First Extensive Immune Profiling of Sarcomas Shows Possible Susceptibility to Immunotherapy

Key Points

Researchers aimed to identify patterns of immune response in these sarcomas to identify promising targets for therapies. They measured:

  • Expression of 760 genes, mainly related to immune function
  • Levels of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) on T cells
  • The proportion of T cells in tumors, which indicates how successful the immune system is at attacking cancer on its own
  • T-cell receptor clonality, which indicates the precision of the T-cell response

Sarcomas come in dozens of subtypes. Clinical trial results have been mixed when treating these diverse tumors with immunotherapy, a targeted therapeutic strategy that has success in other cancers. However, a study published by Pollack et al in the journal Cancer suggests how both existing and emerging immunotherapy treatments could be successful in the treatment of sarcomas.

Two sarcoma subtypes—leiomyosarcoma and pleomorphic sarcoma—showed biologic characteristics suggesting they are susceptible to the immunotherapy approach based on the use of checkpoint inhibitors. This treatment works by blocking a protein that keeps immune cells from attacking cancerous cells.

“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 Seth Pollack, MD, a clinical researcher at Fred Hutchinson Cancer Research Center and the study’s senior author. “Before this study, we had a feeling based on preliminary data that some of the sarcomas would behave very differently based on the immune response, and these findings suggest that we’re on the right track.”

Study Goals

In the most extensive sarcoma immune profiling to date, Dr. Pollack and his colleagues examined tumor samples from 81 patients with types of sarcoma that comprise 75% of the disease: leiomyosarcoma, pleomorphic sarcoma, synovial sarcoma, and liposarcoma. The samples came from patients who had agreed to allow researchers to study their tumors for developing new therapies.

The researchers aimed to identify patterns of immune response in these sarcomas to identify promising targets for therapies. They measured:

  • Expression of 760 genes, mainly related to immune function
  • Levels of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) on T cells
  • The proportion of T cells in tumors, which indicates how successful the immune system is at attacking cancer on its own
  • T-cell receptor clonality, which indicates the precision of the T-cell response.

Major Findings

Leiomyosarcoma and pleomorphic sarcomas were the two subtypes that had a greater immune response by nearly all of the measures in the study, which means that they’re more visible to the immune system.

“These findings suggest that there are certain sarcoma subtypes that lend themselves to the development of checkpoint inhibitor–based strategies,” Dr. Pollack said.

Meanwhile, synovial sarcoma and liposarcoma had low levels of the immune response markers, suggesting that other immunotherapeutic strategies, such as adoptive T-cell therapies or vaccines, may work better.

“It’s too early to change how doctors will treat patients, but these findings are influencing the design of clinical trials in sarcoma,” Dr. Pollack said.

Other studies have suggested there may be unexpected challenges treating leiomyosarcoma with these therapies and that those patients may benefit from combination approaches with other treatments.

“Our results show that even though other studies have been unclear about whether checkpoint inhibitors work for leiomyosarcoma, that there’s still a way to make them work for this subtype and that we need to keep working on it,” Dr. Pollack said.

Ongoing Study

Dr. Pollack is conducting ongoing clinical trials combining chemotherapies and checkpoint inhibitors in patients with metastatic or unresectable sarcomas—one focusing on pembrolizumab (Keytruda) and doxorubicin hydrochloride combination treatment and the other studying the combination of avelumab (Bavencio) and trabectedin (Yondelis). Ultimately, he hopes to expand treatment options for patients with advanced sarcoma, who have an estimated survival of 12 to 18 months.

The Sarcoma Alliance for Research through Collaboration, the Sarcoma Foundation for America, and the Gilman Sarcoma Foundation funded the research.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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