T lymphocytes had high levels of CTLA-4 and PD-1 expression (> 20%) and six patients whose cytotoxic T lymphocytes had lower levels ( 20%). Higher expression correlated significantly with PFS (31.6 months vs. 9.6 months; P = 0.17) and objective response rate (85.7% vs. 0%).
Researchers tested these potential biomarkers for anti–PD-1 therapy response in a validation cohort (n = 20). In this group, high levels of CTLA-4 and PD-1 expression in cytotoxic T lymphocytes remained associated with longer PFS (15.9 months vs. 9.9 months; P = .04) and response to therapy (78.6% vs. 0%).
CTLA-4 and PD-1 expression also appeared associated with OS; however, this did not reach statistical significance due to the relatively short study period, Daud and colleagues wrote.
“In our assay, patients who had more than 20% of total tumor-infiltrating CD8–positive T cells that co-expressed high levels of PD-1 and CTLA-4 had an increased likelihood of responding to anti–PD-1 therapy,” Daud and colleagues wrote. “However, response rates were more variable the closer the percentages were to 20%. This suggests that there is a subset of patients who have partially exhausted cytotoxic T lymphocytes that hover around the threshold required to achieve a response.”
The results suggested attempts to augment or induce these cells before therapy may improve response rates in this patient population, the researchers wrote.
“Furthermore, because patients with low percentages of [high-expressing CTLA-4 and PD-1 cytotoxic T lymphocytes] are less likely to respond to anti–PD-1 monotherapy, the risk–benefit profile in this patient subset may favor combination therapy with multiple checkpoint inhibitors,” Daud and colleagues wrote. “Further clinical investigation is required to discern whether the relative abundance of tumor-infiltrating partially exhausted cytotoxic T lymphocytes can be used to make meaningful clinical therapeutic decisions. In addition, the utility of this biomarker in cancers other than melanoma remains to be determined.” – by Mark Leiser
Disclosure: The researchers report no relevant financial disclosures.
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