Predicting Responders to ICB Therapy in Advanced Melanoma

Recent work looking at the response to immune checkpoint blockade (ICB) therapy given before surgery for advanced melanoma found increased infiltration of B cells, a type of white blood cell, in patients who responded to therapy compared with those who did not.

The results, from an ongoing phase 2 study at the University of Texas MD Anderson Cancer Center, will be presented at the American Association for Cancer Research Annual Meeting 2019 in Atlanta April 2.

Cytotoxic T cell markers, programmed death ligand-1 (PD-L1) protein, and mutational burden have previously been identified as biomarkers of response to ICB, the researchers wrote. But they said there is a “growing appreciation of B cells as biomarkers and mediators of response.”

Trials involving immunotherapy in the neoadjuvant setting are gaining attention, both with individual agents and with combinations. This study is comparing how well nivolumab, with or without ipilimumab or relatlimab, works before surgery to shrink the tumor.

The February 2019 issue of Evidence-Based Oncology^TM reported that some biomarker information is turning out not to be as straightforward as it first appeared.

The study, led by Jennifer Wargo, MD, a surgical oncology and genomic medicine professor, found that some B cells predicted response and may be contributing mechanistically to the immune system’s response through secretion of antibodies and/or by processing and delivering antigens to white blood cell subtypes called T lymphocytes. These B cells had activated effector phenotypes and were located within lymphoid formations found at the tumor site, known as tertiary lymphoid structures (TLS).

“This is an exciting and emerging area of study that appears to hold promise for more accurately understanding which patients are most likely to be treated effectively with ICB therapy, and it also could help us identify new therapeutic targets,” Wargo said in a statement. “We are able to demonstrate through single-cell RNA sequencing that switched memory B cells and plasma cells were significantly associated with ICB response in a cohort of metastatic melanoma.”

“Whole transcriptomic analysis of the cohort of melanoma patients receiving ICB initially revealed that most differentially expressed genes by response were related to B cells,” said Wargo. “In further investigation of specific characteristics of B cells located within the tumor, we identified naive, class-switched and unswitched memory B cells, and plasma cell-like populations.”

Class-switch references a B cell’s ability to change production of an antibody from one class to another. The team found higher frequencies of class-switched memory B and plasma-like cells in patients who responded to ICB.

Patients who did not respond to ICB had higher levels of naïve B cells which have not yet been activated for a designated purpose.

Reference

Reddy SR, Helmink B, Gao J, et al. Effector B cells and tertiary lymphoid structures predict response to immune checkpoint blockade in solid tumors. Presented at: American Association for Cancer Research Annual Meeting 2019. March 29-April 3, 2019. Atlanta, Georgia. Abstract 4488.