PD-1 and PD-L1 Inhibitors Could Effectively Treat Advanced Sarcomas, Cancer Study Suggests

Researchers have identified specific characteristics that can help identify responsiveness of patients with soft tissue sarcomas to immunotherapy.

Following evaluation of T-cell infiltration and expression of programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) in formalin-fixed samples of soft tissue sarcomas (STS), researchers are convinced of the potential of immunotherapy agents in treating these cancers.

STS are a rare disease, as they constitute less than 1% of adult malignancies. Patients with advanced STS have poor outcomes, with median overall survival between 12 and 18 months. Some of the more highly mutated liposarcomas are genetically heterogenous and can provide multiple targets for T cells. Results from a phase 2 study, presented at the annual meeting of the American Society of Clinical Oncology last year, found that PD-1 inhibitors can benefit patients with certain sarcoma subtypes.

For their present study published in the journal Cancer, researchers identified 81 patients with the more common STS subtypes, which included leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round-cell liposarcoma. In addition to gene expression analysis of 760 genes, tissue samples were analyzed for expression of both PD-1 and PD-L1 proteins and sequenced for the T-cell receptor Vβ gene.

“Checkpoint inhibitors have transformed the standard of care for melanoma and lung cancer, but it's been tough to make headway in developing immunotherapy strategies for sarcomas,” said lead author Seth M. Pollack, MD, from the Fred Hutchison Cancer Research Center. Preliminary results from studies conducted by their group provided hints to the responsiveness of some of these tumor types, he added.

The authors report that UPS and leiomyosarcoma had high expression of genes involved in antigen presentation and tumor T-cell infiltration. Further, PD-1 and PD-L1 expression was significantly higher in UPS and these tumors also had higher T-cell infiltration compared with SS. For all the sarcomas, the authors found that T-cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression levels.

The authors recommend a combination of comprehensive immune profiling and evaluation of clinical responses following immunotherapeutic intervention as important in establishing predictive algorithms on patient response to immunotherapies in STS.

“To me, these findings say that there are certain sarcoma subtypes that really lend themselves to the development of checkpoint inhibitor-based strategies,” Pollack said. He added that while it might be early to change existing treatment plans, clinical trials have been influenced by these findings.

Two such trials are currently registered on ClinicalTrials.gov:

1. Pembrolizumab and doxorubicin in sarcoma

2. Avelumab and trabectedin in liposarcoma or leiomyosarcoma

Reference

Pollack SM, He Q, Yearley JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas [published online May 2, 2017]. Cancer. doi: 10.1002/cncr.30726