Leiomyosarcoma or LMS, a rare type of soft tissue sarcoma that begins in smooth muscle tissue found in many areas of the body, including the digestive system, urinary system, blood vessels, and uterus, often begins in the abdomen or uterus.

The disease makes up between 10% to 20% of all soft tissue sarcoma cases and is more common in adults than children.

ASCOHistorically, LMS has been reported to have immunohistochemical (IHC) and gene expression signatures suggestive of an immune-responsive tumor microenvironment. However, despite this, immune checkpoint inhibitors have demonstrated minimal activity in LMS.

In a study, sponsored by Caris Life Sciences®, scientists, led by Roman Groisberg, M.D., a medical oncologist at Rutgers Cancer Institute, examined 1,115 LMS specimens, which included a mix of uterine and soft tissue site samples from multiple institutions, to explore mechanisms of immunotherapy (IO) resistance. The study was designed to uncover findings that provide a deeper understanding of how immunotherapies (IO) affect leiomyosarcoma (LMS)

Combination therapies
The results presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4, 2021, by researchers from Columbia University Medical Center, shows that traditional predictive biomarkers of response to immunotherapies (IO) are unlikely to be useful in LMS and suggest future trials should focus on combination therapies instead.

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The study found only a small proportion of LMS specimens were identified as high tumor mutational burden (TMB-H) or high microsatellite instability (MSI-H). TMB-H was observed in 3.8% of LMS specimens, deficient mismatch repair/MSI-H was rarely detected (1.5%), whereas 8.2% (n = 88) were positive for PD-L1 expression.

These results suggest that the neoantigen burden in LMS may not be sufficient to promote a robust anti-tumor response, even in the presence of PD-L1 positive tumor cells. Additionally, LMS has an immune microenvironment characterized by a high fibroblast and low T cell abundance associated with melanoma. The use of combination therapies may reverse T-cell exclusion/desmoplastic phenotype.

Roman Groisberg, M.D., a medical oncologist and the director of the Sarcoma Program for the Division of Medical Oncology Medical Oncologist at the Rutgers Cancer Institute of New Jersey. Photo courtesy: © 2021 Rutgers, The State University of New Jersey. Used with permission.

“This study helps us understand why immune checkpoint inhibitors have demonstrated minimal activity in LMS in the past,” Groisberg said.

“With these findings, future therapies for LMS can become more personalized for patients and ultimately improve care,” he added.

“For many rare cancers, the treatment path can be unclear, and these findings reinforce the impact whole-exome and transcriptome sequencing and collaboration across renowned institutions have on finding effective treatment approaches,” said David Spetzler, M.S., Ph.D., MBA, President and Chief Scientific Officer of Caris Life Sciences.

“Measuring all of the genes and all of the transcripts can increase our understanding of specific cancer subtypes and provide clarity as to why certain therapies may not generate the response expected. This technology continues to improve approaches to treating all types of cancers – from the most common to the rarest,” Spetzler observed.

[1] Lagos G, Groisberg R, Dizon DS, Elliott A, Copeland T, Seeber A, Gibney GT, von Mehren M, et al. Large Scale Multiomic Analysis Suggests Mechanisms of Resistance to Immunotherapy in Leiomyosarcoma. Abstract 11512; Presented at: American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021. J Clin Oncol 39, 2021 (suppl 15; abstr 11512) [Download Presentation]

Featured image: Before the COVID-19 pandemic: General views of the 55th Annual Meeting of the American Association of Clinical Oncology (ASCO) – held in the McCormick Place in Chicago, Ill. Photo Courtesy © 2019 ASCO/Luke Franke. Used with permission.

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