In a somewhat serendipitous turn of events, researchers studying the biological characteristics of upper urinary tract urothelial carcinomas (UTUC) have discovered that a genetic mutation causes a severe shortage of T cells in such tumors, and a recently approved immunotherapy drug can target the mutation and offset the deficit.
The finding could help explain why upper urinary tract carcinomas are so difficult to treat, and it suggests a potential role for a combined immunotherapeutic approach, according to senior author Bishoy Faltas, MD, Director of Bladder Cancer Research at Weill Cornell Medicine's Englander Institute for Precision Medicine in New York City.
"We discovered the defining biological characteristics of UTUC tumors which set them apart from urothelial cancer of the bladder," he said.
Faltas and research colleagues at Baylor College of Medicine and MD Anderson Cancer Center were studying the action of erdafitinib. The immunotherapy drug was approved in April by the FDA for locally advanced or metastatic urothelial carcinoma in patients with fibroblast growth factor receptor 3 (FGFR3) mutations whose cancer has progressed during or after platinum-based chemotherapy. They examined biological UTUC tumor samples and compared them to molecular profiles of urothelial bladder carcinomas in the Cancer Genome Atlas. The findings were reported in the journal Nature Communications (2019;10(1):2977).
Study Details
Fewer than 10 percent of cancers of the urinary tract develop in the lining of the upper portion of the tract that collects and carries urine from the kidneys to the bladder. However, these tumors are typically more aggressive and tend to be detected only after they have advanced.
When it was approved, erdafitinib became the first personalized treatment for metastatic bladder cancer patients with susceptible FGFR mutations. At the same time, the agency approved the FGFR RGQ RT-PCR assay, a diagnostic tool to identify mutations in potential candidates for such treatment. Approval was based on results of a phase II clinical trial that showed a 32.2 percent response rate in 87 patients with tumors with FGFR mutations (J Clin Oncol 2017; doi: 10.1200/JCO.2016.34.15_suppl.TPS4575).
FGFR3 is one of four fibroblast growth factor receptors that share structural and functional similarities and play a role regulating cell growth and division. Erdafinib targets mutations that cause FGFR3 hyperactivity in UTUC, especially tumors with very low numbers of T cells. Inhibition of FGFR3 results in upregulation in the interferon-gamma pathway, a finding the authors said demonstrates a likely link between FGFR3 and the immune system.
The findings also suggest that combining FGFR3 inhibitors like erdafitinib with PD-1/PD-L1 inhibitors, that can stop tumor cells from evading T cells, might be a promising strategy in addressing these difficult-to-treat tumors, Faltas explained.
"Our paper provides the biological rationale for the combination and shows how the FGFR3 signaling and the immune response are linked," he noted.
He also said the same strategy might be potentially applicable to other tumor types harboring FGFR3-activating molecular alterations.
"Our findings suggest that clinical trials of FGFR3 inhibitors as single agents or in combination with immune checkpoint blockade as a UTUC-targeted therapeutic strategy are warranted."
The investigators first sequenced all of the genes and corresponding RNA messages in high-grade UTUC tumors from patients treated at Weill Cornell, Baylor College of Medicine, and MD Anderson Cancer Center. A comprehensive genomic and transcriptomic analysis of each tumor was performed to identify biological features that differentiate UTUC from UCB, and the investigators found that most UTUC tumors were luminal-papillary and T-cell depleted.
"FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment," Faltas explained, adding that sporadic UTUC is characterized by a lower total mutational burden than urothelial bladder carcinoma.
"Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies."
"By inhibiting FGFR3, we are able to upregulate genes that are associated with activation of the antitumor immune response," Faltas said. "In the future, we could potentially use this strategy to reverse the T-cell depletion in these tumors. We are hoping that in the future, as we gain a deeper understanding of the drivers of UTUC's unique biology, that we will be able to develop specifically targeted treatment strategies for this cancer."
Kurt Samson is a contributing writer.