IMMUNOTHERAPY OF SARCOMAS

Differences in the immunologic profiles of soft tissue sarcoma subtypes could have implications for treatment with immune checkpoint inhibitors, researchers report.

"It has always been a problem that there are so many different subtypes for sarcoma,” Dr. Seth M. Pollack from Fred Hutchinson Cancer Research Center, Seattle, Washington told Reuters Health. “Investigators have always wanted to group these patients together.”

“I think there may have been an initial hope that immunotherapy would be unifying and that all patients could be treated the same way with these new treatments,” he said. “This study demonstrates that these are very different diseases from the immunologic perspective that need different approaches with respect to therapy.”

Soft tissue sarcomas (STS) include “simple” tumors - synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) - which often express NY-ESO-1, as well as genetically “complex” tumors - undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), and well-differentiated/dedifferentiated liposarcomas (WD/DD) - which might be inhibited at checkpoints such as programmed cell death protein (PD-1).

Dr. Pollack and colleagues sought to identify key biologic patterns related to the immune response that could potentially serve as a biological rationale for future sarcoma immunotherapy trials and to identify patterns that might be relevant to other solid tumors.

UPS and leiomyosarcoma expressed higher levels of genes related to antigen presentation and T-cell infiltration, according to the May 2nd Cancer online report.

UPS had the highest T-cell infiltration, whereas SS had the lowest, and UPS were more oligoclonal compared with SS and liposarcoma.

For all sarcomas, T-cell infiltration and clonality correlated highly with PD-1 and programmed cell death ligand (PD-L1) expression, which was higher in UPS than in other STS.

“I think it was most surprising how different the sarcomas were from each other with respect to their immune response,” Dr. Pollack said. “Undifferentiated pleomorphic sarcomas are very, very inflammatory tumors, whereas the synovial sarcomas and myxoid/round cell liposarcomas were very ‘quiet’ immunologically."

“It was also surprising that leiomyosarcoma was such an inflammatory tumor,” he said. “Some of the early data treating leiomyosarcoma patients with checkpoint inhibitors has been disappointing. This data suggests that there probably are combinations using checkpoint inhibitors that will be effective for those patients.”

“I think this data, in combination with the small amount of data we've seen from SARC24, suggest that PD-1 inhibitors should be developed further for undifferentiated pleomorphic sarcoma,” Dr. Pollack concluded. “Synovial sarcoma and myxoid liposarcoma were immunologically quiet and may not benefit from single agent PD-1 inhibitors. For those patients, it makes sense to consider trials targeting NY-ESO-1.”